Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.Cl.[O:35]1[CH2:40][CH2:39][N:38]([C:41]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[O:42])[CH2:37][CH2:36]1.FC1C=CC(C(/N=C2\NC3C=CC(CN4CCN(S(C)(=O)=O)CC4)=CC=3N\2[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)=O)=CC=1>>[F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30][N:46]4[CH2:47][CH2:48][CH:43]([C:41]([N:38]5[CH2:37][CH2:36][O:35][CH2:40][CH2:39]5)=[O:42])[CH2:44][CH2:45]4)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:15][CH2:16][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:19]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Reactant: O=C(C1CCNCC1)N1CCOCC1
Agent: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCN(S(C)(=O)=O)CC4)cc32)CC1
Agent: Cl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(C(=O)N5CCOCC5)CC4)cc32)CC1

Procedure:
The title compound was prepared from (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide and morpholino(piperidin-4-yl)methanone hydrochloride using a method analogous to that used in the preparation of (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide, with a reaction temperature of 50° C. for 4 hours. The title compound was isolated as a white powder (49 mg, 35.0% yield). MS, m/z (C35H45FN6O4): calcd, 632.4. found, 633.0 [M+H].
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][S:6][C:5]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:4]=2[C:3]1=[O:15].[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[OH:15][CH:3]1[C:2]([CH3:16])([CH3:1])[CH2:7][S:6][C:5]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:4]1=2
Reactant: CC1(C)CSc2sc(S(N)(=O)=O)cc2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Product: CC1(C)CSc2sc(S(N)(=O)=O)cc2C1O
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A mixture of 5,6-dihydro-5,5-dimethyl-4H-thieno[2,3-b]thiopyran-4-one-2-sulfonamide (12.8 g, 0.046 m) and sodium borohydride (2.27 g, 0.060 m) in ethanol (460 ml) was stirred under reflux for 1 hour. After cooling to ambient temperature, the mixture was acidified by the rapid addition of 1N hydrochloric acid (65 ml), then rendered basic with saturated sodium bicarbonate solution and concentrated in vacuo to remove ethanol. The aqueous suspension was distributed between ethyl acetate (300 ml) and water (200 ml), the aqueous layer was separated and extracted with ethyl acetate (2×300 ml), the combined ethyl acetate layers were washed with saturated sodium bicarbonate solution, twice with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure to yield 11.71 g (91%) of product. An analytical sample melted at 158°-159° C. after recrystallization from nitromethane.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([O:14][C@@H:15]1[C@@H:20]([O:21][CH3:22])[C@@H:19]([CH3:23])[CH2:18][O:17][C@H:16]1[CH2:24][OH:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.C[Si](C=[N+]=[N-])(C)C.CCCCCC.[CH3:40][OH:41]>[Ru]=O.CCOCC.O.C(Cl)(Cl)(Cl)Cl.C(#N)C>[CH2:7]([O:14][C@@H:15]1[C@@H:20]([O:21][CH3:22])[C@@H:19]([CH3:23])[CH2:18][O:17][C@H:16]1[C:24]([O:41][CH3:40])=[O:25])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CO[C@@H]1[C@@H](OCc2ccccc2)[C@H](CO)OC[C@@H]1C
Reactant: CO
Agent: O=[Ru]
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CC#N
Product: COC(=O)[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1OCc1ccccc1
Reaction time: 12 h
Yield: 30 %

Procedure:
Sodium periodate (0.05 g, 0.234 mmole) and ruthenium oxide (0.02 g, 0.15 mmole) were added to a vigorously stirred emulsion of (2S,3R,4S,5S)-(3-benzyloxy-4-methoxy-5-methyltetrahydro-2H-pyran-2-yl)methanol (0.02 g, 0.075 mmole) in a mixed solvent of acetonitrile (2 ml), carbon tetrachloride (2 ml) and water (3 ml). After stirring for 12 hr, the reaction mixture was adjusted to pH 2 with 0.1N aqueous HCl and partitioned between ether (20 ml) and water (10 ml). The ether layer was dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. To a solution of the resulting crude acid in a mixed solvent of ether (5 ml) and MeOH (1 ml) there was added a 10% solution of trimethylsilyldiazomethane in n-hexane (0.5 g, 0.44 mmole). The mixture was stirred at room temperature for 10 min. The solution was evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel using AcOEt/n-hexane (2:8) as an eluent to give methyl (2R,3R,4S,5S)-3-benzyloxy-4-methoxy-5-methyltetrahydro-2H-pyran-2-carboxylate (6.6 mg, 30% yield) as an oil; EI-MS m/z 294 (M+); 1H-NMR (CDCl3)d: 1.0 (3H,d,J=7.2 Hz), 2.2 (1H,m), 3.20 (1H,dd, J=5 & 11 Hz), 3.35 (1H,dd,J=4 & 9 Hz), 3.6 (1H,t,J=9 Hz), 3.65 (3H,s), 3.7 (3H,s), 3.8 (1H,d,J=9 Hz), 4.0 (1H,dd,J=4 & 11 Hz), 4.59 (1H,d,J=12 Hz), 4.62 (1H,d,J=12 Hz), 7.3 (5H,m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[O-])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][O:32][CH3:33])[N:25]=[CH:24][N:23]=[C:22]2[O:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[C:35]([O:34][C:22]3[C:21]4[C:26](=[CH:27][C:28]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:19]([O:18][CH3:17])[CH:20]=4)[N:25]=[CH:24][N:23]=3)[CH:36]=2)=[O:12])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: COc1ccc(NC(=O)[O-])cc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4ccc(OC)c(C(F)(F)F)c4)c3)c2cc1OC
Yield: 10 %

Procedure:
According to the procedure for Example 138B, 4-methoxy-3-(trifluoromethyl)phenylcarbamate described in Example 138A (104 mg, 0.34 mmol) was reacted with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline described in Example 117B (100 mg, 0.28 mmol). To this solution was added diisopropylethyl amine (74 μL, 0.42 mmol) and DMAP (20.0 mg, 0.16 mmol). The reaction was concentrated to dryness and partitioned between water and dichloromethane, and extracted twice. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude oil was purified by silica gel chromatography (methanol/dichloromethane 0-5%) to give 1-(4-methoxy-3-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea as a white solid (18.6 mg, 10% yield). 1H (DMSO-d6) 8.90 (s, 1H), 8.80 (s, 1H), 8.60 (s, 1H), 7.85 (s, 1H), 7.60 (m, 3FI), 7.40 (m, 2H), 7.25 (m, 2H), 6.90 (d, 1H), 4.35 (m, 2H), 3.99 (s, 3H), 3.80 (s, 3H), 3.75 (m, 2H), 3.30 (s, 3H). LCMS (ESI) m/z 559 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C@H:42]2[O:44][CH2:43]2)=[CH:36][C:35]=1[S:45]([CH3:48])(=[O:47])=[O:46])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C(O)C>[CH2:1]([N:8]([CH2:43][C@H:42]([OH:44])[CH2:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:35]([S:45]([CH3:48])(=[O:47])=[O:46])[CH:36]=1)[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(S(C)(=O)=O)c3)CC2)cc1

Procedure:
This product is obtained by carrying out the preparation as described in preparation 3.2 above, using ethyl trans-4-[4-(benzylamino)cyclohexyl]benzoate and 4-benzyloxy-3-methylsulfonyl-1-((2S)-2,3-epoxypropoxy)benzene, disclosed in patent application WO 99/65895, and without adding thereto the solution of hydrochloric acid in ethanol. [M+H+]=672
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[N:19][CH:20]=1.O[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][O:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:18]=[N:19][CH:20]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1cncc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1OCc1cncc(OCc2nc(-c3ccccc3)oc2C)c1
Reaction time: 15 h
Yield: 61 %

Procedure:
To a mixture of [5-(5-methyl-2-phenyl-4-oxazolyl)methoxy-3-pyridyl]methanol (1.50 g), methyl 2-(2-hydroxyphenyl)acetate (0.76 g), triphenylphosphine (1.44 g) and tetrahydrofuran (50 mL) was dropwise added a solution (40%, 2.39 g) of diethyl azodicarboxylate in toluene at room temperature, and the mixture was stirred for 15 hrs. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography to give crude crystals from a fraction eluted with ethyl acetate-hexane (1:1, v/v) which crude crystals were further subjected to silica gel column chromatography to give crystals (1.24 g, 61%) of methyl 2-[2-[[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetate from a fraction eluted with tetrahydrofuran-hexane (3:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 77-78° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:21](Cl)=[N:20][S:19][N:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C.Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:21]2[C:17]([Cl:16])=[N:18][S:19][N:20]=2)[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1nsnc1Cl
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CCN(c2nsnc2Cl)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
4-(tert-Butoxycarbonylaminomethyl)piperidine (3.96 g, 18.4 mmol) was dissolved in DMF (3.5 ml) and heated to 100° C. 3,4-Dichloro-1,2,5-thiadiazole (0.85 mL, 9.0 mmol) was added and the mixture stirred at 100° C. overnight. DIEA (2.0 ml, 11.5 mmol) was added and heating at 100° C. continued until the reaction was complete (˜3 h). The reaction mixture was diluted with 1N HCl and extracted with EtOAc (3×). The combined EtOAc extractions were washed with H2O (1×), sat'd NaCl (1×), dried (MgSO4), and concentrated in vacuo to give 2.39 g (80%) of [1-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester as a tan solid. 1H NMR (DMSO-d6) 6.91 (t, 1H), 3.87 (m, 2H), 2.84 (m, 4H), 1.69 (m, 2H), 1.56 (m, 1H), 1.36 (s, 9H), 1.24 (m, 2H) ppm. LC-MS (MH+)=333.
Reaction SMILES: [Cl:1][C:2]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)=[C:3]([Cl:5])[Cl:4].O[CH2:14][NH:15][C:16](=[O:19])[CH2:17][Cl:18].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:18][CH2:17][C:16]([NH:15][CH2:14][C:9]1[CH:10]=[CH:11][C:6]([C:2]([Cl:1])=[C:3]([Cl:4])[Cl:5])=[CH:7][C:8]=1[OH:12])=[O:19]
Reactant: Oc1cccc(C(Cl)=C(Cl)Cl)c1
Reactant: O=C(CCl)NCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCl)NCc1ccc(C(Cl)=C(Cl)Cl)cc1O
Temperature: 25 °C

Procedure:
A mixture of 2.02 g (9.0 mmol) of the product of Step D and 1.10 g (9.0 mmol) of N-hydroxymethyl-2-chloroacetamide was added in portions to a vigorously stirred solution of 9.0 mL acetic acid and 1.0 mL (98%) sulfuric acid at 0-10° C. The reaction mixture was allowed to warm to room temperature over several hours, and stirring was maintained for a total of 2 days. The reaction mixture was poured into ice-water, neutralized with saturated aqueous NaHCO3 solution and extracted into CH2Cl2. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with a gradient of 10-30% EtOAc in hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([NH2:17])[N:16]=[C:10]2[CH:9]=1)([O-:3])=[O:2].[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>CN(C)C(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([NH:17][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[N:16]=[C:10]2[CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1nc2cc(Oc3cccc([N+](=O)[O-])c3)ccn2n1
Reactant: O=C(Cl)C1CC1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1nc2cc(Oc3cccc([N+](=O)[O-])c3)ccn2n1)C1CC1
Yield: 95.6 %

Procedure:
In the same manner as in Example 18-2 and using 7-(3-nitrophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-amine (112 mg, 0.413 mmol), cyclopropanecarbonyl chloride (135 μL, 0.496 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (134 mg, 96%) was obtained as a white solid.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1C(=O)N(Cl)C(=O)C1.[Cl:21][C:22]1[N:23]([C:32]2[CH:33]=[N:34][N:35]([CH2:37][CH2:38][CH3:39])[CH:36]=2)[C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=2>C(Cl)Cl.O>[Cl:21][C:22]1[N:23]([C:32]2[CH:33]=[N:34][N:35]([CH2:37][CH2:38][CH3:39])[CH:36]=2)[C:24]2[C:29]([C:30]=1[S:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=2
Reactant: CCCn1cc(-n2c(Cl)cc3ccc(Cl)cc32)cn1
Reactant: CCOC(=O)c1cccc(S)c1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O
Product: CCCn1cc(-n2c(Cl)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
To a stirred solution of ethyl 3-mercaptobenzoate (124.9 mg, 0.68 mmol) in CH2Cl2 (20 mL) under inert atmosphere was added NCS (109 mg, 0.81 mmol) at 0° C.; warmed to RT and stirred for 1 h. To this, compound 3 (200 mg, 0.68 mmol) was added at 0° C.; warmed to RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by preparative HPLC to afford compound 4 (15 mg, 5%) as colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.90 (s, 1H), 7.79-7.77 (m, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 7.48 (d, J=9.0 Hz, 1H), 7.26-7.22 (m, 3H), 7.16 (d, J=9.0 Hz, 1H), 4.32 (q, J=7.5 Hz, 2H), 4.20 (t, J=7.0 Hz, 2H), 2.02-1.98 (m, 2H), 1.37-1.34 (t, J=7.5 Hz, 3H), 1.01 (t, J=7.0 Hz, 3H); LC-MS (ESI): 92.7%; m/z 475.8 (M+H+); (column: X Select C-18, 50×3.0 mm, 3.5 μm); RT 5.03 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH:16]([O:18][CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[CH:22]1([CH2:21][O:20][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:17][CH:16]3[O:18][CH3:19])[CH2:23][CH2:24]1
Reactant: COC1CN(C(=O)OC(C)(C)C)Cc2ccc(OCC3CC3)cc21
Agent: Cl
Solvent: C1COCCO1
Product: COC1CNCc2ccc(OCC3CC3)cc21
Temperature: 25 °C

Procedure:
To 200 mg (0.600 mmol) 6-cyclopropylmethoxy-4-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example XLVI) in 3 mL dioxane are added 600 μL (2.40 mmol) HCl solution in dioxane (c=4 mol/L). After stirring over night at r.t. the reaction mixture is treated with DIPE, the precipitate is filtered off and dried at 40° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[N:42][CH:41]=[N:40]2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[N:42][CH:41]=[N:40]2)[CH:34]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J41) (347 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K25) (287 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (430 mg, 77%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nc(C)n(-c2cccnc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), pyridin-3-ylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.45 g, 37%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:23](O)=[O:24])[CH:14]=2)[CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2].CCN(CC)CC.[NH2:33][C:34]1[CH:35]=[CH:36][C:37]([F:44])=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1.CCCP(=O)=O>CN(C=O)C.CN(C1C=CN=CC=1)C.O.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:23](=[O:24])[NH:33][C:34]3[CH:35]=[CH:36][C:37]([F:44])=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:39]=3)[CH:14]=2)[CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: CCOC(=O)c1nccc(Oc2ccc3c(C(=O)O)cccc3c2)n1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)n1
Reaction time: 0.5 h

Procedure:
To a solution of 242 mg (0.717 mMol) 4-(5-carboxy-naphthalen-2-yloxy)-pyrimidine-2-carboxylic acid ethyl ester in 10.7 ml DMF, 1.5 ml (10.8 mMol) Et3N, 38 mg (0.31 mMol) DMAP, 111 μl (0.86 mMol) 5-amino-2-fluorobenzotrifluoride and 880 μl propylphosphonic anhydride (50% in DMF; 1.5 mMol) are added. After 30 min stirring, the reaction mixture is diluted with water and EtOAc, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; CH2Cl2→CH2Cl2/acetone 19:1) gives the title compound: MS: [M+1]+=500; TLC (CH2Cl2/acetone 9:1): Rf=0.54.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=2)[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)=[O:18])=[CH:10][N:9]=1>C1COCC1>[OH:5][CH2:4][CH2:3][O:6][C:8]1[N:9]=[CH:10][C:11]([C:14]2[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=2)[C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=2)=[O:18])=[CH:12][N:13]=1
Reactant: OCCO
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(-c2cnc(Cl)nc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(-c2cnc(OCCO)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of NaH 60% in oil (12.19 mg, 0.508 mmol) in THF (200 μL) was added ethylene glycol (21.24 μL, 0.381 mmol). A solution of 3-(2-chloropyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 2.1, 50 mg, 0.127 mmol) in THF (2.5 mL) was then added and the RM was stirred at RT overnight. Additional ethylene glycol (200 μL, 3.59 mmol) was added and the reaction was stirred at RT for 4 h. The reaction was quenched with HCOOH and the solvent was evaporated off under reduced pressure. The residue was treated with saturated aq. NaHCO3 (10 mL) and extracted with TBME/EtOAc (1:1). The combined extracts were washed with brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 4 g, DCM/MeOH+1% NH4OH, from 1% to 12% MeOH+1% NH4OH) to afford the title compound as a white solid. UPLC-MS (Condition 1) tR=2.44 min, m/z=420.1 [M+H]+, m/z=418.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.76 (dd, 2H) 4.40 (t, 2H) 4.92 (t, J=5.5 Hz, 1H) 7.39 (d, J=8.6 Hz, 2H) 7.64-7.70 (m, 1H) 7.91 (d, J=9.0 Hz, 2H) 7.97 (d, J=8.1 Hz, 2H) 8.28 (s, 1H) 9.04 (s, 2H) 10.48 (s, 1H).