Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[N:8]([CH3:13])[C:7](=[O:14])[C:6]3([CH3:19])[CH2:15][O:16][CH2:17][CH2:18][N:5]3[C:4]=2[N:3]=1.C(N(CC)CC)C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>ClCCl>[Cl:1][C:2]1[N:11]=[C:10]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:9]2[N:8]([CH3:13])[C:7](=[O:14])[C:6]3([CH3:19])[CH2:15][O:16][CH2:17][CH2:18][N:5]3[C:4]=2[N:3]=1
Reactant: C1COCCN1
Reactant: CN1C(=O)C2(C)COCCN2c2nc(Cl)nc(Cl)c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)C2(C)COCCN2c2nc(Cl)nc(N3CCOCC3)c21
Temperature: 50 °C

Procedure:
2,4-Dichloro-5,6a-dimethyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (20 mg, 0.066 mmol), triethylamine (18.44 μL, 0.132 mmol) and morpholine (5.75 μL, 0.066 mmol) were mixed in dichloromethane at room temperature and stirred over the weekend at 50° C. The solvent was removed in vacuo to give crude 2-chloro-5,6a-dimethyl-4-morpholino-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one. MS [M+H] Found 354.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([O:15]CC)=[O:14])[C:7]3[CH:12]=[N:11][NH:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[H-].[Na+].I[CH2:21][CH3:22].[OH-].[Na+]>CN(C=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7]3[CH:12]=[N:11][N:10]([CH2:21][CH3:22])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCI
Reactant: CCOC(=O)c1cc(C2CC2)nc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCn1ncc2c(C(=O)O)cc(C3CC3)nc21
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (200 mg, 0.865 mmol) in DMF (10 mL) was carefully added sodium hydride (29.1 mg, 1.211 mmol). After 15 minutes stirring, iodoethane (0.077 mL, 0.951 mmol) was added and the mixture stirred at room temperature for 2 hr. Sodium hydroxide (1 mL, 1.000 mmol) was added and the mixture allowed to stir at room temperature for 1 h. The contents were concentrated in vacuo. The crude residue was diluted with water (50 mL) and acidified with acetic acid. The contents were then extracted with DCM (4×50 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluent: hexanes to 100% EtOAc, then DCM to 20% MeOH:DCM). The final product was collected as 90 mg (45%). LCMS E-S (M+H)=232.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.17 (m, 4H) 1.41 (t, J=7.33 Hz, 3H) 2.35-2.45 (m, 1H) 4.34-4.57 (m, 2H) 7.62 (s, 1H) 8.24 (s, 1H) 13.83 (br. s., 1H). Regiochemical assignment supported by 2D HNMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[CH:10]=2)[N:5]=[CH:4][N:3]=1.O.[Cl-].[NH4+]>C(O)C.CN(C)C=O.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=2)=[CH:10][C:11]=1[F:18]
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2cc(Cl)ncn2)cc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
After dissolving 4-chloro-6-(3-fluoro-4-nitrophenoxy)pyrimidine (9.726 g) in ethanol (100 ml)-N,N-dimethylformamide (100 ml) at room temperature, water (50 ml), ammonium chloride (20 g) and electrolytic iron powder (10 g) were added and the mixture was stirred for 1 hour at 100° C. The reaction mixture was cooled to room temperature. The insoluble portion was removed using celite prior to washing with ethyl acetate. The filtrate was concentrated under reduced pressure, and then the residue was partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was dried under reduced pressure to provide the title compound (8.204 g, 95%) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])[CH:6]=[CH:5]2.O.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([OH:16])=[O:15])[CH:6]=[CH:5]2
Reactant: COC(=O)c1ccccc1-c1ccc2cc(C)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc2nc(-c3ccccc3C(=O)O)ccc2c1
Temperature: 60 °C

Procedure:
7.08 g (25.5 mmol) of methyl 2-(6-methylquinolin-2-yl)benzoate obtained in Example 5 was suspended in 75 ml of methanol and 35 ml of water in which 3.06 g (76.6 mmol) of sodium hydroxide was dissolved was added thereto. After heating at 60° C. for 3 hours, the reaction mixture was concentrated under reduced pressure and 200 ml of water was added to the residue. The resulting solution was acidified with 2N hydrochloric acid and the thus formed precipitate was collected by filtration. The precipitate was washed with water and dried to obtain 2-(6-methylquinolin-2-yl)benzoic acid. NMR (270 MHz, CD3OD):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[OH-].[K+].Cl[C:19]1[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=1.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[O:15][C:19]1[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: CC(C)(C)C(=O)Nc1ccc(O)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)nc(Oc2ccc(NC(=O)C(C)(C)C)c(Cl)c2)n1
Temperature: 120 °C
Yield: 76.4 %

Procedure:
22.8 g (0.1 mole) of 3-chloro-4-pivaloylamino-phenol were dissolved in 150 ml of dimethylsulphoxide. 5.6 g (0.1 mole) of powdered potassium hydroxide were added in portions at room temperature, with stirring. The mixture was subsequently stirred at room temperature for 30 minutes and 14.25 g (0.1 mole) of 2-chloro-4,6-dimethyl-pyrimidine were then added in portions. The mixture was heated to 120° C. in the course of 1 hour and subsequently stirred at this temperature for a further 5 hours. The mixture was then cooled and poured into one liter of water. The crystals were filtered off with suction and dried in air. 25.5 g (76.5% of theory) of 2-(3-chloro-4-pivaloylamino-phenoxy)-4,6-dimethylpyrimidine were obtained.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:18]3[N:19]=[CH:20][CH:21]=[C:17]3[N:16]=[CH:15][CH:14]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2].[Cl:22]N1C2C=CC=CC=2N=N1>ClCCl>[Cl:22][C:21]1[CH:20]=[N:19][N:18]2[C:13]([C:9]3[CH:8]=[C:7]([N:3]([CH2:1][CH3:2])[C:4](=[O:6])[CH3:5])[CH:12]=[CH:11][CH:10]=3)=[CH:14][CH:15]=[N:16][C:17]=12
Reactant: Cln1nnc2ccccc21
Reactant: CCN(C(C)=O)c1cccc(-c2ccnc3ccnn23)c1
Solvent: ClCCl
Product: CCN(C(C)=O)c1cccc(-c2ccnc3c(Cl)cnn23)c1
Temperature: 0 °C
Yield: 62.3 %

Procedure:
A mixture of 1.0 g of N-ethyl-N-(3-pyrazolo[1,5-a]pyrimidin-7-ylphenyl)acetamide and 4.57 g of 1-chlorobenzotriazole in 50 ml of dichloromethane was refluxed for 25 minutes, then cooled and poured into 50 ml of ice-cold 2.5N aqueous sodium hydroxide. The mixture was filtered through hydrous magnesium silicate, precipitated with hexane and the solid collected, giving 0.7 g of the desired product, mp 157°-159°C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2Br)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCCCCC>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1cccc2ccn(Cc3ccccc3)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(-c2cccc3ccn(Cc4ccccc4)c23)cc1
Yield: 49.6 %

Procedure:
1-Benzyl-7-bromo-1H-indole (0.677 g, 2.37 mmol) was coupled to 4-trifluoromethoxyphenylboronic acid (0.585 g, 2.84 mmol), using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.0585 g, 0.0716 mmol), and potassium carbonate (0.492 g, 3.56 mmol), in dioxane (18 mL) and water (1.8 mL), according to the procedure described in Step 1 of Example 11. Purication by HPLC using hexane as the mobile phase yielded the title compound as a sage green solid (0.432 g, 50%). 1HNMR (300 MHz, DMSO-d6): δ 7.65 (d, 1H, J=7.5 Hz), 7.5 (d, 1H, J=3.8 Hz), 7.15-7.35 (m, 4H), 7.0-7.15 (m, 4H), 6.8 (d, 1H, J=7.5 Hz), 6.65 (d, 1H, J=3.8 Hz), 6.25 (d, 2H, J=7.5 Hz), and 5.05 ppm (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])OC4C=CC=CC=4)=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1.[CH3:34][O:35][CH2:36][CH2:37][CH2:38][NH2:39]>>[CH3:34][O:35][CH2:36][CH2:37][CH2:38][NH:39][C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:6]2[N:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])[C:9]3[CH2:10][N:2]([CH3:1])[CH2:3][C:4]=3[N:5]=2)=[CH:23][CH:22]=1)=[O:33]
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc2c1CN(C)C2
Reactant: COCCCN
Product: COCCCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C)C3)cc1

Procedure:
Method as described for example 51 using intermediate 10 and 3-methoxypropylamine as starting materials. Purified by prep. LCMS (high pH).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[O:5][C:6]=1[C:7](OC)=[O:8].[CH:15]([NH2:17])=O>>[N:1]1[C:2]2[C:3]3[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=3[O:5][C:6]=2[C:7](=[O:8])[NH:17][CH:15]=1
Reactant: COC(=O)c1oc2ccccc2c1N
Reactant: NC=O
Product: O=c1[nH]cnc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.6 %

Procedure:
A solution of methyl 3-aminobenzo[b]furan-2-carboxylate (0.28 g, 1.36 mmol) in formamide (5 mL) is heated at 135 C. for 4 h, then the temperature is raised to 170 C. After 4 h the reaction is cooled to 25° C. and a dark purple solid precipitates. The solid is collected by vacuum filtration and air dried to give 3H-benzofurano[3,2-d]pyrimid-4-one (118 mg, 46.6%). 1H NMR (DMSO) δ13.0 (1H, brs), 8.25 (1H, s), 8.05 (1H, d, J=8.1 Hz), 7.84 (1H, d, J=8.3 Hz), 7.68 (1H, t, J=7.7 Hz), 7.51 (1H, t, J=7.7 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:16])OC(C)(C)C)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.[C:24]([C:26]1[CH:27]=[C:28]([CH:44]([CH3:46])[CH3:45])[C:29]2[O:33][C:32]([C:34]3[CH:42]=[CH:41][C:37](C(O)=O)=[CH:36][CH:35]=3)=[N:31][C:30]=2[CH:43]=1)#[N:25].CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[C:24]([C:26]1[CH:27]=[C:28]([CH:44]([CH3:46])[CH3:45])[C:29]2[O:33][C:32]([C:34]3[CH:42]=[CH:41][C:37]([C:10]([NH:9][CH2:8][CH:5]4[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]4)=[O:16])=[CH:36][CH:35]=3)=[N:31][C:30]=2[CH:43]=1)#[N:25]
Reactant: CC(C)(C)OC(=O)NCC1CCC(=O)CC1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCC(=O)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a solution of tert-butyl [(4-oxocyclohexyl)methyl]carbamate (5.0 g, 22.00 mmol) in dichloromethane (100 ml) was added trifluoroacetic acid (10 ml). The mixture was stirred for 1 h at room temperature, and then concentrated and co-concentrated with toluene (5 ml). A suspension of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (INTERMEDIATE 2, 6.13 g, 20 mmol), o-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (15.2 g, 40.1 mmol), 1-hydroxybenzotriazole (4.0 g, 29.6 mmol), and diisopropylethylamine (20 ml, 115 mmol) in dichloromethane (100 ml) was stirred for 5 min at room temperature, and then a solution of the deprotected amine in dichloromethane (100 ml) was added. The mixture was stirred overnight at 25° C. The mixture was filtered and then diluted with 300 ml of saturated sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with 2×100 ml of dichloromethane. The combined organics were washed with 100 ml of brine, dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 65i column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes. The resulting product was repurified by flash chromatography on a Biotage Horizon, 65i column, eluting with 1 column volume of 100% hexanes followed by a gradient of 0 to 100% acetone in hexanes over 10 column volumes. The resulting product was crystallized from dichloromethane to provide the title compound (5.52 g, 13.29 mmol, 66.4% yield). Mass spectrum (ESI) 416.0 (M+1).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:35][N:36]([CH3:42])[C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][C@@H:37]([N:36]([CH3:42])[CH3:35])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and (R)—N,N-dimethylpyrrolidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (m, 1H), 7.85 (1H), 7.48 (m, 2H), 6.69 (1H), 4.66 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.22 (s, 6H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H). m/z: 467 [M+H]
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[NH:5][N:4]=1.Br.[Br:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.ON1C2N=CC=CC=2N=N1>ClCCl>[Br:14][CH2:15][CH2:16][CH2:17][NH:18][C:8]([C:6]1[NH:5][N:4]=[C:3]([C:2]([F:1])([F:12])[F:11])[CH:7]=1)=[O:10]
Reactant: NCCCBr
Reactant: O=C(O)c1cc(C(F)(F)F)n[nH]1
Agent: Br
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: ClCCl
Product: O=C(NCCCBr)c1cc(C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 500 mg (2.78 mmol) of 3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid, 682 mg (3.05 mmol) of 3-bromopropylamine hydrobromide, and 1.4 mL (1.04 g, 8.04 mmol) of N,N-diisopropylethylamine in 20 mL of dichloromethane were added 1.2 g (3.06 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and 459 mg (3.38 mmol) of 1-hydroxy-7-azabenzotriazole (HOAT). After being stirred at room temperature for 45 min, the reaction mixture was partitioned between dichloromethane and saturated sodium carbonate aqueous solution. The organic phase was washed with 5% aqueous citric acid solution, then dried over sodium sulfate, and concentrated. The residue was leached with dichloromethane containing a little methanol. Concentration of the organic extract yielded the title compound. LC-MS 300, 302 (M+1).
Reaction SMILES: ClC1C=CC(C2NC(C3C=CC([O:19]C)=CC=3OCC)=NC2CC(C)C)=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[N:39]([C:40]([N:42]3[CH2:47][CH2:46][N:45](C)[CH2:44][CH2:43]3)=[O:41])[C:38]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=3[O:57][CH2:58][CH3:59])=[N:37][CH:36]2[CH2:60][CH:61]2[CH2:65]CC[CH2:62]2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]2[N:39]([C:40]([N:42]3[CH2:43][CH2:44][NH:45][C:46](=[O:19])[CH2:47]3)=[O:41])[C:38]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=3[O:57][CH2:58][CH3:59])=[N:37][CH:36]2[CH2:60][CH:61]([CH3:65])[CH3:62])=[CH:33][CH:34]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC(C)C)C(c2ccc(Cl)cc2)N1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Product: CCOc1cc(OC)ccc1C1=NC(CC(C)C)C(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-isobutyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-isobutyl-4,5-dihydro-1H-imidazole (Example 10) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 513.2267, calculated for C27H33N4O3Cl [(M+H)+]513.2263.
Reaction SMILES: [CH:1]([C@@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][C@H:7](N)[CH:6]=[CH:5]1)([CH3:3])[CH3:2].C1(=O)C=CC=CC1=[O:34].Cl.[OH-].[Na+]>CO.O.O1CCCC1>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:5][CH2:6][C:7](=[O:34])[CH2:8]1)([CH3:3])[CH3:2]
Reactant: O=C1C=CC=CC1=O
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)C=C[C@@H](N)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CCC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of (1S,4S)-4-isopropyl-4-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopent-2-en-1-amine (3.5 g, 9.2 mmol) and 3,5-Cyclohexadiene-1,2-dione, 3,5-bis(1,1-dimethylethyl)-(2.20 g, 9.99 mmol) in Methanol (85 mL) was stirred at room temperature for 30 minutes. Tetrahydrofuran (85 mL) and 1N HCl (10 mL) were added and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with water and the organics evaporated. The remaining aqueous was made basic with 1N NaOH and extracted with EtOAc three times. The combined extracts were dried (Magnesium sulfate), filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (1:1 EtOAc/Hexanes) to yield (3.16 g, 90%) of the title compound. MS calculated for C19H22F3N3O2: (M+H) 382; found 382.1. Step B:
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][S:7][C:8]=1/[CH:9]=[CH:10]\[S:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(O)=[O:2].Cl.[C:32]([CH:34]1[CH2:37][NH:36][CH2:35]1)#[N:33]>>[C:32]([CH:34]1[CH2:37][N:36]([C:1]([C:4]2[N:5]=[CH:6][S:7][C:8]=2/[CH:9]=[CH:10]\[S:11][C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:2])[CH2:35]1)#[N:33]
Reactant: O=C(O)c1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#CC1CNC1
Agent: Cl
Product: N#CC1CN(C(=O)c2ncsc2/C=C\SC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Yield: 72.6 %

Procedure:
In the same manner as in step c) in Example 3, 716 mg of the title compound was prepared from 859 mg of 4-carboxy-5-((Z)-2-tritylthioethen-1-yl)thiazole and 237 mg of 3-cyanoazetidine hydrochloride.
Reaction SMILES: [Na].Cl[C:3]1[C:8]([C:9]#[N:10])=[C:7]([CH3:11])[CH:6]=[C:5]([CH3:12])[N:4]=1.[CH3:13][OH:14]>>[CH3:13][O:14][C:3]1[C:8]([C:9]#[N:10])=[C:7]([CH3:11])[CH:6]=[C:5]([CH3:12])[N:4]=1
Reactant: CO
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Agent: [Na]
Product: COc1nc(C)cc(C)c1C#N
Temperature: 70 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Sodium (23 g, 0.99 mol) was added to dry MeOH (800 mL) portion-wise. After the addition, the mixture was stirred for an hour until the sodium was mostly dissolved. To the reaction mixture was added 2-chloro-4,6-dimethylpyridine-3-carbonitrile (110 g, 0.66 mol). The resulting mixture was heated at 70° C. and stirred for four hours. The suspension was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 10:1) to give 2-methoxy-4,6-dimethylpyridine-3-carbonitrile (Cpd S, 103 g, 100%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C@H:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(C[C@@H](C)c2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: C[C@H](Cc1ccc(O)cc1)c1ccccc1
Reaction time: 7 h
Yield: 99.5 %

Procedure:
Into a 1 L four-necked flask equipped with a condenser tube, 28.55 g of (R)-(−)-1-(4-methoxyphenyl)-2-phenylpropane, 570 mL of acetic acid and 59 mL of 48% hydrobromic acid were charged, and a reaction was carried out at 110° C. for 7 hours. After cooling, acetic acid was distilled off under reduced pressure, and 100 mL of water and 140 mL of toluene were added thereto. The organic phase was separated, the aqueous phase was extracted with toluene, the toluene layer and the organic phase were put together, the solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from methanol to obtain 26.65 g of (R)-(−)-1-(4-hydroxyphenyl)-2-phenylpropane [H-Ph-CH(CH3)—CH2-Ph-OH] (yield: 99.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[CH:12][C:11]=2[N+:22]([O-:24])=O)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:22]([OH:24])[C:11]3[CH:12]=[C:13]([CH2:16][N:17]4[CH:21]=[CH:20][N:19]=[CH:18]4)[CH:14]=[CH:15][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cn2ccnc2)ccc1NCc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: On1c(-c2ccc(F)cc2)nc2ccc(Cn3ccnc3)cc21
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a stirred mixture of 5.1 parts of 4-fluoro-N-[4-(1H-imidazol-1-yl-methyl)-2-nitrophenyl]benzenemethanamine and 80 parts of methanol were added 3.6 parts of sodium hydroxide and stirring was continued first for 10 minutes at room temperature and then for 20 hours at reflux temperature. After cooling, the reaction mixture was neutralized with a hydrochloric acid solution 2N. The precipitated product was filtered off, washed successively with water, methylbenzene and 2,2'-oxybispropane and dried, yielding 4.2 parts (91%) of 2-(4-fluorophenyl)-6-(1H-imidazol-1-ylmethyl)-1H-benzimidazol-1-ol; mp. 82° C. (compound 210).