Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:34]3[CH:33]=[N:32][CH:31]=[C:30]([F:29])[CH:35]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using (S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 174.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white solid. HPLC (Condition 4) tR=5.29 min, UPLC-MS (Condition 3) tR=1.06 min, m/z=493.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.47-1.63 (m, 1H) 1.83 (m, J=5.90 Hz, 1H) 2.14-2.28 (m, 1H) 2.96 (dd, J=10.95, 7.04 Hz, 1H) 3.10-3.38 (m, 5H) 4.60 (t, J=5.08 Hz, 1H) 7.32 (d, J=8.21 Hz, 2H) 7.77-7.88 (m, 3H) 8.05 (d, J=1.00 Hz, 1H) 8.50 (s, 1H) 8.57 (d, J=1.96 Hz, 1H) 8.76 (d, J=1.00 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.C(N(CC)C(C)C)(C)C.[CH:36](O)=[O:37]>C(Cl)Cl>[NH2:20][C:16]1[C:15]2[N:14]([C:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH:36]=[O:37])[CH2:23][CH2:22]3)=[N:12][C:11]=2[C:3]2[NH:2][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][N:17]=1
Reactant: O=CO
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nccn2c(C3CCN(C=O)CC3)nc(-c3cc4ccccc4[nH]3)c12
Reaction time: 8 h
Yield: 432.5 %

Procedure:
To a solution of 1-(1H-indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-amine hydrochloride (30.00 mg, 0.0068 mmol) in DCM (0.5 mL, 0.008 mol) was added N-(3-dimethylaminopropyl)-N-ethylcarbodihnide hydrochloride (0.0195 g, 0.102 mmol), N,N-diisopropylethylamine (0.047 mL), 1-hydroxbenzotriaxole hydrate (0.0104 g, 0.0679 mmol) and formic acid (4.7 mg, 0.10 mmol). The reaction was stirred at it overnight then diluted with DCM, washed with saturated NaHCO3 (2×25 mL) and brine (2×25), then dried over Na2SO4 and concentrated in vacuo. The material thus isolated was crystallized from EtOAc to afford 10.6 mg of desired product. 1H NMR (400 MHz, CDCl3): δ 2.04-2.12 (m, 4H), 2.99-3.00 (m, 1H), 3.27-3.32 (m, 2H), 3.85 (m, 1H), 4.49 (m, 1H), 5.70 (br, 2H), 6.80 (s, 1H), 7.13-7.24 (m, 4H), 7.45 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 8.10 (s, 1H), 8.97 (br, 1H). MS (ES+): m/z 361.16 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[CH2:28][CH2:29][CH3:30])=[CH:4][C:3]=1[CH2:31]O.[CH3:33][C:34]1([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH:48]([CH3:50])[CH3:49])=[CH:43][CH:42]=2)[NH:38][C:37](=[O:39])[NH:36][C:35]1=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O1CCCC1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:16]([F:17])([F:18])[F:19])[C:20]([F:23])([F:22])[F:21])=[CH:11][C:10]=2[CH2:28][CH2:29][CH3:30])=[CH:4][C:3]=1[CH2:31][N:36]1[C:35](=[O:40])[C:34]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH:48]([CH3:50])[CH3:49])=[CH:43][CH:42]=2)([CH3:33])[NH:38][C:37]1=[O:39]
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(Cl)c(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(Cl)c(CN2C(=O)NC(C)(c3ccc(OC(C)C)cc3)C2=O)c1
Yield: 50 %

Procedure:
(2-Chloro-5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy) phenyl)methanol (10 mg, 0.0212 mmol), 5-methyl-5-(4-(1-methylethoxy)phenyl)imidazolidine-2,4-dione (16 mg, 0.0635 mmol) and triphenylphosphine (16 mg, 0.0635 mmol) were added and dried in vacuo. N, N-dimethylformamide (300 μL) was added, and under ice-cold conditions, a solution of diethyl azodicarboxylate in tetrahydrofuran (29 μL, 0.0635 mmol) was added. The resultant mixture was stirred at room temperature for 4 hours. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using preparative thin-layer chromatography (hexane/ethyl acetate). 3-(2-Chloro-5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy) benzyl)-5-(4-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione (7.6 mg, yield >100%) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[S:13](=[O:15])(=[O:14])[N:12]([CH3:16])[C:11]([C:17](OC)=[O:18])=[C:10]([OH:21])[C:9]=3[S:22][C:4]=2[CH:3]=1.[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[S:13](=[O:14])(=[O:15])[N:12]([CH3:16])[C:11]([C:17]([NH:23][C:24]4[S:25][CH:26]=[CH:27][N:28]=4)=[O:18])=[C:10]([OH:21])[C:9]=3[S:22][C:4]=2[CH:3]=1
Reactant: Nc1nccs1
Reactant: COC(=O)C1=C(O)c2sc3cc(Cl)ccc3c2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2sc3cc(Cl)ccc3c2S1(=O)=O
Yield: 56 %

Procedure:
Prepared analogous to Example 1 from methyl 7-chloro-4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-aminothiazole with a yield of 56% of theory.
Reaction SMILES: [OH-].[Na+].C([O:10][C:11](=[O:27])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:13]=1)C1C=CC=CC=1>CO.O>[CH2:20]([O:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[CH3:18])[C:11]([OH:27])=[O:10])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 87.5 %

Procedure:
K2CO3 (18.1 g, 131.2 mmol) was added to a stirred solution of 3-hydroxy-4-methyl-benzoic acid (5 g, 33 mmol) in DMF (50 mL) followed by benzyl bromide (11.8 g, 69 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filterate was diluted with water and extracted with EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 11.3 g (crude) of 3-benzyloxy-4-methyl-benzoic acid benzyl ester which was such taken for the next step without purification. NaOH (4.0 g, 102 mmol) was added to a stirred solution of 3-benzyloxy-4-methyl-benzoic acid benzyl ester (11.3 g, 34 mmol) in a mixture of MeOH (50 mL) and H2O (50 mL), stirring was continued at ambient temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure Cold water was then added and acidified it with 10% aqueous HCl, the precipitate was collected to afford 7.21 g (87.8% Yield) of 3-benzyloxy-4-methyl-benzoic acid. A mixture of 3-benzyloxy-4-methyl-benzoic acid (7.21 g, 29.7 mmol) in thionyl chloride (50 mL) was stirred at 79° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure to afford 7.75 g (crude) of 3-benzyloxy-4-methyl-benzoyl chloride. A solution of 3-benzyloxy-4-methyl-benzoyl chloride (7.75 g) in THF (10 mL) was poured to cold aqueous solution of ammonia (50 mL) with stirring, The precipitate was collected to afford 6.7 g (94% Yield) of 3-benzyloxy-4-methyl-benzamide. A solution of 3-benzyloxy-4-methyl-benzamide (3.0 g, 12.4 mmol) in pyridine (4 mL) was cooled to −30° C. Imidazole (1.68 g, 24.8 mmol) followed by POCl3 (2.64 g, 49.6 mmol) were added to the cold solution with stirring and the reaction was continued at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water followed by 110% aqueous HCl solution. The organic layer separated was dried over sodium sulfate and concentrated under reduced pressure to afford 2.46 g (89% Yield) of 3-benzyloxy-4-methyl-benzonitrile. Pd/C (476 mg) was added to a stirred solution of 3-benzyloxy-4-methyl-benzonitrile (2.46 g, 11.0 mmol) in MeOH (25 mL) in an inert atmosphere and stirring was continued under H2 gas atmosphere at ambient temperature, overnight. The reaction mixture was filtered through celite. The filtrate collected was concentrated under reduced pressure to afford 1.367 g (93.6% Yield) of 3-hydroxy-4-methyl-benzonitrile.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Cl:13])[CH:12]=1)[CH2:9][N:8]([CH3:14])[CH2:7][CH:6]2[C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH2:34].C(N(CC)CC)C>C(Cl)Cl>[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH:34][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:6]2[C:5]3[C:10](=[C:11]([Cl:13])[CH:12]=[C:3]([Cl:2])[CH:4]=3)[CH2:9][N:8]([CH3:14])[CH2:7]2)=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: NCCOCCOCCN
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)Cl)cc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCN)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride hydrochloride (intermediate 10.6) (9 g, 20.02 mmol, 1.00 equiv, 95%) in DCM (200 mL) was added 2-(2-(2-aminoethoxy)ethoxy)ethanamine (15.6 g, 105.41 mmol, 5.00 equiv) and triethylamine (4.26 g, 42.18 mmol, 2.00 equiv) and the resulting solution was stirred for 3 h at room temperature. The reaction mixture was diluted with 100 mL of DCM and then washed with 2×50 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/methanol (10:1). This resulted in 3 g (28%) of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as brown oil.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:8][C@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([Cl:18])[C:12]=3[C:11]([I:19])=[CH:10]2)[CH2:6]1)=O.C(=O)=O.CC(C)=O.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Cl:18][C:17]1[C:12]2[C:11]([I:19])=[CH:10][N:9]([C@H:7]3[CH2:6][C@H:5]([CH2:3][OH:2])[CH2:8]3)[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: COC(=O)[C@H]1C[C@H](n2cc(I)c3c(Cl)ncnc32)C1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: OC[C@H]1C[C@H](n2cc(I)c3c(Cl)ncnc32)C1
Reaction time: 0.67 h

Procedure:
To a solution of trans-3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylic acid methyl ester (trans/cis=5:1) (116.5 mg, 0.297 mmol) in CH2Cl2 (5 mL), cooled by dry ice/acetone, was added DIBAL (1M in toluene, 0.65 mL, 0.65 mmol). After 40 min, the dry ice/acetone bath was replaced with and ice/water bath. The reaction was quenched 2 h later by adding potassium sodium tartrate solution, the mixture was extracted with CH2Cl2 (3×20 mL), the combined extracts were washed with NaHCO3 solution and brine, dried over MgSO4, filtered, and concentrated to give the target compound as 5:1 trans/cis mixture. This material was chromatographed on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-8)→CH2Cl2:EtOAc 9:1 (9-19)→CH2Cl2:EtOAc 5:1 (20-47)→CH2Cl2:EtOAc 3:1 (48-60)] to give the title compound with trans/cis=25:1. A forerunning fraction enriched with the cis isomer was also isolated. 1H NMR (CDCl3, 400 MHz) δ 2.42-2.57 (m, 2H), 2.58-2.72 (m, 3H), 3.85 (brs, 2H), 5.36-5.48 (mc, 1H), 7.61 (s, 1H), 8.60 (s, 1H). MS (ES+): m/z 363.9/365.9 (100/36) [MH+]. HPLC: tR=3.0 min (OpenLynx, polar—5 min).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([S:12]([N:15]2[CH2:20][CH:19]3[CH2:21][CH:16]2[CH2:17][S:18]3)(=[O:14])=[O:13])[CH:3]=1.Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Cl)[CH:24]=1.[H-].[Na+]>CN(C=O)C>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([S:12]([N:15]3[CH2:20][CH:19]4[CH2:21][CH:16]3[CH2:17][S:18]4)(=[O:14])=[O:13])[CH:3]=2)[CH:24]=1
Reactant: O=S(=O)(c1cc(O)c2ccccc2c1)N1CC2CC1CS2
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1cc(OCc2cccnc2)c2ccccc2c1)N1CC2CC1CS2
Temperature: 90 °C
Reaction time: 15 h
Yield: 58 %

Procedure:
The product from Example 62 (66 mg, 0.20 mmol), 3-picolylchloride hydrochloride (40 mg, 0.20 mmol and a crystal of KI were combined in DMF (30 ml). Sodium hydride (41 mg, 1.1 mmol, a 60% dispersion in oil) was added and the mixture was stirred at 90° C. for 15 hr. At this time the solvent was evaporated under reduced pressure and the residue was partitioned between 1N aq KOH and CHCl3. The CHCl3 phase was dried (Na2SO4) and concentrated and the residue was purified by flash chromatography using 5% acetone in CHCl3. The pure product was obtained as a tan foam (49 mg, 58% yield): 1H NMR (CDCl3) δ 1.52 (1H, d, J=10.57 Hz, 1/2 CH2), 1.69 (1H, J=10.74 Hz, 1/2 CH2), 1.81 (1H, br s, CH), 2.91 (1H, dd, J=10.12, 2.53, 1/2 CH2), 3.09 (1H, d, J=10.15 Hz, 1/2 CH2), 3.50 (2H, m, CH2), 3.61 (1H, dd, J=10.21, 1.14 Hz, CH), 4.62 (2H, s, CH2Ar), 7.19 (1H, d, J=1.39 Hz, ArH). 7.39 (1H, dd, J=11.61, 4.87 Hz, 7.60-7.69 (2H, m, ArH), 7.82-7.98 (2H, m, ArH), 8.01 (1H, s, ArH), 8.30-8.38 (1H, m, ArH), 8.68 (1H, dd, J=10.19, 1.35 Hz, ArH), 8.81 (1H, d, J=1.86 Hz, ArH).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=4[F:43])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]3[CH2:28][CH2:27]3)[N:21]=2)[CH:16]1[CH3:44])C1C=CC=CC=1.[H][H]>C1COCC1.[OH-].[OH-].[Pd+2]>[CH:26]1([NH:25][C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH:16]([CH3:44])[C:17]3=[N:18][C:19]=2[N:29]2[CH2:30][CH2:31][CH:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])[CH2:33][CH2:34]2)[CH2:28][CH2:27]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC1c2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC3CC3)nc2CCN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC1NCCc2nc(NC3CC3)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc21
Reaction time: 8 h

Procedure:
Combined 6-benzyl-N-cyclopropyl-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (110 mg, 0.178 mmol) and Pd(OH)2 (20 wt %, 12.5 mg, 0.018 mmol) in THF (888 μL) was purged with hydrogen and allowed to stir under hydrogen (balloon) overnight. The reaction mixture was filtered through Celite™, washed with EtOAc, and concentrated under reduced pressure to give the title compound as a TFA salt (78 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.ClC[CH:12]([O:15]C(CCl)CCl)CCl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH:12]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)=[O:15]
Reactant: c1ccc2c(c1)CCO2
Reactant: ClCC(CCl)OC(CCl)CCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 9.4 ml (83.4 mmol) 2,3-dihydrobenzofuran in 250 ml methylene dichloride was cooled under nitrogen to 0° to -5° C. and 18 ml (167 mmole) titanium tetrachloride was added dropwise at 0° C. The resulting brown mixture was stirred 10 minutes and 8.3 ml (91.6 mmole) 1,1-dichloromethylmethyl ether was then added dropwise at 0° C. During this addition the reaction mixture became dark red in color. The mixture was allowed to warm to room temperature, stirred for 2 hours and poured slowly into a 2 liter beaker containing 700 ml saturated aqueous sodium bicarbonate solution The resulting mixture was filtered through diatomaceous earth and the solids washed with methylene dichloride. The separated organic layer was dried (Na2SO4) and the solvent evaporated to afford a residual oil, 10 g, (81%) which appeared homogeneous on silica gel thin-layer chromatography (TLC), eluting with an ethyl acetate/hexane/5% acetic acid, 1:5:5 by volume. Mass spectrum (m/e): 148 (M+), 147, 119.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16]>O1CCCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: C#CCCCCl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(C#CCCCCl)cc1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-iodonitrobenzene (25 g, 100 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.30 g, 0.43 mmol) and copper (I) iodide (0.18 g, 0.95 mmol) in tetrahydrofuran (300 mL) and triethylamine (150 mL) was degassed under Argon for 10 minutes. The mixture was then heated to 55° C. and treated with 5-chloropentyne (12 mL, 110 mmol) via syringe. After 30 minutes of stirring, additional quantities of dichlorobis(triphenylphosphine)palladium(II) (0.10 g) and 5-chloropentyne (1 mL) were added. After another 30 minutes of stirring, the mixture was allowed to cool to room temperature and then was filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to provide 1-(5-chloropent-1-ynyl)-4-nitrobenzene, which was carried on without further purification. ES/MS calcd. for C11H11ClNO2+ 224.1, found m/z=224.2 (M+H)+.
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1.Cl>O>[CH2:2]([O:9][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Reactant: OCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Product: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Temperature: 148 °C
Yield: 88.2 %

Procedure:
Sodium (368 mg, 16 mmol) was added to benzyl alcohol (10 ml, 96 mmol) and the mixture was heated at 148° C. for 30 minutes. 7-Fluoro-3,4-dihydroquinazolin-4-one (656 mg, 4 mmol), (J. Chem. Soc. section B 1967, 449), was added and the mixture maintained at 148° C. for 24 hours. The reaction mixture was allowed to cool, the solution was poured on to water (170 ml) and the aqueous mixture adjusted to pH3 with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water, ether and dried under vacuum to give 7-benzyloxy-3,4-dihydroquinazolin-4-one (890 mg, 89%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6]1.CCN(C(C)C)C(C)C.Cl[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][N:6]1[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2ccccc2F)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccccc2F)C1
Reaction time: 1.5 h
Yield: 111.6 %

Procedure:
To a solution of methyl 2-(2-fluorobenzyl)piperidine-4-carboxylate (4.49 g, 17.85 mmol) and DIPEA (9.35 mL, 53.55 mmol) in DCM (100 mL) was added methyl chloroformate (1.798 mL, 23.21 mmol) in DCM (50 mL). The reaction mixture was stirred for 1.5 h. The organic phase was washed with satd NaHCO3. The phases were separated and the organic phase dried using a phase separator to yield crude dimethyl 2-(2-fluorobenzyl)piperidine-1,4-dicarboxylate (6.16 g, 112%). MS m/z 310 (M+H)+
Reaction SMILES: [C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28][C:29]([C:31]4[CH:40]=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[CH:33][CH:32]=4)=[O:30])=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28][C:29]([C:31]4[CH:40]=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=4)=[O:30])=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)N[C@@H]2CCCC[C@@H]2C(=O)N2CC[C@@H]3[C@H](c4ccccc4)Nc4ccccc4[C@@H]32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)N[C@@H]2CCCC[C@@H]2C(=O)N2CC[C@@H]3[C@H](c4ccccc4)Nc4ccccc4[C@@H]32)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a solution of methyl 4-{[((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexyl)amino]carbonyl}benzoate (77 mg, 0.14 mmol) in tetrahydrofuran (4 ml) and methanol (1 ml) was added 2N aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at 60° C. for 16 hrs. The reaction mixture was neutralized (pH 7) by adding 3N hydrochloric acid under ice-cooling. The mixture was concentrated under reduced pressure and extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (2:1, v/v). The extract was dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. The obtained solid was washed with isopropyl ether-hexane (1:2, v/v) to give the title compound (51 mg, 68%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[N:24]=[C:25]([CH3:28])[NH:26][CH:27]=1>>[Br:22][C:23]1[N:24]=[C:25]([CH3:28])[N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: Cc1nc(Br)c[nH]1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: Cc1nc(Br)cn1-c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.2) (0.65 g, 2.0 mmol) and commercially available 4-bromo-2-methyl-imidazole (0.48 g, 3.0 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.73 g, 81%). MS (ISP) 451.0 [(M+H)+]; mp 174° C.
Reaction SMILES: Cl[C:2]([Cl:13])([Cl:12])[CH2:3][CH:4]1[C:7]([CH3:9])([CH3:8])[CH:6](Cl)[C:5]1=[O:11].[O:14](C1C=C(C=CC=1)CO)C1C=CC=CC=1.[H-].[Na+].Cl>C(COC)OC.O>[Cl:13][C:2]([Cl:12])=[CH:3][CH:4]1[C:7]([CH3:8])([CH3:9])[CH:6]1[C:5]([OH:11])=[O:14]
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(Cl)C(=O)C1CC(Cl)(Cl)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
5.28 g (0.02 mol) of 2-(2',2',2'-trichloroethyl)-3,3-dimethyl-4-chlorocyclobutan-1-one, dissolved in 25 ml of absolute dimethoxyethane, are added dropwise to a solution of 4.0 g (0.02 mol) of m-phenoxybenzyl alcohol, 0.5 g (0.021 mol) of NaH and 40 ml of absolute dimethoxyethane. The reaction mixture is then stirred for 1 hour at 45° C., 2.25 g (0.02 mol) of potassium tert.-butylate are then added and the mixture is refluxed for 3 hours. After it has been discharged into water, it is acidified with dilute hydrochloric acid and extracted with benzene. The evaporated extract is chromatographed on silica gel using diethyl ether/n-hexane as the eluant (1:4 mixture by volume). This gives the m-phenoxybenzyl ester of 2-(2',2'-dichlorovinyl)-3,3-dimethylcyclopropane-1-carboxylic acid in the form of a viscous oil, which has the same properties as the substance obtained according to (a).