Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20](O)=[O:21])[C:6]2=[O:17].C(N1C=CN=C1)([N:36]1C=CN=C1)=O.[NH4+].[OH-].O>C1COCC1>[C:20]([CH2:19][C@@H:18]([N:5]1[C:6](=[O:17])[C:7]2[C:3](=[C:2]([Cl:1])[CH:10]=[CH:9][C:8]=2[NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:4]1)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)(=[O:21])[NH2:36]
Reactant: CCOc1cc([C@@H](CC(=O)O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc([C@@H](CC(N)=O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a solution of (3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid (0.62 g, 1.3 mmol) in THF (5 ml) was added carbonyldiimidazole (0.3 g, 2 mmol) at room temperature. The solution was stirred for 2 hrs at room temperature. To the mixture was added NH4OH (13.8 N, 0.3 ml, 3.9 mmol). The resulting mixture was stirred at room temperature for 4 hrs. Water (20 ml) was added to the reaction mixture. THF was removed in vacuo and to the resulting mixture was added ethyl acetate (30 ml). The mixture was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was stirred with ether (5 ml) for 2 hrs and filtered to give (1R)-cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.5 g, 82%): mp 201–203° C.; 1HNMR (CDCl3): δ 0.88–0.91 (m, 2H, c-CH2), 1.08–1.11(m, 2H, c-CH2), 1.45 (t, J=7.5 Hz, 3H, OCH2CH3), 1.65–1.68 (m, 1H, c-CH), 2.98 (dd, J=5, 16 Hz, 1H, CHH), 3.36 (dd, J=5, 16 Hz, 1H, CHH), 3.86 (s, 3H, OCH3), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 4.13 (d, J=17 Hz, 1H, NCHH), 4.35 (d, J=17 Hz, 1H, NCHH), 5.42 (broad s, 1H), 5.58–5.64 (m, 1H, CHN), 6.00 (broad s, 1H), 6.83–6.95 (m, 3H, Ar), 7.36 (d, J=9 Hz, 1H, Ar), 8.43 (d, J=9 Hz, 1H, Ar), 10.41 (s, 1H); 13C NMR (CDCl3): 8.4, 14.7, 16.1, 38.6, 48.6, 46.7, 53.2, 53.4, 56.0, 64.5, 65.8, 112.2, 119.0, 119.1, 119.5, 121.8, 130.6, 132.8, 136.6, 139.1, 148.7, 149.4, 169.0, 171.8, 172.6; Anal. Calcd. for C24H26ClN3O5: C, 61.08; H, 5.55; N, 8.90. Found: C, 60.89; H, 5.42; N, 8.51.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CN([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)C2)=NC=1CC.[CH2:33]([O:35][C@H:36]1[CH2:40][NH:39][CH2:38][C@H:37]1[NH:41][C:42]1[C:47]([CH2:48][CH3:49])=[N:46][C:45]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][C:51]=2[CH3:58])=[C:44]([CH2:59][CH3:60])[N:43]=1)[CH3:34]>>[CH2:33]([O:35][C@H:36]1[CH2:40][N:39]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[CH2:38][C@H:37]1[NH:41][C:42]1[C:47]([CH2:48][CH3:49])=[N:46][C:45]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][C:51]=2[CH3:58])=[C:44]([CH2:59][CH3:60])[N:43]=1)[CH3:34]
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl}-3,6-diethylpyrazin-2-amine but starting with N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.15, 1.31, 2.13, 2.47, 2.71, 3.45˜3.59, 3.77, 3.85, 4.03, 4.28, 4.93, 5.21, 6.54, 6.81, 6.83, 7.11, 7.26; IR (diffuse reflectance) 2970, 2932, 2403 (w), 2350 (w), 2334 (w), 2212 (w), 1965 (w), 1608, 1537 (s), 1482 (s), 1393, 1294, 1242, 1200, 1165 cm−1 HRMS (ESI) calcd for C25H33N5O2S+H1 468.2433. found 468.2416.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:15][OH:16])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C1C[O:24]CC1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:15]([OH:24])=[O:16])[CH2:17][CH:18]([CH3:20])[CH3:19])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](CO)N[C@@H](c1ccc(Cl)nc1)C(F)(F)F
Reactant: C1CCOC1
Product: CC(C)C[C@H](N[C@@H](c1ccc(Cl)nc1)C(F)(F)F)C(=O)O

Procedure:
A stock solution of H5IO6/CrO3 was prepared by dissolving H5IO6 (68.4 g, 0.3 mol) and CrO3 (138 mg, 1.2 mol %) in CH3CN (684 mL) to give a 0.44 M solution. To a solution of H5IO6/CrO3 (16 mmol, 36 mL, 0.44 M in THF) at −5° C. (ice and salt bath) was added a solution of (2S)-2-{[(1S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl]amino}-4-methylpentan-1-ol (1 g) in 3 mL THF dropwise. The internal temperature was monitored and reaction temperature was not allowed to rise above 0° C. The reaction was monitored by TLC until the reaction was complete (3-4 h). Na2HPO4 (80 mL) was added to the reaction mixture which was then extracted with EtOAc. The organic extract was washed with brine, NaHSO3 (120 mL) and brine again, dried over anhyd. MgSO4 and concentrated to an oil. The oil was redissolved in EtOAc and filtered through a short pad of silica gel, eluted with EtOAc and the filtrated was concentrated to give the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[N:38]O)[NH2:37])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:38]=[C:26]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:37]=2)=[CH:32][CH:31]=1
Reactant: NC(=NO)c1ccc(F)cc1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccc(F)cc3)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 42.3 (0.275 mmol) of 4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 59.1 mg (46% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[C:25]([OH:27])=O)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35]>>[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:25](=[O:27])/[CH:24]=[CH:23]/[C:11]1[CH:12]=[CH:13][C:14]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Product: Nc1ccccc1NC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1

Procedure:
The title compound is prepared from (E)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid (Example 100, step B) and 1,2-diaminobenzene analogous to Example 131, step C.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([CH:14]([CH3:18])[C:15](O)=[O:16])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:2].C([N:21](CC)CC)C.ClC(OCC)=O.N.Cl>O1CCCC1>[CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([CH:14]([CH3:18])[C:15]([NH2:21])=[O:16])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CCC1CC(=O)c2cc(C(C)C(=O)O)ccc2O1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: CCC1CC(=O)c2cc(C(C)C(N)=O)ccc2O1
Yield: 51.6 %

Procedure:
To a stirred solution of 2-(2,3-dihydro-2-ethyl-4-oxo-4H-1-benzopyran-6-yl)propionic acid (10.0 g; 0.04 mol) in dry tetrahydrofuran (100 ml) at -20° C. was added triethylamine (4.05 g; 0.04 mol) followed by ethyl chloroformate (6.0 g; 0.056 mol). After 10 minutes the mixture was saturated with gaseous ammonia. It was then acidified with dilute hydrochloric acid, the organic solvent was removed in vacuo and the product was extracted with chloroform (4×80 ml). The combined extracts were washed with water (2×100 ml), brine (200 ml), and dried over MgSO4. Evaporation of the solvent and recrystallisation of the residue from ethyl acetate gave the title compound (wt=5.1 g). m.p. 148°-150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7](=O)[C:6]=2[CH:14]=1.[NH2:15][CH2:16]C(O)=O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[CH2:16][NH:15][C:7](=[O:8])[C:6]=2[CH:14]=1
Reactant: NCC(=O)O
Reactant: Cn1c(=O)oc(=O)c2cc(F)ccc21
Solvent: CC(=O)O
Product: CN1C(=O)CNC(=O)c2cc(F)ccc21
Temperature: 0 °C

Procedure:
As illustrated in the scheme above, a mixture of 6-fluoro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (1.00 g, 5.12 mmol) and glycine (0.385 g, 5.13 mmol) in glacial acetic acid (13 mL) was heated at reflux for 4 h. The reaction was cooled and concentrated in vacuo. Water was added to the residue, and the mixture was cooled to 0° C. NaHCO3 was added to adjust the pH of the aqueous layer to approximately 8, and then the aqueous layer was extracted with CH2Cl2 (4×). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with Et2O, the solvent was removed by filtration, and the resulting solid was washed with additional Et2O to provide the title compound as a slightly yellow solid (0.560 g, 52%). 1H-NMR (DMSO-d6): δ 8.80 (br s, 1H), 7.49-7.38 (m, 3H), 3.76 (br d, 1H), 3.47 (br d, 1H), 3.26 (s, 3H). MS (ESI) (M+H)+=209.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][C:17]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][N:21]=2)=[CH:16][CH2:15]1.[C:29](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH3:29])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][C:17]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][N:21]=2)=[CH:16][CH2:15]1
Reactant: Fc1ccnc(C2=CCC(c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)c1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1Cc2cc(Cl)ccc2-n2c(nnc2C2CC=C(c3cc(F)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
A mixture of (RS)-8-chloro-1-[4-(4-fluoro-pyridin-2-yl)-cyclohex-3-enyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (0.032 g, 0.081 mmol), acetic acid (0.028 ml, 0.49 mmol) and paraformaldehyde (0.010 g, 0.32 mmol) in 1,2-dichloroethane (0.8 ml) was stirred for 16 h at room temperature. Addition of sodium triacetoxyborohydride (0.103 g, 0.49 mmol) was followed by stirring at room temperature for further 3 h. The mixture was partitioned between dichloromethane (50 ml) and 0.5 M aqueous sodium hydroxide solution (50 ml). The layers were separated. The aqueous layer was extracted with one 50 ml-portion of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography with n-heptane/isopropanol as eluent gave the title compound (0.026 g, 79%) as white solid. MS m/e: 410 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[CH:4][CH:3]=1.I[CH:26]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1.[H-].[Na+].[OH-].[Na+]>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH:26]4[CH2:27][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29]4)[CH:21]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(n2cc(-c3c[nH]c4cc(F)ccc34)cn2)C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 346 mg; 1.0 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (283 mg; 1.0 mmol) and NaH (100 mg; 2.5 mmol; 60% w/w) in DMF (5 mL) was heated to 120° C. for 0.5 hour in a microwave reactor. The reaction mixture was added NaOH (100 mg; 2.50 mmol) in water (0.5 mL) and stirred for 0.5 hour at 85° C. The mixture was concentrated and purified by a silica gel chromatography (petroleum ether/EtOAc=1/1) to afford 220 mg (62%) of the title compound as a yellow solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]3[C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=4[N:29]=[C:25]3[N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)C(=O)OC(C)(C)C)=[N+:2]=[N-:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]([CH2:4][CH2:5][CH2:6][NH:7][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:26]3[C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=4[N:29]=[C:25]3[N:24]=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N(CCCN=[N+]=[N-])c1ccc(-c2ccnc3nc4ccccc4n23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NCCCNc1ccc(-c2ccnc3nc4ccccc4n23)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (3-azidopropyl)(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-4-yl)phenyl)carbamate (above mentioned material) in 3 mL of DCM was added TFA (1 mL). The mixture was stirred at rt for 1.5 h and concentrated under reduced pressure. The residue was purified by reversed phase HPLC (TFA buffered water/MeCN) to afford the title compound as a orange-colored oil (61 mg, TFA salt). MS (ESI) m/z [M-1-H]+344.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C:17]1([C:26]([OH:28])=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1>>[C:26]([C:17]1([NH:16][C:2]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=3)[N:3]=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)([OH:28])=[O:27]
Reactant: NC1(C(=O)O)CCc2ccccc21
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC1(C(=O)O)CCc2ccccc21
Yield: 8 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-1-aminoindan-1-carboxylic acid to provide the title compound in 8% yield as yellow needles (flash chromatography on SiO2, eluent CHCl3, MeOH, AcOH—15, 1, 0.2 and recrystallization from MeOH).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>C(Cl)Cl>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:13](=[O:14])[N:12]([CH3:11])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: OCCc1ccc(O)cc1
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
To a solution of 4-(2-Hydroxyethyl)phenol (10 mmol) and 4-diazabicyclo[2.2.2]octane (DABCO) (10 mmol) in CH2Cl2 (30 mL) was added N-methyl-N-phenylcarbamoyl chloride (10 mmol). The reaction mixture was stirred for 16 hours at rt, added CH2Cl2 (20 mL), and washed with 1M aqueous HCl and brine. The organic phase was dried (MgSO4) and evaporated to give the 2.69 g (99%) of the title compound as crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[OH:20])[CH:15]=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:20][C:19]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[O:11][CH3:10]
Reactant: COc1cc(C=O)ccc1O
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1ccccc1F
Yield: 99.5 %

Procedure:
0.5M solution of 1-bromomethyl-2-fluoro-benzene (1.5 mg, 8 mmol) in DMF was added dropwise to a suspension of 3-methoxy-4-hydroxy-benzaldehyde (1.1 g, 7.3 mmol), K2CO3 (1.51 g, 11 mmol) and KI (120 mg, 7.3 mmol) in DMF (100 ml). The reaction mixture was treated as described in Example 4. The residue was purified on silica gel, obtaining 1.89 g (quantitative yield) of the title compound, yield 100%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.COC(=O)C1C=CC(OCC2[C:36]([C:41]3[CH:46]=[CH:45]C=C(F)C=3)=[N:37]OC=2C)=NC=1>>[CH:41]1([CH2:36][NH:37][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:46][CH2:45]1
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 63 %

Procedure:
As described for example 90, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (93 mg, 0.3 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted to the title compound (69 mg, 63%) which was obtained as an off white solid. MS: m/e=365.1 [M+H]′.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12>COCCO.O=[Pt]=O>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12
Reactant: c1cn2ccnc2cn1
Agent: O=[Pt]=O
Solvent: COCCO
Product: c1cn2c(n1)CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The imidazo[1,2-a]pyrazine (7.2 g, 60.44 mmole) was dissolved in 2-methoxyethanol (100 ml) and PtO2 (1.2 g, 5.13 mmole) was added. The reaction mixture was stirred overnight at RT in an autoclave under a hydrogen atmosphere (4 bar). The autoclave was then flushed with nitrogen, the reaction mixture was filtered through filter earth, concentrated, and the solvent residues were then extracted with toluene. Purification was carried out by column chromatography on silica gel (DCM/7 N NH3 in methanol, 95:5)
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30]>>[CH:18]1([N:13]2[C:12]([C:34]3[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2c3c(nn2C2CC2)CCNCC3)cc1
Yield: 69.5 %

Procedure:
The title compound (91 mg) was prepared according to Example 281 using 200 mg of 2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 281, Step C) and 97 mg of 4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C17H18N4, 278.15; found, m/z 279.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.94-7.92 (m, 2H), 7.71-7.70 (m, 2H), 4.66 (br s, 1H), 3.71-3.68 (m, 1H), 3.47 (br s, 1H), 3.39-3.19 (m, 4H), 3.01-2.88 (m, 2H), 0.96-0.90 (m, 4H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:15]([N:22]1[CH2:27][CH2:26][N:25]([CH2:13][CH2:12][CH2:11][C:9]2[O:8][N:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:10]=2)[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=CCCc1cc(-c2nccs2)no1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CN2CCN(CCCc3cc(-c4nccs4)no3)CC2)cc1
Yield: 55.9 %

Procedure:
About 2 min after dissolving 3-(3-(1,3-thiazol-2-yl)isoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-benylpiperazine (8.3, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (31 mg, 0.14 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 4.1 hr and followed the same processes as in Example 1 to obtain 10.3 mg (58.2%) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:17][C:18]([O:20]CC)=[O:19])[C:15](=[O:23])[N:14]([CH3:24])[C:13](=[N:25][C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=3[CH3:34])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>CO.O>[C:18]([CH2:17][N:16]1[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][C:13](=[N:25][C:26]2[C:27]([CH3:34])=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=2[CH3:32])[N:14]([CH3:24])[C:15]1=[O:23])([OH:20])=[O:19]
Reactant: CCOC(=O)Cn1c(-c2ccc(OC)c(OC)c2)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethoxycarbonylmethyl-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (4 g) in methanol (30 ml) was added a solution of sodium hydroxide (0.52 g) in water (6 ml) and stirred at room temperature for 3 hours. After removal of methanol, the residue was dissolved in water (40 ml) and adjusted to pH 5.8 and extracted with chloroform. The chloroform layer was washed with brine, dried over magnesium sulfate and evaporated to give a residue, which was triturated in n-hexane to give colorless powders (3.3 g) of 3,4-dihydro-1-carboxymethyl-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH2:24][OH:25])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:25][CH2:24][CH2:23][O:22][CH2:21][C@@H:12]1[CH2:13][C@@H:14]([O:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH2:15][NH:11]1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCCO)N(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)O[C@H]1CN[C@H](COCCO)C1
Yield: 90 %

Procedure:
A solution of (2S,4R)-1-benzyloxycarbonyl-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxypyrrolidine (53.0 g) in methanol (530 ml) was hydrogenated under atmospheric pressure of hydrogen at ambient temperature for 4 hours in the presence of 10% palladium on carbon (5.3 g, 50% wet). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (200 g) and eluted with a mixture of methanol and dichloromethane (5:95 V/V) to give (2S,4R)-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxypyrrolidine (30.55 g).
Reaction SMILES: N1C=CC(C2C=[N:10][NH:9][C:8]=2C2C=CC(CCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=CC=1.[Cl:30][C:31]1[CH:36]=[C:35]([CH2:37][C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]3[CH:57]=[CH:56][C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[N:49]=3)=[CH:42][CH:41]=2)=O)[CH:34]=[CH:33][N:32]=1>>[Cl:30][C:31]1[CH:36]=[C:35]([C:37]2[C:38]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]4[CH:57]=[CH:56][C:55]5[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=5)[N:49]=4)=[CH:42][CH:41]=3)=[N:10][NH:9][CH:8]=2)[CH:34]=[CH:33][N:32]=1
Reactant: O=C(Cc1ccnc(Cl)c1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: c1ccc2nc(CCc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Product: Clc1cc(-c2c[nH]nc2-c2ccc(OCc3ccc4ccccc4n3)cc2)ccn1

Procedure:
Following the procedure for the preparation of 2-{2-[4-(4-Pyridin4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline but substituting 2-(2-Chloro-pyridin-4-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.23 (m, 2 H), 8.08 (d, J=8.7 Hz, 1 H), 7.83 (d, J=8.3 Hz, 1 H), 7.80 (s, 1H), 7.75 (t, J=7.1 Hz, 1 H), 7.67 (d, J=8.3 Hz, 1H), 7.57 (t, J=7.1 Hz, 1 H), 7.33 (d, J=9.1 Hz, 2H), 7.05 (m, 4H), 5.40 (s, 2H); MS: (M+H m/z=413.1).