Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:32])[CH2:23][NH:24]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)=[C:4]([O:33]C)[CH:3]=1.B(Br)(Br)Br>>[ClH:1].[NH2:24][CH2:23][CH:22]([C:19]1[CH:18]=[CH:17][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([Cl:1])=[CH:3][C:4]=2[OH:33])=[CH:21][CH:20]=1)[CH3:32]
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: CC(CN)c1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Yield: 77.1 %

Procedure:
Following General Procedure F, tert-butyl 2-(4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (40 mg, 0.08 mmol) was treated with BBr3 (1.0 M in CH2Cl2, 3 mL, 3 mmol) to afford the desired product as an yellow solid (13 mg, 40%): 1H NMR (500 MHz, CD3OD) δ 7.63 (d, J=5.4 Hz, 1H), 7.56 (dd, J=7.9, 1.8 Hz, 1H), 7.48 (dd, J=7.8, 1.8 Hz, 1H), 7.40-7.28 (m, 3H), 6.12 (d, J=5.4 Hz, 1H), 3.29-3.19 (m, 3H), 1.49 (d, J=6.3 Hz, 3H); ESI MS m/z 385 [C20H17ClN2O2S+H]+; HPLC 99% (AUC), tR=8.12 min.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:7])=[CH:5][CH:6]=1.I.[PH2](O)=O.[CH3:12][CH:13]1OC(C)OC(C)O1.[C:21](O)(=O)[CH3:22]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:7])=[C:5]([CH2:21][CH3:22])[C:6]=1[CH2:12][CH3:13]
Reactant: CC1OC(C)OC(C)O1
Reactant: CC(=O)O
Reactant: Cc1ccc(C)[nH]1
Agent: I
Agent: O=[PH2]O
Product: CCc1c(C)[nH]c(C)c1CC

Procedure:
As in Example 58, using 2,5-dimethyl-pyrrole (2g), acetic acid (50 ml), hydriodic acid (50 ml), hypophosphorous acid (10 ml) and paraldehyde (1.4 ml). The product (46%) was an oil, b.p. 48°-50° (0.05 mm). Anal. Calc. for C10H17N: C, 79.40; H, 11.34; N, 9.26. Found: C, 79.21; H, 11.53; N, 9.09.
Reaction SMILES: [S:1]([CH2:11][N+:12]#[C-:13])([C:4]1[CH:10]=[CH:9][C:7](C)=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:14]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15].[C-:27]#N.[Na+]>>[C:14]([O:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:23]2[O:24][CH:13]=[N:12][C@@H:11]2[S:1]([C:4]2[C:5]([CH3:27])=[CH:6][CH:7]=[CH:9][CH:10]=2)(=[O:2])=[O:3])=[CH:25][CH:26]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)Oc1ccc(C=O)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: [C-]#N
Agent: [Na+]
Product: Cc1ccccc1S(=O)(=O)[C@H]1N=CO[C@H]1c1ccc(OC(C)(C)C)cc1

Procedure:
In a manner analogous to Preparation 1, tosylmethylisocyanide (0.23 g, 1.20 mmol), 4-(tert-butoxy)benzaldehyde (0.23 g, 1.26 mmol) and NaCN (5.9 mg, 0.12 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 374.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:17]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[O:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCl>[ClH:1].[Cl:1][C:2]1[C:17]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][N:13]([CH:25]4[CH2:26][CH2:27][O:22][CH2:23][CH2:24]4)[CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=C1CCOCC1
Reactant: CC(C)Oc1cc2c(cc1Cl)[nH]c(=O)n2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc2c(cc1Cl)[nH]c(=O)n2C1CCN(C2CCOCC2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 26666.7 %

Procedure:
A solution of 5-chloro-6-[(1-methylethyl)oxy]-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (D87, 94 mg, 0.30 mmol) in dichloromethane (3 ml) was treated with tetrahydro-4H-pyran-4-one (0.213 g, 0.21 mmol, 7 eq), sodium triacetoxyborohydride (0.445 g, 0.21 mmol, 7 eq) and triethylamine (0.101 g, 1 mmol, 3 eq) and stirred at room temperature under argon overnight. The mixture was diluted with dichloromethane and washed with aqueous NaOH solution (pH12). The NaOH wash was extracted with dichloromethane (×2) and the combined extracts was washed with aqu, NaOH solution, dried (MgSO4) and concentrated under vacuum. The residue was purified by MDAP to afford the title compound as a white solid (14 mg, 0.04 mol, 13%). M++H=394.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[CH:12][N+:13]([O-])=O)[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.[BH4-].[Na+].C(O)(=O)C(O)=[O:28]>O.C(O)(C)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([CH2:12][NH2:13])[CH2:9][N+:8]([O-:28])=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: O=C(O)C(=O)O
Reactant: O=[N+]([O-])C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: NCC1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reaction time: 2 h

Procedure:
To 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine (IV, J. Heterocyclic Chem., 13, 433 (1976)--compound 4b, 40 g, 115 mmol) and sodium borohydride (6.68 g, 176 mmol, 10 mesh) is added THF (100 ml) and i-propyl alcohol (50 ml). The resulting slurry is treated with a slow addition of water (3.1 ml, 176 mmol) while the temperature is maintained at about 23°. The reaction mixture is stirred for 2 hr. Water (9.3 ml) is added slowly to quench the reaction mixture. Methanol (50 ml) is used to facilitate transfer of the reaction mixture to a 500 ml capacity stainless steel Buchi hydrogenator. Raney nickel (40 g of water wet material) is added and the hydrogenation is performed at 5° and 60 psig pressure. After 17 hr, HPLC showed the reduction is complete. The reaction mixture is removed from the Buchi and the hydrogenator is rinsed with methanol (200 ml). The combined reaction mixture and rinses are filtered through a 5 g pad of solka floc to remove spent catalyst. The catalyst cake is then rinsed with methanol (200 ml). The combined filtrate and rinses are concentrated. Water is added to the concentrate. The product is extracted from the aqueous layer using ethyl acetate (200 ml). The ethyl acetate extract is concentrated to near dryness to azeotrope any residual water. Finally, ethyl acetate (600 ml) is used to dissolve the crude product and the mixture is heated to 50-60°. Then oxalic acid (10.36 g, 115 mmol) is added. The slurry that forms is stirred overnight at 20-25° and is then cooled to 0° for 1 hr and the product is collected by vacuum filtration. The product is washed with ethyl acetate (100 ml) and dried at 40° in a vacuum oven to give the title compound as the oxalic salt, mp=144-148°; TLC (methylene chloride/methanol/ammonium hydroxide, 90/10/1) Rf =0.17.
Reaction SMILES: C([C:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1)CCC.CCCCCC.C([Li])CCC.[Cl:21][Si:22](Cl)([CH2:24][Cl:25])[CH3:23]>C1COCC1>[Cl:21][Si:22]([CH2:24][Cl:25])([CH:9]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:23]
Reactant: C[Si](Cl)(Cl)CCl
Reactant: CCCCC1=CC=CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](Cl)(CCl)C1C=CC=C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
THF in a volume of 100 ml was added to 6 g (49 mmol) of n-butylcyclopentadiene, and the mixture was cooled to −78° C. A 1.65 M hexane solution of n-butyllithium in a volume of 29.6 ml (48.8 mmol) was added thereto dropwise. The mixture was stirred at room temperature for 2 hours and was cooled again to −78° C. Dichloro(chloromethyl)(methyl)silane in an amount of 8.0 g (49 mmol) dissolved in 50 ml of THF was added dropwise. The mixture was stirred at room temperature for 3 hours and was concentrated under reduced pressure. Hexane was added, and the mixture was filtered. The filtrate was distilled under reduced pressure to give 3.43 g of target chloro(chloromethyl) (cyclopentadienyl)(methyl) silane.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])O.[CH:6]1[C:15]2[C:16]3[C:25]([C:13]4[C:14]=2[C:9]([CH:10]=[CH:11][CH:12]=4)=[CH:8][CH:7]=1)=[N:24][C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]=3>O>[CH:6]1[C:15]2[C:16]3[C:25]([C:13]4[C:14]=2[C:9]([CH:10]=[C:11]([S:1]([OH:3])(=[O:5])=[O:4])[CH:12]=4)=[CH:8][C:7]=1[S:1]([OH:5])(=[O:4])=[O:3])=[N:24][C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]=3
Reactant: O=S(=O)(O)O
Reactant: c1cc2c3c(cccc3c1)-c1nc3ccccc3nc1-2
Solvent: O
Product: O=S(=O)(O)c1cc2c3c(cc(S(=O)(=O)O)cc3c1)-c1nc3ccccc3nc1-2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
As represented by the following reaction pathway, after 30% fuming sulfuric acid (2.1-liter) was added to 300 g of acenaphtho[1,2-b]quinoxaline obtained by synthesis example 1 and the mixture was stirred at room temperature for 24 hours, the resultant was heated to 130° C. and stirred for 32 hours for reaction. While keeping the obtained solution at 40° C. to 50° C., 4.5-liter of ion exchange water was added for dilution, and the resultant was further stirred for 3 hours. The precipitate was filtered and recrystallized with sulfuric acid to obtain acenaphtho[1,2-b]quinoxaline-2,5-disulfonic acid as represented by the following formula (c).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:31]=[CH:30][C:19]([CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)=[C:4]([O:32]C)[CH:3]=1.B(Br)(Br)Br>>[ClH:1].[NH2:22][CH2:21][CH2:20][C:19]1[CH:30]=[CH:31][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([Cl:1])=[CH:3][C:4]=2[OH:32])=[CH:17][CH:18]=1
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: Cl
Product: NCCc1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Yield: 23.6 %

Procedure:
Following General Procedure F, tert-butyl 4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethylcarbamate (79 mg, 0.25 mmol) was treated with BBr3 (1.0 M in CH2Cl2, 9 mL, 9 mmol) to afford the desired product as a yellow solid (12 mg, 20%). 1H NMR (500 MHz, CD3OD) δ 7.61 (d, J=5.4 Hz, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.31 (d, J=7.0 Hz, 3H), 6.10 (d, J=5.4 Hz, 1H), 3.37-3.27 (m, 2H), 3.12 (t, J=7.6 Hz, 2H); ESI MS m/z 371 [C19H15ClN2O2S+H]+; HPLC 96.9% (AUC), tR=8.83 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:9]=[N+:8]([O-:10])[C:7]3[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:12][CH2:13][NH:14][C:6]=3[N:5]2[CH:21]=1.[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[C:15]1([C:11]2[C:7]3[N+:8]([O-:10])=[CH:9][C:4]4[N:5]([CH:21]=[C:2]([N:32]5[CH2:33][CH2:34][N:29]([CH2:22][C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=6)[CH2:30][CH2:31]5)[N:3]=4)[C:6]=3[NH:14][CH2:13][CH:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: [O-][n+]1cc2nc(Cl)cn2c2c1C(c1ccccc1)=CCN2
Solvent: CC(C)O
Product: [O-][n+]1cc2nc(N3CCN(Cc4ccccc4)CC3)cn2c2c1C(c1ccccc1)=CCN2
Temperature: 25 °C
Yield: 84.4 %

Procedure:
8-Chloro-1,2-dihydro-4-phenylimidazo[1,2-a]pyrido[3,2-e]pyrazine 5-oxide (3 g, 0.01 mol) and benzylpiperazine (3.6 g, 0.02 mol) were heated at 80° C., in isopropanol (100 ml) under an atmosphere of nitrogen for 16 hrs. As the reaction mixture cooled to room temperature, a yellow solid precipitated. The yellow solid was collected by filtration, washed with cold isopropanol and recrystallized from isopropanol to yield 1,2-dihydro-4-phenyl-8-(4-phenylmethylpiperazinyl)imidazo [1,2-a]pyrido[3,2-e]pyrazine 5-oxide (3.7 g), as orange needles, m.p. 184°-187° C. (Found: C,71.03; H,6.02; N,19.30%; C26H24N6O.O.1H2O requires C,70.92; H,6.00; N,19.09%), represented by the structural formula: ##STR30##
Reaction SMILES: [CH3:1][O:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4].[CH2:12]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:12]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:11][C:8]2[CH:9]=[CH:10][C:5]([CH:3]([O:2][CH3:1])[CH3:4])=[CH:6][CH:7]=2)=[O:26])=[CH:28][CH:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC(C)c1ccc(O)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(C(C)OC)cc2)cc1

Procedure:
The procedure of Example 26 was followed except for use of (-)-4-(1-methoxyethyl)phenol in place of (+)-4-(1-methoxyethyl)phenol and 4-octyloxybenzoic acid chloride in place of 4'-octyloxy-4-biphenylcarboxylic acid chloride to obtain (-)-4-(1-methoxyethyl)phenyl 4-octyloxybenzoate. [α]D20 =-57.5° (c=1, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][C:4]=1[NH2:13].[NH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]2[CH:26]=[CH:27][C:28]([CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[N:29][CH:30]=2)=[CH:17][CH:16]=1.C(C1C=CC(OC)=C(N[C:49](NC2C3C(=CC=CC=3)C(OC3C=CN=C(C#N)N=3)=CC=2)=[O:50])C=1)(C)(C)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][C:4]=1[NH:13][C:49]([NH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]2[CH:30]=[N:29][C:28]([CH2:31][N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:27][CH:26]=2)=[CH:17][CH:16]=1)=[O:50]
Reactant: COc1ccc(C(C)(C)C)cc1NC(=O)Nc1ccc(Oc2ccnc(C#N)n2)c2ccccc12
Reactant: COc1ccc([Si](C)(C)C)cc1N
Reactant: Nc1ccc(-c2ccc(CN3CCOCC3)nc2)c2ccccc12
Product: COc1ccc([Si](C)(C)C)cc1NC(=O)Nc1ccc(-c2ccc(CN3CCOCC3)nc2)c2ccccc12

Procedure:
The title compound was prepared from the above amine and 4-[5-(4-aminonaphthyl)pyridin-2-ylmethyl]morpholine by the procedure described for 1-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(2-cyano-pyrimidin-4-yloxy)-naphthalen-1-yl]-urea (Example 1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[CH2:16]1[O:25][C:24]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=2[O:17]1>>[O:25]1[C:24]2[CH:23]=[CH:22][C:20]([NH:21][C:6]3[N:5]=[C:4]([NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:19][C:18]=2[O:17][CH2:16]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: Clc1nc(Cl)nc(Nc2ccccc2)n1
Product: Clc1nc(Nc2ccccc2)nc(Nc2ccc3c(c2)OCO3)n1
Yield: 42 %

Procedure:
The reaction of 4,6-dichloro-N-phenyl-[1,3,5]triazine-2-amine with 3,4-methylenedioxyaniline using the method described for the synthesis of CT-32028 provided CT-32042 (51 mg, 42% yield). 1H NMR (d6-DMSO) δ 10.05-10.29 (m, 2H), 7.57-7.80 (m, 2H), 7.21-7.42 (m, 3H), 6.80-7.13 (m, 3H), 6.03 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:27]=[CH:26][C:10]([CH2:11][CH2:12][O:13][C:14]3[NH:15][CH:16]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:18](=[O:20])[N:19]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31].[CH3:34]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:27]=[CH:26][C:10]([CH2:11][CH2:12][O:13][C:14]3[N:15]([CH3:34])[CH:16]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:18](=[O:20])[N:19]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:30]([F:31])([F:33])[F:32]
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1CC(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: Cn1cc(CC(F)(F)F)c(=O)nc1OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.2 %

Procedure:
To a solution of 2-(4-(4-chloro-3-(trifluoromethyl)phenoxy)phenethoxy)-5-(2,2,2-trifluoroethyl)pyrimidin-4(1H)-one (66 mg, 0.134 mmol) in DCM (10 mL) was added DIPEA (0.070 mL, 0.402 mmol) and MeI (0.013 mL, 0.201 mmol). The mixture was stirred at room temperature for 3 h. Purification via reverse phase flash chromatography then afforded the title compound (28 mg, 41.3% yield). LCMS: rt=3.73 min, [M+H+]=507
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=2[N:3]=1.C(O[CH:17]1[O:29][C@H:28]([CH3:30])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C>>[Cl:1][C:2]1[N:6]([C@@H:17]2[O:29][C@H:28]([CH3:30])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])[C:5]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=2[N:3]=1
Reactant: COc1ccc2[nH]c(Cl)nc2c1
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Product: COc1ccc2c(c1)nc(Cl)n2[C@@H]1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 65 %

Procedure:
2-Chloro-5-methoxy-1H-benzimidazole (0.661 g, 3.6 mmol) was coupled to 1,2,3-tri-O-acetyl-5deoxy-D-ribofuranose according to General Procedure II. The crude product was purified by flash chromatography (9:1 methylene chloride/ether) to yield the title compound (0.900 g, 65%) as a ˜1:1 mix of regioisomers (1H NMR); MS (AP): m/z 405 (M+Na); 1H NMR (DMSO-d6) δ: 7.65-7.54 (two d, 1H), 7.21 (s, 1H), 6.97 (m, 1H), 6.18-6.11 (two d, 1H), 5.70-5.59 (m, 1H), 5.21 (q, 1H), 4.27 (m, 1H), 3.83 (two s, 3H), 2.16 (s, 3H), 2.05 (s, 3H), 1.51 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2([CH3:30])[NH:28][C:27](=[S:29])[CH2:26][O:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1>>[CH3:30][C:23]1([C:19]2[CH:18]=[C:17]([NH:16][C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:15])[F:14])=[CH:10][N:9]=3)=[O:13])[CH:22]=[CH:21][CH:20]=2)[CH2:24][O:25][CH2:26][C:27](=[S:29])[NH:28]1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Reactant: CC1(c2cccc(N)c2)COCC(=S)N1
Product: CC1(c2cccc(NC(=O)c3ccc(OCC(F)(F)F)cn3)c2)COCC(=S)N1

Procedure:
In a reaction analogous to that described in example 6 (method B), the condensation of 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (CAS 881409-53-6) with Building block F, (RS)-5-(3-amino-phenyl)-5-methyl-morpholine-3-thione, yielded the title compound as a as light yellow oil (64% of theory). Mass (calculated) C19H18F3N3O3S [425.43]; (found) [M+H]+=426.
Reaction SMILES: CS(N)(=O)=O.[OH2:6].[F:7][C:8]1([F:20])[CH2:13][CH2:12][C:11]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)=[CH:10][CH2:9]1.S([O-])([O-])=[O:22].[Na+].[Na+]>C(O)(C)(C)C>[F:20][C:8]1([F:7])[CH2:13][CH2:12][C@@:11]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)([OH:6])[C@H:10]([OH:22])[CH2:9]1
Reactant: O
Reactant: Cn1nccc1C1=CCC(F)(F)CC1
Reactant: O=S([O-])[O-]
Agent: CS(N)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: Cn1nccc1[C@@]1(O)CCC(F)(F)C[C@H]1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methanesulfonamide (480 mg, 5.05 mmol) in a mixed solvent of t-butanol (10 mL) and water (10 mL), AD-mixα (Sigma-Aldrich Corp.; 7.10 g) was added, and the reaction solution was stirred at room temperature for 10 minutes. To the reaction solution, a solution of the 5-(4,4-difluorocyclohex-1-en-1-yl)-1-methyl-1H-pyrazole (1.0 g, 5.05 mmol) prepared in Example 47a in t-butanol (5 mL) was added with cooling on ice, and the reaction solution was vigorously stirred at room temperature for 16 hours. To the reaction solution, an aqueous sodium sulfite solution (10 mL) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate to yield the title compound in a crude form.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:20]([O:24][C:25](ON=C(C1C=CC=CC=1)C#N)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCOCC1>[C:20]([O:24][C:25]([N:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:12][CH2:11]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CCOC(=O)CN1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
1-(Ethoxycarbonylmethyl)-piperazine (5.00 g, 29.0 mmol) is dissolved in 35 mL of 50% aqueous dioxane. Triethylamine (4.41 g, 43.5 mmol) is added followed by 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (7.86 g, 31.9 mmol). The reaction is stirred for 14.5 hours at ambient temperature, then poured onto water and extracted with ethyl acetate (2×100 mL). The combined organic extracts are washed with water (3×100 mL), brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (20%→50% ethyl acetate in hexanes) affording the desired product as an oil. CIMS: MH+ 273.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=[O:8].[O:12]1[CH2:14][C@H:13]1[C:15]([O:17][CH3:18])=[O:16].[CH3:19][O:20][CH2:21][C@H:22](O)[CH3:23]>C(OCC)(=O)C>[OH:8][C@@H:13]([CH2:14][O:12][C@H:22]([CH3:23])[CH2:21][O:20][CH3:19])[C:15]([O:17][CH3:18])=[O:16]
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Reactant: COC[C@@H](C)O
Reactant: COC(=O)[C@@H]1CO1
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: COC[C@@H](C)OC[C@H](O)C(=O)OC
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Magnesium perchlorate (2.73 g, 12.24 mmol) was added in one portion to (S)-methyl oxirane-2-carboxylate (CAS no. 118712-39-3) (5 g, 48.98 mmol) and (R)-1-methoxypropan-2-ol (CAS no. 4984-22-9) (4.41 g, 48.98 mmol) at room temperature. The resulting suspension was stirred at 50° C. for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (20 mL), dried (MgSO4) and evaporated. This was not isolated and used crude in next step.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:16]=O.[BH3-][C:19]#[N:20].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:16][N:20]([CH3:19])[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1cc(N)cc(C(=O)O)c1
Reactant: C=O
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(=O)O)cc(N(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-(ethoxycarbonyl)-5-nitrobenzoic acid (5 g, 20.905 mmol) and 10% Pd/C (1.11 g, 1.045 mmol) in 100 mL of MeOH was stirred under H2 gas at room temperature. After 4 hours, the mixture was filtered through Celite and concentrated to give 3-amino-5-(ethoxycarbonyl)benzoic acid. To a solution of 3-amino-5-(ethoxycarbonyl)benzoic acid (2 g, 9.56 mmol) in 10 mL of DMF was added formaldehyde (about 37% wt % in H2O, 7.118 mL, 95.60 mmol) at room temperature. After 10 minutes, the solution was cooled to 0° C. and NaBH3CN (1.897 g, 28.68 mmol) was added. The mixture was stirred at room temperature for 3 hours. The solution was diluted with EtOAc. The solution was washed with 5% citric acid and saturated brine and dried with Na2SO4. The solution was filtered and concentrated to give 3-(Dimethylamino)-5-(ethoxycarbonyl)benzoic acid Compound 1 (2.1 g, 92% in two steps). 1H-NMR (500 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.44 (s, 1H), 7.41 (s, 1H), 4.32 (q, J=7.1 Hz, 2H), 2.99 (s, 6H), 1.33 (t, J=7.1 Hz, 3H); 13C-NMR (125 MHz, DMSO-d6) δ 166.99, 165.54, 150.14, 131.76, 130.79, 116.89, 116.25, 115.59, 60.79, 39.84, 14.05; ESI-MS: m/z (MH+): 238.1074 (calc'd), 238.1076 (found).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].S(=O)(=O)(O)O.O.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[C:7]#[N:8])(=[O:19])[CH3:18]
Reactant: N#Cc1cc(Cl)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(Cl)cc1C#N
Temperature: 60 °C
Yield: 92 %

Procedure:
Further, 39.25 g (0.25 mol) of the 5-chloro-2-hydroxybenzonitrile were dissolved in 40 ml of acetic anhydride, followed by the addition of 0.5 ml of concentrated sulfuric acid. After the reaction mixture was heated at 60° C. for 10 minutes, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with 1N NaOH and a saturated aqueous solution of sodium chloride and was then dried over Na2SO4. The solvent was distilled off under reduced pressure, whereby 45 g of 2-acetoxy-5-chlorobenzonitrile (yield: 92%). A mixture of 44 g of the 2-acetoxy-5-chlorobenzonitrile and 99 g (0.75 mol) of aluminum chloride was then heated at 160° C. for 3 hours. The reaction mixture was allowed to cool down to room temperature, and was then poured into ice water which contained 100 ml of concentrated hydrochloric acid. The slurry was extracted with ethyl acetate (3×350 ml). The extract was washed with 1N hydrochloric acid (3×200 ml) and a saturated aqueous solution of sodium chloride (400 ml) and was then dried over Na2SO4. The solvent was distilled off under reduced pressure. The residue was washed with dichloromethane to remove byproducts, and was then collected by filtration, whereby 16.5 g of the title compound were obtained as brown powder (yield: 38%).