Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:8]([O-:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Cl.[CH3:21]O>>[C:1]1([CH:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:8]([O:10][CH3:21])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C([O-])C(SCc1ccncc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Product: COC(=O)C(SCc1ccncc1)c1ccccc1
Reaction time: 16 h

Procedure:
Sodium 2-phenyl-2-(4-picolylthio)acetate was dissolved in methanol and dry hydrogen chloride added slowly so as to maintain gentle reflux for 1 hour. After cooling and stirring for approximately 16 hours, the reaction mixture was filtered and concentrated to yield title product (11.6 g.; oil; ms, calcd.: m/e 273; found: 273, 214, 150, 136, 124, 121, 105, 77, 65).
Reaction SMILES: O[C:2]1[C:3](=[O:23])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:5][CH2:6][C:7]=1[C:8](=[O:13])C(F)(F)F.Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1.C(N(CC)CC)C.Cl>C1COCC1>[OH:13][C:8]1[C:7]2[CH2:6][CH2:5][N:4]([C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)[C:3](=[O:23])[C:2]=2[N:33]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[N:34]=1
Reactant: O=C1C(O)=C(C(=O)C(F)(F)F)CCN1c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(O)c3c2C(=O)N(c2ccc([N+](=O)[O-])cc2)CC3)cc1

Procedure:
Part C. A mixture of the 3-hydroxy-1-(4-nitrophenyl)-4-(trifluoroacetyl)-5,6-dihydro-2(1H)-pyridinone made above (4.91 g, 12.94 mmol), p-methoxyphenylhyrazine HCl salt (2.37 g, 13.59 mmol) in 100 mL of THF was treated with 3.62 mL of triethylamine at rt overnight. To the reaction mixture was added 100 mL of 1N HCl. The resulting mixture was refluxed for 2 h. After cool to rt the title compound was collect by filtration (4.5 g, 92%). 1H NMR (DMSO-d6, 300 MHz) δ 8.24 (2H, d, J=9.2 Hz), 7.64 (2H, d, J=9.0 Hz), 7.39 (2H, d, J=9.0 Hz), 6.94(2H, t, J=9.2 Hz), 4.13 (2H, t, J=6.6 Hz), 3.77 (3H, s), 2.85 (2H, t, J=6.6 Hz) ppm.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:27]3[CH2:28][CH2:29][CH:24]([C:20]4[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=4)[CH2:25][CH2:26]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(c3)OCCO4)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 395.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:19][C:20]([SH:23])(Cl)Cl>C(Cl)(Cl)Cl>[C:3]1([CH3:2])[CH:11]=[CH:10][C:6]([C:7]2[N:9]=[C:20]([Cl:19])[S:23][N:8]=2)=[CH:5][CH:4]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: Cc1ccc(C(=N)N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nsc(Cl)n2)cc1
Temperature: 5 °C
Yield: 44 %

Procedure:
To a mixture of p-methylbenzamidine hydrochloride (5.1 g, 30.0 mmol) in CHCl3 (100 ml) is added triethyl amine (15.12 g, 20.9 ml, 150.0 mmol) and cooled to 5° C. in an ice-water bath. To the mixture is slowly added perchloromethyl mercaptan (95%, 6.16 g, 31.5 mmol) in CHCl3 (10 ml) over 1 hour. The yellow solution is allowed to warm up to room temperature. After 2 hours the mixture is washed with water (100 ml×2) and brine (100 ml). The organic layer is dried over MgSO4 and the solvent is removed under reduced pressure to yield a brown oil. The oil is purified on a bed of silica gel, eluting with 1:1 CHCl3 :hexanes to yield 3-(p-tolyl)-5-chloro-1,2,4-thiadiazole as a yellow solid (2.78 g, 44%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)[CH3:2].C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:17][C:5]1[C:6](=[O:9])[CH2:7][CH2:8][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOC1=CC(=O)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC1=C(Br)C(=O)CC1

Procedure:
3-Ethoxy-cyclopent-2-enone (Intermediate NINE1) (commercially available from Aldrich) (10.0 g, 77.6 mmol) in carbon tetrachloride (15 mL) at 0° C. was treated with NBS (15.3 g, 85 mmol) added portion-wise over 30 m. After 1 h at 0° C. the mixture was partitioned between CH2Cl2 and saturated NaHCO3. The aqueous layer was extracted with CH2Cl2. The pooled organic layers were washed with H2O (2×) and dried over MgSO4. The mixture was filtered and evaporated to dryness. The solid was recrystallized from pentane:ether to give 13.3 g of 2-bromo-3-ethoxy-cyclopent-2-enone (Intermediate NINE2).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]([O:19]CC)=O)[CH2:6]1)(=[O:4])=[O:3].[NH2:22][CH2:23][CH:24]([OH:36])[CH2:25][N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1>CCO.CO>[CH2:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH2:35][N:26]1[CH2:25][CH:24]([OH:36])[CH2:23][NH:22][C:17](=[O:19])[CH2:16][O:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH2:14][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6]2
Reactant: CCOC(=O)COc1cccc2c1CCN(S(C)(=O)=O)C2
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCO
Solvent: CO
Product: CS(=O)(=O)N1CCc2c(cccc2OCC(=O)NCC(O)CN2CCc3ccccc3C2)C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
A mixture of ethyl 2-((2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)acetate (140 mg, 0.447 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (184 mg, 0.89 mmol) in EtOH (0.2 mL) was stirred at 120° C. for 30 min under microwave conditions. The mixture was diluted with MeOH and purified by prep-HPLC to afford N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-((2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)acetamide (53.5 mg, 25%). 1H NMR (400 MHz, MeOD) δ 0.84 (s, 1H), 7.29-7.15 (m, 5H), 6.80 (d, J=8.2 Hz, 1H), 6.83 (d, J=7.7 Hz, 1H), 4.61 (s, 2H), 4.41 (s, 2H), 4.35-4.17 (m, 3H), 3.54 (t, J=6.1 Hz, 2H), 3.48-3.38 (m, 4H), 3.17-3.04 (m, 4H), 2.98 (t, J=6.0 Hz, 2H), 2.92 (s, 3H). LCMS (m/z): 474.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([F:10])=[CH:4][C:3]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:10])=[CH:4][C:3]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCc1cc(F)c(OC)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(F)c(O)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with 3 mL of dichloromethane. To the stirred solvent was added Ethyl 3-(2,5-difluoro-4-methoxyphenyl)propanoate (0.08 g, 0.327 mmol). The reaction mixture was cooled to 0° C. and boron tribromide (0.04 mL, 0.425 mmol) was added drop wise. After stirred for 30 minutes, the reaction mixture was quenched with ethanol (1 mL) at 0° C. by slow addition. The reaction mixture was concentrated to distill off the solvent; ethyl acetate (10 mL) was added. The organic layer was washed with saturated NaHCO3 solution (10 mL), followed by brine solution (10 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as colorless oil (0.06 g, yield: 80.0%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35][O:36]S(C)(=O)=O)=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].[CH3:41]O>>[F:1][C:2]1[C:3]([CH2:35][O:36][CH3:41])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: CO
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(COS(C)(=O)=O)c(F)c3o2)cc1F
Product: COCc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Yield: 86 %

Procedure:
800 mg (1.37 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methanesulfonyloxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 120 (1) was dissolved in 200 mL of methanol and the solution was heated at reflux for 24 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:acetonitrile=20:1) to give 610 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methoxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C@H:10]([CH3:11])[O:9]1.[N:18]1([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[CH:32][NH:31][C:30]3=[O:34])=[CH:25][CH:24]=2)[CH:22]=[N:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:9])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C@H:10]([N:31]1[CH:32]=[CH:33][N:29]([C:26]2[CH:25]=[CH:24][C:23]([N:18]3[CH:22]=[N:21][CH:20]=[N:19]3)=[CH:28][CH:27]=2)[C:30]1=[O:34])[CH3:11]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Reactant: O=c1[nH]ccn1-c1ccc(-n2cncn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(-n3cncn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 100 °C
Reaction time: 17 h
Yield: 10.2 %

Procedure:
(2R,3S)-2-(2-fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (2.24 g), 1-[4-(1H-1,2,4-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (2.17 g) and cesium carbonate (powder: 7.76 g) were added to dimethylsulfoxide (100 ml), and the mixture was heated with stirring at 100° C. for 17 hours. After being cooled, the reaction solution was diluted with ethyl acetate (200 ml). Ice water (200 ml) was added thereto to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and washed with 0.5N-sodium hydroxide (100 ml), 1N-hydrochloric acid (100 ml×2) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent:ethyl acetate/acetone=4/1) to give 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-[1H-1,2,4-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (Compound 38; 0.45 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH2:22][C@@H:23]([CH2:27][CH3:28])[CH2:24][C:25]#[N:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([NH:22][C@@H:23]([CH2:27][CH3:28])[CH2:24][C:25]#[N:26])=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC[C@H](N)CC#N
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC[C@@H](CC#N)NC(=O)[C@@H](C(C)C)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 25 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol). THF (0.5 mL), (S)-3-aminopentanenitrile (3.19 mg, 0.032 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (3.1 mg, 24.6%). 1H NMR (400 MHz, CD3OD) δ 0.93 (d, J=6.57 Hz, 3 H) 0.97 (t, J=7.33 Hz, 3 H) 1.07 (d, J=6.57 Hz, 3 H) 1.51-1.69 (m, 2 H) 2.44-2.58 (m, 2 H) 2.58-2.72 (m, 1 H) 4.07 (br. s., 1 H) 4.86-4.97 (m, 1 H) 5.08 (d, J=11.12 Hz, 1 H) 5.31 (d, J=19.71 Hz, 1 H) 7.84 (s, 1 H) 8.23 (s, 1 H). [M+H] calc'd for C19H22ClN5O2, 388; found, 388.4.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:36]1[CH2:41][CH2:40][N:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:45]3[CH2:46][CH2:47][CH:42]([N:39]4[CH2:40][CH2:41][O:36][CH2:37][CH2:38]4)[CH2:43][CH2:44]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCOCC2)CC1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 4-morpholinopiperidine (Aldrich) in an analogous manner as described in example 25. HR-MS (ES, m/z): observed 663.2859, calculated for C37H45Cl2N4O3 [(M+H)+] 663.2863.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(OC)(C)C>[CH3:16][C:11]1([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13][B:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:4][CH:5]=2)[O:10]1
Reactant: C1CCNCC1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC1(C)OB(c2ccc(CN3CCCCC3)cc2)OC1(C)C
Temperature: 25 °C

Procedure:
2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (250 mg; 0.84 mmol), piperidine (94 mg; 1.1 mmol) and K2CO3 (140 mg; 1.01 mmol) in DMF (4 ml) are heated to 80° C. for 45 minutes. The reaction mixture is cooled to room temperature, diluted with TBME, filtered and evaporated to dryness to deliver the title compound as orange crystals.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]([F:16])([F:15])[F:14])=[C:8]([CH2:10][OH:11])[CH:9]=1.[CH3:17][O:18][CH2:19][CH2:20]Br>CCCCC.CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]([F:14])([F:15])[F:16])=[C:8]([CH2:10][O:11][CH2:20][CH2:19][O:18][CH3:17])[CH:9]=1
Reactant: OCc1cc(Br)ccc1OC(F)(F)F
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: COCCOCc1cc(Br)ccc1OC(F)(F)F
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
In a 3-neck flask under argon, a 55-65% dispersion of NaH in oil (0.097 g, 2.44 mmol) is washed with n-pentane, the organics are removed and DMF (10 mL) is added. The mixture is cooled to 0-5° C., and a solution of (5-bromo-2-trifluoromethoxy-phenyl)-methanol (0.60 g, 2.21 mmol) in DMF (3.0 mL) is added dropwise. After warming to room temperature, stirring is continued for 1 h before this mixture is added to a solution of 2-bromoethyl methyl ether (0.312 mL, 3.32 mmol) in DMF (3mL). After 4 hrs at room temperature, the reaction is still incomplete by TLC. Another aliquot of NaH (1 equiv; oil dispersion washed with pentane) and 2-bromoethyl methyl ether (0.312 mL, 3.32 mmol) are added, followed by stirring for 18 hrs at room temperature. The mixture is poured into ice-water and extracted with AcOEt, the combined organics are dried (Na2SO4) and evaporated to dryness to give the title compound as yellowish oil. MS: 346.0/348.0 [M+H2l O]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.80 min. 1H-NMR (CDCl3): δ 3.49 (s, 3H), 3.64 (m, 2H), 3.72 (m, 2H), 4.69 (s, 2H), 7.13 (dd, 1H), 7.46 (dd, 1H), 7.77 (d, 1H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[NH2:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1)=[O:5])[CH3:2]
Reactant: Nc1cncc(Cl)c1
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cncc(Cl)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 using 2-bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate B) and 3-amino-5-chloro-pyridine as starting materials. tR: 1.31 min (LC-MS 2); ESI-MS: 511.1/513.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCOCC1>[C:7]([C:6]1[C:5]([CH3:9])=[C:4]([CH3:10])[S:3][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:21])#[N:8]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1sc(N)c(C#N)c1C
Solvent: C1COCCO1
Product: Cc1sc(NC(=O)NC(=O)c2ccccc2)c(C#N)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 2-amino-4,5-dimethylthiophene-3-carbonitrile (example 4b) (25 g, 164.5 mmol) in 1.4-dioxane (600 mL) was added benzoyl isocyanate (24.2 g, 164.5 mmol). The reaction mixture was then stirred at room temperature under nitrogen overnight. The precipitate was collected by filtration, washed with 1.4-dioxane (20 mL×3), and dried under vacuum at 40° C. for 3 hours to give N-(3-cyano-4,5-dimethylthiophen-2-ylcarbamoyl)benzamide (44.35 g, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ2.10 (s, 3H), 2.24 (s, 3H), 7.52-7.56 (m, 2H), 7.64-7.69 (m, 1H), 8.01-8.03 (m, 2H), 11.57 (brs, 1H), 12.05 (brs, 1H). MS 300 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:13]=O)=[N:4][CH:5]=[C:6]([N:8]([CH3:12])[CH:9]([CH3:11])[CH3:10])[N:7]=1.[CH2:15]([NH:22][CH2:23][C@@H:24]([OH:28])[CH2:25][O:26][CH3:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:15]([N:22]([CH2:13][C:3]1[C:2]([Cl:1])=[N:7][C:6]([N:8]([CH3:12])[CH:9]([CH3:10])[CH3:11])=[CH:5][N:4]=1)[CH2:23][C@@H:24]([OH:28])[CH2:25][O:26][CH3:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)N(C)c1cnc(C=O)c(Cl)n1
Reactant: COC[C@H](O)CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COC[C@H](O)CN(Cc1ccccc1)Cc1ncc(N(C)C(C)C)nc1Cl
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 62.7 %

Procedure:
To a solution of 3-chloro-5-[methyl(1-methylethyl)amino]pyrazine-2-carbaldehyde (321 mg), (2R)-1-(benzylamino)-3-methoxypropan-2-ol (351 mg) and acetic acid (258 μL) in acetonitrile (5 mL) was added sodium triacetoxyborohydride (477 mg), and the mixture was stirred at room temperature for 5.5 hr. To the reaction mixture was added dropwise saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (370 mg, 70%).
Reaction SMILES: Cl.[C:2](O)(=O)C.[CH:6]1([CH2:12][C:13]2[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][C:14]=2[OH:20])[CH2:11][CH2:10][CH2:9][CH2:8]C1>CO>[CH:12]1([C:13]2[CH:19]=[CH:18][C:16]([OH:17])=[C:15]([CH3:2])[C:14]=2[OH:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:6]1
Reactant: CC(=O)O
Reactant: Oc1ccc(CC2CCCCC2)c(O)c1
Agent: Cl
Solvent: CO
Product: Cc1c(O)ccc(C2CCCCC2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
3 M HCl (13 ml) was added to a solution of crude 4-cyclohexylmethyl resorcinol monoacetate (2.71 g) in methanol (70 ml) and the solution stirred at room temperature for 16 h. At this time, TLC showed the clean formation of product (Rf 0.14) and traces of starting material (Rf 0.48) (Note 11). The solvent was reduced to ⅓ volume under reduced pressure and partitioned between ethyl ether (300 ml) and 1 M HCl (100 ml), washed with saturated NaCl (100 ml), the aqueous layer back extracted with ethyl ether (200 ml), the organic layers dried (Na2SO4), filtered and the solvent removed to give 4-cyclohexyl methyl resorcinol as a light amber-colored oil which crystallized upon standing at room temperature (1.1 g, 75% yield). The crude product was purified by flash chromatography to give 4-cyclohexyl methyl resorcinol B2 as a white solid (617 mg, 51% yield) (Note 12): m.p. 112-113° C.; 1H NMR (60 MHz, acetone-d6) delta 1.08-1.76 (m, 11H), 2.44 (d, JJ=6.2 Hz, 2H), 6.26 (dd, JJ=7.9, 2.3 Hz, 1H), 6.39 (m, 1H), 6.86 (d, JJ=7.9 Hz, 1H), 7.90 (s, 1H); 13C NMR (60 MHz, acetone-d6) delta 27.3, 33.3, 38.2, 39.5, 102.9, 106.7, 119.0, 132.5, 157.0, 157.4; m/z (EI; TMS derivatized; M+) 350.
Reaction SMILES: [C:1]1([C@@:7]23[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C@@H:8]2[CH2:9][NH:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]#[N:29]>CN(C)C=O>[C:28]([CH2:27][N:10]1[CH2:11][CH2:12][C@:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C@@H:8]2[CH2:9]1)#[N:29]
Reactant: c1ccc([C@]23CCNC[C@H]2c2ccccc2O3)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCN1CC[C@]2(c3ccccc3)Oc3ccccc3[C@@H]2C1
Yield: 99.7 %

Procedure:
To a solution of 3.02 g of cis-1,2,3,4,4a,9b-hexahydro-4a-phenyl-benzofuro[3,2-c]pyridine in 48 ml of dry dimethylformamide was added 3.6 g of anhydrous potassium carbonate and 0.982 g of chloroacetonitrile. The resulting suspension was heated at 80° under nitrogen for 19 hours. The cooled reaction mixture was dried with 500 ml of ether and washed with water (4×250 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give 3.48 g (99.9%) of a gum, which crystallized on standing. A 0.35 g portion of this material was recrystallized from ethanol to afford 0.22 g of crystals, m.p. s 93, 94°-96°.