Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCC[CH2:5][C:6]([CH3:21])([C:15]1C=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[Br:22]CCCCCC(C)(C)CO.O1C=CCCC1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:22][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:6]([CH3:21])([CH3:5])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CC(C)(CO)CCCCCBr
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CCCCCBr)COC1CCCCO1
Yield: 46 %

Procedure:
According to the method described for the synthesis of 207d, 206g (36.0 g, 161 mmol) was treated with 3,4-dihydro-2H-pyran (18.5 g, 220 mmol) and p-toluenesulfonic acid hydrate (0.28 g, 1.5 mmol) in CH2Cl2 (60 mL). After filtration through neutral aluminum oxide (200 g) and concentration, the crude product was purified by column chromatography (silica gel; hexanes/ethyl acetate=50/1), affording 207g (23.0 g, 46%) as an oil. 1H NMR (CDCl3): δ 4.54 (t, 1H, J=3.0), 3.84 (m, 1H), 3.51-3.39 (m, 4H), 2.98 (d, 1H, J=9.3), 1.89-1.80 (m, 3H), 1.70-1.40 (m, 7H), 1.29-1.22 (m, 4H), 0.89 (s, 6H). 13C NMR (CDCl3): δ 99.3, 76.6, 62.1, 39.3, 34.3, 34.2, 33.0, 30.8, 29.2, 25.7, 24.7, 23.2, 19.6. HRMS (LSIMS, gly): Calcd for C14H28BrO2 (MH+): 307.1272, found: 307.1245.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([NH:34][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: NC1CCCCC1
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCCCC3)c2)cc1
Yield: 99.6 %

Procedure:
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.5 g (1.4 mmol) and cyclohexylamine (0.14 g, 1.4 mmol) were used to afford 0.61 g of the required product. Percentage purity (LCMS): 78.1%, (M+1)=437.0+1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C:5]([NH2:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][C:18](Cl)=[O:19]>C(OCC)(=O)C.O>[Cl:16][CH2:17][C:18]([NH:8][C:5]([CH3:7])([CH3:6])[C:4]([O:3][CH3:2])=[O:9])=[O:19]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C)(C)NC(=O)CCl
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
To a rapidly stirring biphasic solution of aminoisobutyric acid methyl ester hydrochloride (5.1 g, 33 mmol) in ethyl acetate (40 mL) and water (27 mL) was added potassium carbonate (13.7 g, 99.6 mmol) followed by chloroacetyl chloride (3.4 mL, 43 mmol). The reaction was cooled with an ice bath to prevent warming above ambient temperature, and stirred at room temperature for four hours. The mixture was diluted with ethyl acetate and the organic layer was successively washed with 10% citric acid and sat. NaCl, dried over sodium sulfate and concentrated in vacuo to give the desired product as a white solid (5.78 g, 29.9 mmol, 91%). 1H NMR (CDCl3, 400 MHz) δ 1.61 (s, 6H), 3.78 (s, 3H), 4.01 (s, 2H); LRMS (ESI/APCI) m/z 194 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][C:10]=1[CH:23]=O)([CH3:7])[CH3:6])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:23])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1C=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reaction time: 6 h

Procedure:
2-(4-Benzyloxy-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (9.00 g, 26.3 mmol) in ethanol (250 mL) is treated with 5% Pd/C (1.25 g) and hydrogen (60 psi, rt, overnight). Additional 5% Pd/C (1.25 g) is added, and the reaction is continued for 6 h at 40° C. The mixture is filtered and concentrated to a tan oil (6.25 g). This oil contained 9 mol % of 2-(4-Hydroxy-2-hydroxymethyl-phenoxy)-2-methyl-propionic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ 1.26 (t, 3H, J=7.3 Hz), 1.51 (s, 6H), 2.14 (s, 3H), 4.24 (q, 2H, J=7.3 Hz), 5.68 (brs, 1H), 6.47 (dd, 1H, J=3.4, 8.8 Hz), 6.59 (d, 1H, J=8.3 Hz), 6.60 (brs, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([S:9][CH2:10][C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15][CH2:14]3)=[O:12])[S:8][C:4]=2[CH:3]=1.[CH3:25][C:26](OC(C)=O)=[O:27].CCN(CC)CC>C(Cl)Cl>[N:13]1([C:11](=[O:12])[CH2:10][S:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([NH:1][C:26](=[O:27])[CH3:25])[CH:24]=[CH:23][C:5]=3[N:6]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2nc(SCC(=O)N3CCCc4ccccc43)sc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2nc(SCC(=O)N3CCCc4ccccc43)sc2c1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a 0° C. solution of compound 49 (0.16 g, 0.45 mmol) in dry CH2Cl2 (5 mL) was added Ac2O (0.25 mL, 2.70 mmol) followed by dropwise addition of Et3N (0.25 mL, 1.80 mmol). The reaction was stirred for 2 h under N2. The reaction mixture was diluted with CH2Cl2 (40 mL), washed with saturated NaHCO3 (10 mL), water (2×10 mL), and saturated NaCl (2×10 mL). Dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the product was purified by column chromatography (EtOAc/hexanes 3:7) to afford 51 as a white solid (154 mg, 86%); MS m/z: 398 (M+H)+. Anal. Calcd. For, C20H19N3O2S2: C, 60.43; H, 4.82; N, 10.57; S, 16.13. Found: C, 60.54; H, 4.91; N, 10.41; S, 15.87.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C.O>[CH:20]1([CH2:19][N:8]2[C:5]3=[N:6][CH:7]=[C:2]([F:1])[CH:3]=[C:4]3[C:10]([I:11])=[N:9]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Fc1cnc2[nH]nc(I)c2c1
Reactant: ICC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cnc2c(c1)c(I)nn2CC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.000 g (38.021 mmol) of 5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine and 13.627 g (41.823 mmol) of cesium carbonate were initially charged in 270 ml of DMF, and 8.785 g (41.823 mmol) of (iodomethyl)cyclopentane were added. The reaction mixture was stirred at RT overnight, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. This gave 6.370 g of the target compound (purity 83%, 49% of theory), which was reacted further as a crude product.
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[S:18][C:14]=3[C:13](=[O:26])[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[O:6][N:5]=1)[CH3:3].[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:12]5[C:13](=[O:26])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=7[F:25])=[CH:16][C:15]=6[N:10]([CH2:9][C:7]6[O:6][N:5]=[C:4]([CH2:2][CH3:3])[N:8]=6)[C:11]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4F)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6F)cc5n(Cc5nc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-(2-fluorophenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (272 mg; compound B88) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (237 mg; compound C10) and HBTU (249 mg) in DCM (7 ml) in the presence of DIPEA (0.42 ml) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: DCM/MeOH, 1/0 to 1/1 (v/v)] and preparative HPLC as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH:9]([NH2:21])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]([C:33](O)=[O:34])[CH2:25]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:22])[CH:9]([NH:21][C:33]([CH:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24](=[O:23])[CH2:25]2)=[O:34])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C1CC(C(=O)O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C1CC(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine (150 mg, 0.42 mmol) in acetonitrile (10 ml) were added 3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid (73 mg, 0.42 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119 mg, 0.62 mmol) and 1-hydroxy-1H-benzotriazole (63.6 mg, 0.42 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from ethyl acetate-hexane to give a highly polar isomer (61 mg, 31%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][Cl:9])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:7]([CH2:8][Cl:9])=[C:6]([CH3:10])[CH:5]=[CH:4][N+:3]=1[O-:19]
Reactant: Cc1ccnc(C)c1CCl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc[n+]([O-])c(C)c1CCl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
The 2,4-dimethyl-3-chloromethylpyridine (21.5 g, 138 mmol) was dissolved in CHCl3 (800 mL) and cooled under nitrogen to 0° C. and m-chloroperbenzoic acid (55%, 35 g) was added in small portions. The reaction was stirred for 4 hours. The solution was extracted twice with saturated aqueous sodium bicarbonate (500 mL). The organic phase was dried with MgSO4, filtered and the solvent removed under reduced pressure. The residue was chromatographed on silica gel packed in 98:2 CH2 Cl2 :MeOH and eluted with same. The appropriate fractions were combined and the solvent was removed under reduced pressure the give the desired 2,4-dimethyl-3-chloromethylpyridine-N-oxide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]([C:26]3[C:27](=[O:42])[NH:28][C:29](=[O:41])[C:30]=3[C:31]3[C:39]4[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:9]21[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:43]=[O:44]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]([C:26]3[C:27](=[O:42])[N:28]([CH2:43][OH:44])[C:29](=[O:41])[C:30]=3[C:31]3[C:39]4[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:9]21[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=O
Reactant: Cc1cccc2c(C3=C(c4nc(N5CCN(C(=O)OC(C)(C)C)C6(CC6)C5)cc5ccccc45)C(=O)NC3=O)c[nH]c12
Solvent: CO
Product: Cc1cccc2c(C3=C(c4nc(N5CCN(C(=O)OC(C)(C)C)C6(CC6)C5)cc5ccccc45)C(=O)N(CO)C3=O)c[nH]c12
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a solution of 7-{1-[4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-isoquinolin-3-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (3.00 g, 5.32 mmol) in MeOH (25 mL) was added an aqueous 37% solution of formaldehyde (9.5 g, 8.72 mL, 117 mmol) under argon at r.t. The reaction mixture was heated to 85° C. and stirred for 4 h. The reaction mixture was cooled to r.t. under continuous stirring and filtered. The solids were washed with ice-water and dried at high vacuum (<1 mm Hg) to afford the title compound as dark red crystals. 1H-NMR (400 MHz, DMSO-d6): 11.96 (s, 1H), 8.05 (s, 1H), 7.69-7.64 (m, 2H), 7.47 (t, 1H), 7.12-7.06 (m, 2H), 6.76 (d, 1H), 6.42 (t, 1H), 6.01 (d, 1H), 5.00 (d, 2H), 3.49-3.10 (m, 6H), 2.39 (s, 3H), 1.41 (s, 9H), 0.89-0.57 (m, 4H). LCMS: [M]+=593.7, Rt(1)=2.34 min.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2]1.CN(C)C=O.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>O>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH2:1][CH2:2][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5][C:6]1=2)[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (3.557 g, 12.42 mmol) and N,N-dimethylformamide (30 mL) was added 60% sodium hydride (0.596 g, 14.90 mmol). The mixture stirred for 1 h, and then cooled in a 0° C. bath. Ethyl bromoacetate was added, and the mixture warmed to room temperature. Water then was added and the mixture was evaporated in vacuo. The residue was taken up in ethyl acetate and washed with water. Evaporation and trituration with hexanes provided 3.289 g of the title compound, the structure of which is shown in FIG. 6 as (23) (where n=1).
Reaction SMILES: ClC(N(C)C)=C(C)C.[F:9][CH:10]([F:33])[O:11][CH2:12][C@@H:13]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1)[C:19]([OH:21])=O)[CH3:14].[CH3:34][C:35]1[N:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=1.N1C=CC=CC=1>C(Cl)Cl>[F:33][CH:10]([F:9])[O:11][CH2:12][C@@H:13]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1)[C:19]([NH:41][C:38]1[CH:37]=[N:36][C:35]([CH3:34])=[CH:40][N:39]=1)=[O:21])[CH3:14]
Reactant: C[C@@H](COC(F)F)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cc1cnc(N)cn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)COC(F)F)c2)cn1
Reaction time: 1 h

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.26 mL, 2.0 mmol) was added to a solution of 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-phenylmethoxy-benzoic acid (0.54 g, 1.5 mmol) in DCM (20 mL) and stirred for 1 hour. 5-Methylpyrazin-2-amine (CAS no. 5521-58-4) (335 mg, 3.1 mmol) then pyridine (0.25 mL, 3.1 mmol) were added and the reaction stirred for a further 30 minutes before being reduced in vacuo and partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was further extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo. The crude residue was chromatographed on silica, eluting with 40-100% ethyl acetate in isohexane, to give the desired compound (0.48 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].IC1C=CC(N2C(C)=CN=C2)=C(C=1)C#N>>[I:10][C:7]1[CH:8]=[CH:9][C:2]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cc(I)ccc1F
Agent: Cc1cncn1-c1ccc(I)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccc(I)cc2C#N)cn1

Procedure:
In analogy to example 5a, 2-fluoro-5-iodo-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 20 h at 90° C. Aqueous workup afforded a 1.9:1 mixture of the title compound and its regioisomer [5-iodo-2-(5-methyl-imidazol-1-yl)-benzonitrile] as a white solid (yield: 92%). MS: m/e=310.1 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:19]=[C:18]([C:20](=[O:26])[N:21]([CH3:25])[CH2:22][CH2:23][CH3:24])[CH:17]=[C:13]([C:14](O)=[O:15])[CH:12]=1)[CH3:8].ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>ClCCl>[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:12]=[C:13]([C:14]([N:3]2[CH2:4][CH2:5][CH2:6][CH:2]2[CH3:1])=[O:15])[CH:17]=[C:18]([C:20]([N:21]([CH3:25])[CH2:22][CH2:23][CH3:24])=[O:26])[CH:19]=1)[CH3:8]
Reactant: CC1CCCN1
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)N2CCCC2C)c1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
Add 2-methyl pyrrolidine (204 mg, 2.4 mmol) to a solution of 5-(methyl-propylcarbamoyl)-isophthalic acid monoethyl ester (640 mg, 2.18 mmol) in dichloromethane (8 mL) followed by 1-hydroxybenzotriazole (20 mg, 0.15 mmol) and diisopropyl carbodiimide (375 μL, 2.4 mmol). Stir the solution at room temperature over the weekend. Add ethyl acetate (25 mL) and wash with saturated aqueous ammonium chloride (2×10 mL), saturated aqueous sodium bicarbonate (10 mL), saturated aqueous sodium chloride (10 mL), dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound as an oil (218 mg, 28%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]([CH2:11][Cl:12])[CH:3]=1.[F-:13].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.C(OCC)C>[Cl:12][CH2:11][C:4]1[CH:3]=[C:2]([F:13])[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=1
Reactant: CC(C)c1nc(Cl)cc(CCl)n1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)c1nc(F)cc(CCl)n1

Procedure:
A mixture of 0.8 g (0.0039 mol) of 6-chloro-4-chloromethyl-2-isopropyl-pyrimidine (see Example 61), 0.51 g (0.0089 mol) of anhydrous potassium fluoride and 0.14 g (0.0004 mol) of 18-crown-6 in 7 ml of acetonitrile is heated at reflux temperature for 48 hours. The mixture is then taken up in diethyl ether and the solution is washed with saturated sodium chloride solution, dried over anhydrous sodium sulphate and freed from solvent under reduced pressure. The 4-chloromethyl-6-fluoro-2-isopropyl-pyrimidine is obtained in the form of a yellow oil, 1H-NMR (CDCl3): 1.32 (d, CH(CH3)2), 3.18 (m, CH(CH3)2), 4.62 (s, CH2Cl), 6.99 (d, CH).
Reaction SMILES: [C:1]([O:7][C@H:8]1[C@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:11][C@@H:10]([CH3:17])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:18](OCC)(=[O:22])/[CH:19]=[CH:20]/[CH3:21]>C(O)(C)(C)C>[CH3:21][C@@H:20]1[CH2:19][C:18](=[O:22])[CH2:5][C:3](=[O:4])[C@H:2]1[C:1]([O:7][C@H:8]1[C@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:11][C@@H:10]([CH3:17])[CH2:9]1)=[O:6]
Reactant: CC(=O)CC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Reactant: C/C=C/C(=O)OCC
Solvent: CC(C)(C)O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)[C@@H]1C(=O)CC(=O)C[C@H]1C
Temperature: 23 °C

Procedure:
A 2-L 3-necked round bottom flask fitted with a reflux condenser, a mechanical stirrer, and a glass stopper was charged with t-butyl alcohol (300 mL) and potassium 1-butoxide (68.7 g, 612 mmol, 1.04 equiv). The glass stopper was removed and, with efficient mechanical stirring, (1R,3R,4S)-p-menth-3-yl acetoacetate (1, 150 g, 624 mmol, 1.06 equiv) was added rapidly to the yellow slurry. The open neck of the reaction flask was fitted with a 100-mL addition funnel containing (E)-ethyl crotonate (73.2 mL, 588 mmol, 1 equiv). The largely solid reaction mixture was heated to reflux with a heating mantle. At this point, (E)-ethyl crotonate was added to the refluxing, dark yellow slurry over 15 min via the addition funnel. The addition funnel was replaced with a glass stopper and heating at reflux was continued. Solids were observed to dissolve within 1 h after addition of (E)-ethyl crotonate; the product began to crystallize from solution after about 1.5 h. After a total reflux period of 2.5 h (from addition of (E)-ethyl crotonate), heating was discontinued and the reaction mixture was allowed to cool to 23° C. The cooled reaction mixture was partitioned between aqueous sulfuric acid solution (5% v/v, 500 mL) and dichloromethane (600 mL). The aqueous layer was separated and extracted further with two 600-mL portions of dichloromethane. The combined organic layers were dried over sodium sulfate and then were concentrated. The solid residue was dissolved in boiling benzene (ca. 600 mL) and the resulting solution was allowed to cool slowly to 23° C. whereupon (1R,3R,4S)-p-menth-3-yl(1R,2S)-2-methyl-4,6-dioxocyclo-hexanecarboxylate (2) crystallized as a white powder (mp 180°-181° C., 64.5 g, 36%). To isolate the diastereomeric diketone product, (1R,3R,4S)-p-menth-3-yl(1S,2R)-2-methyl-4,6-dioxocyclohexanecarboxylate (3), the mother liquors were concentrated and the solid residue was dissolved in boiling ethyl acetate (ca. 200 mL). Hexanes (50 mL) were added to the hot solution and the mixture was allowed to cool to 23° C. Further cooling to -20° C. induced crystallization of diketone diastereomer 3 over a period of 12 h (mp 140°-141° C., 45 g, 25%). ##STR15##
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[OH-].[K+].C(O)(=[O:14])C.C(O)(=O)C.IC1C=CC=CC=1>CO>[OH:14][CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9]
Reactant: CC(=O)O
Reactant: O=C1CCc2sccc21
Agent: [K+]
Agent: [OH-]
Solvent: Ic1ccccc1
Solvent: CO
Product: O=C1c2ccsc2CC1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5,6-dihydro-cyclopenta[b]thiophen-4-one (36.8 g, 0.266 mol) in MeOH (1000 mL) was added at about 5° C. to a solution of potassium hydroxide 85% (52.7 g, 0.798 mol) in MeOH (500 mL). Between 0° C. and 5° C. iodobenzene diacetate (94.4 g, 0.293 mol) was added in portions and the mixture was allowed to come to room temperature. The mixture was stirred overnight at room temperature. The mixture was evaporated and a 20% solution of potassium carbonate (500 mL) was added. The mixture was extracted for times with DCM dried with sodium sulphate and evaporated under reduced pressure. The residue was dissolved in 1,4-dioxane (400 mL) and water (150 mL) and concentrated hydrochloric acid (150 mL) was added. The mixture was stirred for two hours at room temperature. The mixture was neutralized by the addition of potassium carbonate and extracted four times with dichloromethane. The organic phase was dried with sodium sulphate and evaporated under reduced pressure. The product was crystallized with ether ethyl acetate and the mother liquid was purified by silica gel chromatography with toluene and acetone. Yield: 33.5 g=81.6%.