Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1)C1CC1

Procedure:
Example 113 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclo propanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.84–7.80 (br, 1H), 7.80–7.69 (br, 1H), 7.64–7.46 (br, 1H), 7.40–6.90 (m, 9H), 6.85–6.66 (m, 1H), 4.94–4.74 (br, 1H), 4.69 (s, 1H), 3.41–3.25 (m, 2H), 3.25–3.07 (m, 2H), 2.77–2.61 (m, 2H), 2.61–2.45 (m, 1H), 2.45–2.17 (m, 2H), 1.99–1.63 (m, 6H), 1.61–1.39 (m, 1H), 1.14–0.94 (m, 2H), 0.92–0.70 (m, 2H); ESMS m/e: 564.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C1CSCCN1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCSCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, thiomorpholine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.45 minutes; C21H20Cl2N4O2S (463.39); mass spectrum: (M−H)−=462/464/466 (chlorine isotope).
Reaction SMILES: C(OC([N:11]1[CH2:17][C@@H:16]2[C@@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][C@@H:15]2[CH3:18])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[C:23]([O:22][C:20]([NH:19][C@@:13]12[CH2:14][C@H:15]([CH3:18])[C@@H:16]1[CH2:17][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: [H][H]
Reactant: C[C@H]1C[C@@]2(NC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@@H]12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1C[C@@]2(NC(=O)OC(C)(C)C)CNC[C@@H]12

Procedure:
(1S,5R,6S)-1-tert-Butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylic acid benzyl ester (1.4 g, 3.8 mmol) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (10 mL). A small amount of 10% palladium-carbon (50% wet) was added, and the mixture was stirred in a hydrogen atmosphere for three hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 0.85 g (quantitative) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:31][CH:15]([CH2:16][CH2:17][N:18]3[C:23](=[O:24])[C:22]([OH:25])=[C:21]([C:26](OCC)=[O:27])[N:20]=[C:19]31)[O:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1.CCN(CC)CC>CCO>[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH:40][C:26]([C:21]2[N:20]=[C:19]3[N:18]([C:23](=[O:24])[C:22]=2[OH:25])[CH2:17][CH2:16][CH:15]2[CH2:31][C:12]3([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][O:14]2)=[O:27])=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCC1CC2(NC(=O)OCc2ccccc2)CO1
Reactant: NCc1ccc(F)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NC12COC(CCn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)C2)OCc1ccccc1
Yield: 49.1 %

Procedure:
A mixture of ethyl 11-(((benzyloxy)carbonyl)amino)-3-hydroxy-4-oxo-7,8,10,11-tetrahydro-4 H,6H-8,11-methanopyrimido[2,1-d][1,5]oxazocine-2-carboxylate (0.070 g, 0.163 mmol), (4-fluorophenyl)methanamine (0.125 g, 1 mmol) and Et3N (0.418 mL, 3 mmol) in EtOH (5 mL) was heated at reflux for 7 h. The reaction was cooled, concentrated and the residue purified by preparative-HPLC to afford title compound (0.0405 g, 0.080 mmol, 49%) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 11.99 (0.6 H, brs), 11.92 (0.4 H, brs), 7.82 (0.4 H, t, J=5.8 Hz), 7.58 (0.6 H, t, J=5.8 Hz), 7.32-7.39 (3 H, m), 7.17-7.28 (2 H, m), 7.09 (1 H, dd, J=8.1, 5.6 Hz), 7.01-7.06 (1 H, m), 6.91-6.99 (2 H, m), 5.60 (0.6 H, s), 5.41-5.51 (1 H, m), 5.10 (0.4 H, s), 5.02 (0.6 H, d, J=12.5 Hz), 4.89 (1 H, d, JAB=12.4 Hz.), 4.79 (0.6 H, d, J=10.7 Hz), 4.69-4.75 (2 H, m), 4.60 (0.4 H, d, J=10.4 Hz), 4.37-4.49 (2.8 H, m), 4.12 (0.6 H, dd, J=18.8, 6.0 Hz), 3.70 (0.6 H, t, J=13.7 Hz), 3.63 (0.4 H, t, J=13.7 Hz), 2.47-2.60 (1 H, m), 2.13-2.21 (1 H, m.), 1.97-2.05 (1 H, m). LCMS (M+H) calcd for C26H26FN4O6: 509.18; found: 509.14.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:20])[CH3:19]
Reactant: COC(=O)c1cc(CO)cc(-n2cccc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(COC(C)=O)cc(-n2cccc2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 3-hydroxymethyl-5-(pyrrol-1-yl)benzoate (4.0 g) in pyridine (40 ml) was added acetic anhydride (4.9 ml) under ice cooling. After being stirred for 3 hours under ice cooling, the reaction mixture was poured into ice-water and the product was extracted with diethyl ether. The diethyl ether extracts were washed with water, 1N-hydrochloric acid and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (5:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to afford methyl 3-acetoxymethyl-5-(pyrrol-1-yl)benzoate (4.68 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CNC)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reactant: CCOC(=O)Cl
Product: CCOC(=O)c1c(CN(C)C(=O)OCC)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
5-Fluoro-3-methylaminomethyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 86.1.) was reacted with ethyl chloroformate as described in Example 77.1. to give 3-[(ethoxycarbonyl-methyl-amino)-methyl]-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless solid. MS: 433.5 ([M−H]−).
Reaction SMILES: [CH2:1]([C@@H:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[C@@H:4]([CH3:7])[CH2:5]O)[CH3:2].S(Cl)([Cl:24])=O>ClCCl.CN(C)C=O>[Cl:24][CH2:5][C@H:4]([CH3:7])[C@H:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH2:1][CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CCl
Yield: 88.1 %

Procedure:
The product of Example 32 (2.6 g, 9 mmol) was dissolved in dichloromethane, the mixture was cooled in an ice-water bath, then N, N-dimethylformamide (2 drops) was added and thionyl chloride (0.64 mL, 10 mmol) was added dropwise, after the addition was complete, the reaction was conducted under reflux for 6 hours and quenched by adding water. After the reaction solution was separated, the aqueous phase was extracted with dichloromethane three times, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the target compound 2.4 g, yield: 90%.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].I[CH2:10][CH2:11][CH2:12][CH3:13]>[Ag]=O.CCOCC>[CH2:10]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CCCCI
Agent: O=[Ag]
Solvent: CCOCC
Product: CCCCO[C@@H](C)C(=O)OCC
Reaction time: 72 h
Yield: 44 %

Procedure:
Silver oxide (77.5 g, 0.3 mol) was added to a mixture of (S)-(+)-ethyl lactate (49.4 g, 0.4 mol) with 1-iodobutane (100 g, 0.5 mol) over 2 hours, followed by allowing the mixture to stand at room temperature for 3 days, adding ether (30 ml) for dilution, filtering the resulting mixture, distilling off ether, washing the residue with 2N-NaOH aqueous solution, drying it over anhydrous MgSO4 and distilling under reduced pressure, to obtain (S)-ethyl 2-butoxypropionate (30.7 g, b.p. 64° C./7 mmHg), adding thereto 5N-NaOH aqueous solution (50 ml), agitating the mixture at room temperature for 5 hours, pouring it in 6N-hydrochloric acid (75 ml) to extract the resulting organic layer with ether, washing the resulting organic layer with water and distilling off ether, to obtain (S)-2-butoxypropionic acid (21. 4 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1>CC(N(C)C)=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]>[CH3:11][N:12]1[CH:16]=[C:15]([C:2]2[CH:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:14]=[N:13]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CC(=O)N(C)C
Product: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Temperature: 75 °C
Yield: 77.9 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (1.0 g, 5.05 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.17 g, 5.55 mmol) and Pd(dppf)Cl2 (37 mg, 0.045 mmol) were placed in a N2 purged round-bottom flask. The reagents were dissolved in DMA (6 ml) and purged with N2. An aqueous solution of K2CO3 (978 mg in 6 ml) was then added slowly to the reaction mixture, while maintaining the temperature below 40° C., and purged for 10 minutes with N2. The solution was then heated to 75° C. overnight. Heating was discontinued and 12 ml of H2O was added. The solution was then heated to 60° C. for 1 h. Next, the solution was transferred to a separatory funnel and extracted with dichloromethane (100 ml×2). The organic layer was dried over Na2SO4 and concentrated down onto silica gel. The reaction mixture was purified by flash chromatography using a gradient of 0-10% methanol/di-chloromethane to afford 780 mg of 5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (78% yield): 1H NMR (DMSO-d6) δ 3.94 (3H, s), 6.49 (1H, d), 7.38 (1H, d), 7.84 (1H, s), 7.97 (1H, s), 8.12 (1H, d), 8.38 (1H, d); MS (m/z) 199 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12](OC)=[O:13])=[CH:7][CH:6]=2.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][OH:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2ncc(Cl)cc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2ncc(Cl)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Methyl 3-chloroquinoline-6-carboxylate (145 mg, 0.654 mmol) in THF (6 ml) Lithiumaluminium hydride 1M in THF (0.654 ml, 0.654 mmol) was added slowly at rt. The reaction was stirred for 2 h at rt. Sodium sulfate decahydrate was added to the reaction mixture to destroy the excess of Lithiumaluminium hydride. After 1 h, methanol was added and the fine suspension was filtered off. The filtrate was concentrated under vacuum, to afford crude (3-chloroquinolin-6-yl)methanol. MS (Method V) [M+H]+=194.2.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=2)[O:17][CH:18]=1.Br[CH2:30][CH2:31][CH:32]=[CH2:33]>>[CH2:33]([O:27][C:21]1[CH:20]=[C:19]([C:16]2[O:17][CH:18]=[C:14]([CH2:13][CH2:12][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3][CH2:2][F:1])=[O:28])[N:15]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26])[CH2:32][CH:31]=[CH2:30]
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCCF)co2)cc1O
Reactant: C=CCCBr
Product: C=CCCOc1cc(-c2nc(CCC(=O)c3ccccc3OCCF)co2)ccc1OC

Procedure:
Using the compound obtained in Example 271 and 4-bromo-1-butene, white powdery 3-[2-(3-but-3-enyloxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2-fluoroethoxy)phenyl]propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@H:14]([O:15][Si](C(C)(C)C)(C)C)[C@@H:13]([CH3:23])[CH2:12][N:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH:30][C:31]([C:33]2[C:42]([NH:43]C(=O)OCC3C=CC=CC=3)=[CH:41][C:40]3[C:35](=[CH:36][C:37]([N:54]4[CH2:59][CH2:58][O:57][CH2:56][CH2:55]4)=[CH:38][CH:39]=3)[N:34]=2)=[O:32])[CH2:10]1)=O)(C)(C)C.[H][H]>CO.[Pd]>[NH2:43][C:42]1[C:33]([C:31]([NH:30][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][C:24]=2[N:11]2[CH2:12][C@H:13]([CH3:23])[C@@H:14]([OH:15])[C@H:9]([NH2:8])[CH2:10]2)=[O:32])=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([N:54]1[CH2:55][CH2:56][O:57][CH2:58][CH2:59]1)[CH:36]=2
Reactant: [H][H]
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2N)C[C@@H](N)[C@@H]1O

Procedure:
A mixture of benzyl [2-({[4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)pyridin-3-yl]amino}carbonyl)-7-morpholin-4-ylquinolin-3-yl]carbamate (0.0035 g, 0.0042 mmol) in 3 mL of MeOH was hydrogenated under a balloon of hydrogen, in the presence of 3 mg of 10% Pd on carbon, at room temperature for 1 h. The reaction mixture was diluted with 5 mL of MeOH then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was treated with 2 mL of MeOH and 2 mL of 4 M HCl in dioxane at room temperature for 1 h. The volatile solvents were removed under reduced pressure. The residue was dissolved in 4 mL of MeOH and treated with 0.5 mL of NH4OH solution, then filtered. The filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C25H32N7O3 [M+H]+: m/z=478.3. found: 478.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccccc2)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-phenyl-boronic acid (CAN 98-80-6) as starting materials; LC-MS (UV peak area/ESI) 100%, 374.1107 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:21])([CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10])[C:4]([F:7])([F:6])[F:5].[CH2:22]([O:29][C:30](ON1C(=O)CCC1=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:23]1([CH2:22][O:29][C:30](=[O:31])[NH:1][CH2:2][C:3]([OH:21])([C:4]([F:7])([F:6])[F:5])[CH2:8][C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])([CH3:11])[CH3:10])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNC(=O)OCc1ccccc1)C(F)(F)F
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
Racemic 2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol (which may be prepared according to WO03/082827, 894 mg, 2.89 mmol) was dissolved in dichloromethane (15 mL). N-(benzyloxycarbonyloxy)succinimide (1.08 g, 4.34 mmol) was added and the mixture was stirred for 5 min. Triethylamine (804 μL, 5.78 mmol) was added and stirring was continued for 3.5 hours after which time the reaction mixture was washed with saturated sodium bicarbonate solution and evaporated in vacuo. Purification of the residue by Flashmaster II using a 100 g silica cartridge and a solvent gradient of cyclohexane:EtOAc 100:0 to 0:100 over a period of 1 hour gave the racemic product as an oil (1.12 g). This oil was applied to a 2 inch×20 cm Chiralpak AD column eluted with heptane:IPA 97.5:2.5 with a flow rate of 75 mL/min to give Intermediate 7 (2R isomer, 443 mg) after ca. 42 min and Intermediate 8 (2S isomer, 441 mg) after ca. 60 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22].Cl.[OH-].[Na+]>O.C(O)C>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(OC)c(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c1
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol), 2,5-dimethoxyaniline and aqueous 2N HCl (150 μl) in water:ethanol (1:1, 10 ml) was refluxed for 48 h. The mixture was cooled to room temperature and then basified with aqueous 2N NaOH to pH 10–12. The resulting precipitate was filtered, washed with water, water:ethanol (2:1) and isolated as a green-yellow solid (46 mg, 64%). 1H NMR (CDCl3): 9.74 (d, J=1.5 Hz, 1H), 8.79 (dd, J=1.8, 2.4 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H), 7.80 (bs, 1H), 7.70 (s, 1H), 7.07 (s, 1H), 6.91 (d, J=9.3 Hz, 1H), 6.72 (dd, J=3.0, 9.0 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Br[CH:11]([Cl:14])[CH2:12][CH3:13].[OH-].[K+]>C(O)C>[Cl:14][CH2:11][CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1
Reactant: OCc1ccc(O)cc1
Reactant: CCC(Cl)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccc(OCCCCl)cc1

Procedure:
A solution of 4-hydroxy benzyl alcohol CAS No. [623-05-2] (10 g, 80.5 mmol) in ethanol (70 mL) was treated with 1, 3 bromochloro propane (16.0 g, 100 mmol) and potassium hydroxide (5.0 g, 89 mmol) was refluxed for 2 hours. The solution was cooled and filtered and then the filtrate concentrated. The concentrate was taken up in ether and washed with water, brine and dried over magnesium sulfate. The material was chromatographed on silica gel using ethyl acetate/hexanes (3:7) to yield 11.6 g of the product as a white solid: Mp=65° C.; 1H NMR (DMSO) 7.21 (d, 2 H, J=8.8 Hz), 6.88 (d, 2 H, J=8.8 Hz), 5.03 (t, 1 H, J=5.7 Hz), 4.40 (d, 2H, J=5.5 Hz), 4.05 (t, 2 H, J=6.1 Hz), 3.77 (t, 2 H, J=6.4 Hz); MS eI m/z 200.
Reaction SMILES: [N:1]1([C:7]([NH:9]C(=O)C2C=CC=CC=2)=[S:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[N:1]1([C:7](=[S:8])[NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(NC(=S)N1CCOCC1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=S)N1CCOCC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask was added a solution of N-(morpholine-4-carbonothioyl)benzamide (compound 211.9, 3.00 g, 12.0 mmol, 1.00 equiv) in methanol (20 mL). A solution of sodium hydroxide (1.44 g, 36.0 mmol, 3.00 equiv) in water (20 mL) was added to the reaction. The resulting solution was stirred overnight at 60° C. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The residue was extracted with 2×20 mL of ethyl acetate/petroleum ether(1:1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 430 mg (25%) of morpholine-4-carbothioamide as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.[OH-].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: c1ccc2c(c1)CCN2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1cc(Cl)ncn1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.50 g (2.83 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 20 mL dichloromethane were cooled with an ice/ethanol bath and combined with 0.30 mL (2.68 mmol) 2,3-dihydro-1H-indole. 2.7 mL (2.7 mmol) of a 1M sodium hydroxide solution were added dropwise. The reaction mixture was stirred for 2 h with cooling and for 1 h at RT. Then 50 mL of an aqueous saturated sodium hydrogen carbonate solution were added. After 10 min stirring the organic phases was separated off and washed with water and 1 M hydrochloric acid. The organic phases was dried on magnesium sulphate, filtered and evaporated down i.vac.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32]O.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][O:17][C:14]([C:12]1[CH:11]=[CH:10][C:9]([NH:18][C:19]([C:21]2[NH:25][C:24]([C:26]#[N:27])=[CH:23][N:22]=2)=[O:20])=[C:8]([C:5]2[CH2:6][CH2:7][C:2]([CH3:28])([CH3:1])[CH2:3][CH:4]=2)[CH:13]=1)([CH3:15])[CH3:16]
Reactant: CN(C)CCO
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCOC(C)(C)c1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)c1
Temperature: 60 °C
Yield: 11.1 %

Procedure:
To a suspension of 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (60 mg, 0.16 mmol)(as prepared in Example 14, step (d)) in 1 mL of DCM was added 2-dimethylamino-ethanol (0.32 mL, 3.20 mmol), TFA (0.37 mL, 4.80 mmol), and the mixture heated to 60° C. for 6 h. The mixture was concentrated and the title compound purified by RP-HPLC on a C18 column eluting with a linear gradient of 30-55% CH3CN in 0.1% TFA/H2O over 9 min to give 10 mg (11%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.26 (d, J=8.5 Hz, 1H), 8.09 (s, 1H), 7.44 (dd, J=8.5, 2.2 Hz, 1H), 7.30 (d, J=2.2 Hz, 1H), 5.77 (m, 1H), 3.52 (m, 2H), 3.30 (m, 2H), 2.91 (s, 6H), 2.34 (m, 2H), 2.11 (m, 2H), 1.64 (s, 6H), 1.60 (m, 2H), 1.12 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H35N5O2, 450.3 (M+H). found 450.0.