Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH:60]([O:62]CCCC)=[CH2:61].Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C=O>[C:60]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11])(=[O:62])[CH3:61]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(Br)cccc21
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cccc2c1C1(COc3cc4c(cc31)OCCO4)C(=O)N2C
Temperature: 120 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A 10 mL septum-capped microwave pressure tube was charged with 4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.39 g, 1.0 mmol), palladium (II) acetate (0.022 g, 0.1 mmol), 1,3-bis(diphenylphosphino)propane (0.10 g, 0.25 mmol) and potassium carbonate (0.17 g, 1.2 mmol). The tube was capped and purged for 5 min with dry nitrogen, and butyl vinyl ether (0.52 mL, 4.0 mmol), N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added. The reaction mixture was heated for 1 h under microwave irradiation (100 W, 120° C.) and was allowed to cool to ambient temperature, poured into 10% v/v aqueous hydrochloric acid (5 mL) and stirred at ambient temperature for 1 h. The mixture was diluted with water (20 mL) and was neutralized with 2 M aqueous sodium carbonate. Ethyl acetate (20 mL) was added and the biphasic mixture was filtered through a pad of diatomaceous earth. The pad was washed with ethyl acetate (20 mL) and the filtrate was transferred to a separatory funnel. The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with water (3×20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography and eluted with a 0% to 100% gradient of ethyl acetate in hexanes, followed by recrystallization from dichloromethane/diethyl ether to afford 4′-acetyl-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.264 g, 75%) as an off-white solid: mp 234-235° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.55-7.44 (m, 2H), 7.14-7.08 (m, 1H), 6.50 (s, 1H), 5.99 (s, 1H), 4.95-4.77 (m, 2H), 4.19-4.04 (m, 4H), 3.28 (m, 3H), 2.43 (m, 3H); 13C NMR (75 MHz, CDCl3) δ198.3, 178.6, 157.2, 145.4, 144.3, 137.4, 134.5, 130.6, 129.5, 124.4, 119.9, 112.1, 110.2, 98.9, 78.9, 64.5, 64.0, 59.4, 28.5, 27.0; MS (ES+) m/z 351.8 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>CC#N>[OH:4][CH2:3][CH2:2][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: OCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCCO)cc1
Temperature: 25 °C

Procedure:
2-Bromoethanol (5.8 mL) and potassium carbonate (11.3 g) were successively added to a solution of 4-hydroxybenzaldehyde (5.0 g) in MeCN (100 mL). The resulting mixture was stirred and heated at reflux for 3 days under argon. The reaction mixture was cooled to RT and partitioned between EtOAc (100 mL) and 1M aqueous NaOH solution (100 mL). The organic layer was washed with brine (100 mL). The aqueous layers were combined and extracted with EtOAc (50 mL). The organic layers were combined, dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a yellow oil. Yield 6.4 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH2:30])[CH3:29].C(N(CC)CC)C>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH:30][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[CH3:29]
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(N)c1ccc(F)cc1-c1cc(F)ccc1F
Solvent: CCN(CC)CC
Product: COc1cccc(S(=O)(=O)NC(C)c2ccc(F)cc2-c2cc(F)ccc2F)c1
Yield: 100 %

Procedure:
The title compound was prepared from 3-methoxybenzenesulfonyl chloride (153 mg, 0.74 mmol), 1-(-2′,5′,5-trifluoro-1,1′-biphenyl-2-yl)ethylamine (177 mg, 0.70 mmol), and triethylamine (147 uL, 1.1 mmol) according to the procedure and in the same manner as described in Example 105, step c. The product was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the desired compound (295 mg, 100%) as a white solid;
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C@@:7]23[CH2:26][N:20]([C@H:21]([C:23](O)=[O:24])[CH2:22]2)[C:19](=[O:27])[C@@H:18]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:8]3)=[CH:3][CH:2]=1.[NH2:42][C@:43]1([C:48]([NH:50][S:51]([CH:54]2[CH2:56][CH2:55]2)(=[O:53])=[O:52])=[O:49])[CH2:45][C@H:44]1[CH:46]=[CH2:47].CC1C=CC(S(O)(=O)=O)=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CCOC(C)=O>[C:1]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:6]=[CH:5][C:4]([C@@:7]23[CH2:26][N:20]([C@H:21]([C:23](=[O:24])[NH:42][C@:43]4([C:48](=[O:49])[NH:50][S:51]([CH:54]5[CH2:56][CH2:55]5)(=[O:53])=[O:52])[CH2:45][C@H:44]4[CH:46]=[CH2:47])[CH2:22]2)[C:19](=[O:27])[C@@H:18]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:8]3)=[CH:3][CH:2]=1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCCCCCS[C@@]2(c3ccc(-c4ccccc4)cc3)C[C@@H](C(=O)O)N(C2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCCCCCCS2)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
To an iced slurry of (3S,14R,16S)-14-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadecane-16-carboxylic acid (20 mg, 0.034 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide, pTSA, 0.68H2O (17.85 mg, 0.043 mmol), and HATU (32.5 mg, 0.0855 mmol) in DCM (1 mL) was added N,N-Diisopropylethylamine (0.030 mL, 0.172 mmol). The formed light brown solution was stirred at room temperature overnight. Diluted with EtOAc, washed it with 5% citric acid, and brine, dried over MgSO4, filtered, evaporated. The formed residue was purified by prep-HPLC to afford the desired product tert-butyl (3S,14R,16S)-14-(biphenyl-4-yl)-16-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadecan-3-ylcarbamate (7 mg, 8.65 mmol, 25.1% A yield) as a white foam. 1H NMR (400 MHz, MeOD) δ ppm 0.94-1.37 (m, 13 H) 1.35-1.63 (m, 12 H) 1.84 (dd, J=8.16, 5.40 Hz, 1 H) 1.91-2.08 (m, 4 H) 2.08-2.19 (m, 1 H) 2.19-2.45 (m, 4 H) 2.59 (dd, J=12.30, 6.53 Hz, 1 H) 2.82-2.99 (m, 1 H) 3.87 (dd, J=10.29, 6.53 Hz, 1 H) 4.00-4.22 (m, 2 H) 4.64 (t, J=8.53 Hz, 1 H) 5.07 (dd, J=10.29, 1.51 Hz, 1 H) 5.24 (dd, J=17.19, 1.38 Hz, 1 H) 5.60-5.78 (m, 1 H) 6.36 (d, J=8.53 Hz, 1 H) 7.32 (t, J=7.28 Hz, 1 H) 7.42 (t, J=7.53 Hz, 2 H) 7.53-7.74 (m, 6 H); LC-MS (retention time: 3.50 min, method C), MS m/z 793.5 (M+H), 737 (M-t-Bu), 693 (M-BOC).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][S:7]([CH2:10][CH:11]([CH2:15][C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])[C:12](O)=[O:13])(=[O:9])=[O:8].[NH2:29][CH:30]([CH2:42][O:43][CH3:44])[CH:31]([C:33]1[O:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[OH:32].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[O:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[CH:31]([OH:32])[CH:30]([NH:29][C:12](=[O:13])[CH:11]([CH2:10][S:7]([CH2:6][C:5]1[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=1[O:3][CH:2]([F:28])[F:1])(=[O:8])=[O:9])[CH2:15][C:16]([N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)=[O:17])[CH2:42][O:43][CH3:44]
Reactant: COCC(N)C(O)c1nc2ccccc2o1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1OC(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COCC(NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1OC(F)F)C(O)c1nc2ccccc2o1
Reaction time: 14 h
Yield: 96.2 %

Procedure:
To a stirred mixture of 2-(2-difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid (210.5 mg, 0.5 mmol), 2-amino-1-benzooxazol-2-yl-3-methoxy-propan-1-ol (112.5 mg), and HOBt (91.8 mg, 0.6 mmol) in MeCl2 (5 ml), was added EDC (144 mg, 0.75 mmol) and N-methylmorpholine (0.35 ml) at room temperature. After stirring for 14 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, brine, dried with MgSO4 and concentrated to yield 301 mg of N-(2-benzooxazol-2-yl-2-hydroxy-1-methoxymethyl-ethyl)-2-(2-difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide; MS: 624.5(M−1), 626.3(M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:29][C:30]4[CH:35]=[CH:34][N:33]=[C:32]([NH2:36])[N:31]=4)=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:12][C:11]=1[C:37]([F:40])([F:39])[F:38]>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O.O>[CH2:5]([O:4][C:2](=[O:3])[NH:36][C:32]1[N:31]=[C:30]([O:29][C:25]2[CH:26]=[CH:27][C:28]3[C:23](=[CH:22][CH:21]=[CH:20][C:19]=3[C:17](=[O:18])[NH:16][C:13]3[CH:14]=[CH:15][C:10]([F:9])=[C:11]([C:37]([F:40])([F:39])[F:38])[CH:12]=3)[CH:24]=2)[CH:35]=[CH:34][N:33]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)COC(=O)Cl
Reactant: Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)n1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)n1
Reaction time: 1 h

Procedure:
110 μl (0.84 mMol) isobutyl chloroformate are added portionwise to a solution of 300 mg (0.68 mMol) 6-(2-amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide (Step 10.3) in 4.5 ml CH2Cl2 and 7.5 ml pyridine. After 1 h, the solution is diluted with EtOAc and water, 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/EtOH 19:1) gives the title compound: MS: [M+1]+=543.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][NH2:41])[CH:35]=1>>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:41][CH2:40][C:36]4[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=4)=[O:30])=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])(=[O:16])=[O:17])=[CH:11][CH:10]=1
Reactant: COc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)cc1
Yield: 51.3 %

Procedure:
Reaction of oxalyl chloride (76 λL, 0.88 mmol) and benzoic acid 35 (226 mg, 0.58 mmol) with subsequent coupling to 3-pyridinylmethylamine (65 λL, 0.64 mmol) gave benzamide 36 (142 mg, 51%) as a white powder: mp (MeOH/EtOAc) 189-191° C.; 1H NMR δ 9.22 (t, J=5.8 Hz, 1H, CONH), 8.57 (d, J=1.7 Hz, 1H, H-2′), 8.47 (dd, J=4.7, 1.6 Hz, 1H, H-6′), 8.00 (dd, J=8.6, 1.8 Hz, 2H, H-2, H-6), 7.91 (dd, J=8.6, 1.8 Hz, 2H, H-3, H-5), 7.74 (ddd, J=8.0, 2.1, 1.4 Hz, 1H, H-4′), 7.70 (ddd, J=8.9, 3.0, 2.0 Hz, 2H, H-2″, H-6″), 7.36 (ddd, J=7.9, 4.7, 0.7 Hz, 1H, H-5′), 7.13 (ddd, J=8.9, 3.0, 2.0 Hz, 2H, H-3″, H-5″), 4.60 (s, 2H, CH2SO2), 4.51 (d, J=5.8 Hz, 2H, CH2N), 3.84 (s, 3H, OCH3), 2.13 (s, 3H, CH3); 13C NMR δ 165.5, 163.3, 157.9, 149.8, 148.9, 148.0, 135.3, 135.1, 134.8, 130.4 (2), 129.8, 128.8, 128.0 (2), 126.1, 125.3 (2), 123.4, 114.3 (2), 55.7, 53.0, 40.4, 9.6; MS m/z 477.6 (MH+, 100%). Anal. calcd for C25H23N3O5S.½CH3OH: C, 62.06; H, 5.11; N, 8.51. Found: C, 61.85; H, 4.88; N, 8.62%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O:12][C:13]([C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:40])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH2:25][CH2:24]3)=[N:19][N:18]2[CH:41]=1)=O)C>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:13]([C:15]2[N:16]=[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][N:26]([C:29](=[O:40])[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[C:36]([F:37])([F:39])[F:38])[CH2:27][CH2:28]4)=[N:19][N:18]3[CH:41]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Product: O=C(NCc1ccc(F)cc1)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Yield: 30 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to 4-fluorobenzylamine in place of isoamylamine to react with 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 30% yield (0.035 g). m.p. 205-207° C. 1H NMR (300 MHz, CDCl3) δ 8.18 (s, 1H), 7.77-7.5 (m, 5H), 7.38-7.27 (m, 3H), 7.03-6.94 (m, 2H), 6.9 (d, J=9.6 Hz, 1H), 4.58 (d, J=6 Hz, 2H), 4.06-3.94 (m, 1H), 3.93-3.81 (m, 1H), 3.69-3.54 (m, 2H), 3.52-3.42 (m, 2H), 3.36-3.27 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6, 163.7, 162.3, 160.5, 154.8, 137.8, 135.7, 134.2, 132.4, 129.6, 129.5, 126.9, 126.8, 126.7, 125.3, 124.4, 121.8, 118.4, 115.6, 115.3, 112.0, 46.2, 46.2, 45.6, 42.4, 41.2. MS (ES+) m/z 527.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]([OH:14])=[O:13].[CH3:15][Si](Cl)(C)C>CO>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]([O:14][CH3:15])=[O:13]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cccc2c1CCOC2C(=O)O
Solvent: CO
Product: COC(=O)C1OCCc2c(C)cccc21
Reaction time: 1.5 h

Procedure:
The mixture of 5-methylisochroman-1-carboxylic acid (1 g), methanol (20 ml) and trimethylsilylchloride (2 ml) was stirred for 1.5 hrs and volatiles evaporated. Separation method E yielded the title compound (0.5 g) as yellowish oil. Alternatively sulphuric acid can be used instead of trimethylsilylchloride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: CCCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: NCc1ccccc1
Product: CCCN(CC(=O)NCc1ccccc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-propylglycine and benzyl amine: MS (APCI) m/z 376 (M+1).
Reaction SMILES: CN1CCCC1=O.[C:8]([OH:12])(=[O:11])[CH2:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][C:26](=[N:56]O)[C:27]1[CH:55]=[CH:54][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][O:44][C:45]3[CH:53]=[CH:52][C:48]([C:49]([NH2:51])=[O:50])=[CH:47][CH:46]=3)[CH2:37][CH2:36]2)=[CH:29][CH:28]=1>O.C(Cl)(Cl)Cl>[NH2:56][C:26](=[N:25][O:11][C:8](=[O:12])[CH2:9][CH3:10])[C:27]1[CH:55]=[CH:54][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][O:44][C:45]3[CH:46]=[CH:47][C:48]([C:49]([NH2:51])=[O:50])=[CH:52][CH:53]=3)[CH2:37][CH2:36]2)=[CH:29][CH:28]=1
Reactant: CCC(=O)O
Reactant: NC(=O)c1ccc(OCCCN2CCC(CCCOc3ccc(C(N)=NO)cc3)CC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC(=O)ON=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=O)cc3)CC2)cc1
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To an N-methyl-2-pyrrolidone (10 mL) solution of 0.35 g of propionic acid was added 0.76 g of 1,1′-carbonyldiimidazole at room temperature, which was then stirred at the same temperature for one hour. An N-methyl-2-pyrrolidone (10 mL) solution of 1.00 g of 4-{3-[4-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=oxime was added to the mixture at room temperature, which was then stirred for 15 hours. The reaction mixture was added to a mixture of chloroform and water. The precipitate was collected by filtration and washed with ethyl acetate to provide 0.58 g of 4-{3-[4-(3-{4-[amino(propionyloxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=O-(propionyl)oxime as white solid form.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[CH:26]=[C:25]([CH3:27])[C:24](=S)[NH:23][C:22]3=[O:29])[CH2:13][CH2:12]2)[CH:8]=[C:7]([C:30]([F:33])([F:32])[F:31])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:34]1[CH2:37][CH2:36][CH2:35]1>C(O)C>[N:34]1([C:24]2[C:25]([CH3:27])=[CH:26][N:21]([CH2:20][CH2:19][CH2:18][CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:9]4[CH:8]=[C:7]([C:30]([F:33])([F:32])[F:31])[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:10]=4)[CH2:12][CH2:13]3)[C:22](=[O:29])[N:23]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: C1CNC1
Reactant: Cc1cn(CCCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)[nH]c1=S
Solvent: CCO
Product: Cc1cn(CCCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)nc1N1CCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A mixture of 1-{4-[4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-methyl-4-thioxo-3,4-dihydro-1H-pyrimidin-2-one from Example 2 (0.24 mmol, 0.12 g) and azetidine (5.81 mmol, 0.33 g) in ethanol (1.9 ml) was stirred at 60° C. in a microwave (Milestone Ethos 1600) for 1 hour. The reaction mixture was then concentrated and the resulting residue was purified by column chromatography on silica gel (eluent: CH2Cl2/methanol 95/5), resulting in 0.08 g of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[C:36]4[C:31](=[C:32]([CH3:39])[C:33]([O:37][CH3:38])=[CH:34][CH:35]=4)[N:30]=[C:29]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=4)[N:28]=3)[CH2:12]1)[C:8](=[O:47])[NH:7]2)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[F:46][C:42]1[CH:41]=[C:40]([C:29]2[N:28]=[C:27]([O:26][CH:11]3[CH2:10][CH:9]4[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]5[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]4=[O:47])[CH2:23]5)[CH2:12]3)[C:36]3[C:31](=[C:32]([CH3:39])[C:33]([O:37][CH3:38])=[CH:34][CH:35]=3)[N:30]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3nc(-c4cccc(F)c4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3cccc(F)c3)nc2c1C
Temperature: 50 °C
Yield: 82.6 %

Procedure:
The ethyl ester 158 (460 mg, 0.713 mmol) was dissolved in THF:MeOH:H2O (2:1:1, 100 mL) and LiOH (1M) (7.13 mL mg, 7.13 mmol) was added to the solution. The reaction was heated to 50° C. for 16 hrs. THF and MeOH was then removed by rotary evaporation and the remaining solution was acidified with 20 mL 10% citric acid (aq). The water phase was extracted with CHCl3 (3×50 mL) and the organic phase was washed with brine. The organic phase was dried with Na2SO4, filtered and concentrated by rotary evaporation. The product was obtained as a white solid (0.363 g, 82%), LRMS (M+H) 617.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27].O>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: NCCCO
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 2,4-dichloro-3-nitroquinoline (32 g, 130 mmol) in DMF (100 mL) was cooled to 0° C. Triethylamine (27.5 mL, 198 mmol) was added, and 3-amino-1-propanol (11.9 g, 158 mmol) was slowly added. The reaction was stirred for two hours at room temperature and cooled again to 0° C. Water (300 mL) was added, and the mixture was stirred for 30 minutes at 0° C. A solid was present and was isolated by filtration, washed with water, and dried overnight in a vacuum oven to provide 34.5 g of 3-[(2-chloro-3-nitroquinolin-4-yl)amino]propan-1-ol as a yellow and orange solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CO>[Br:13][CH2:2][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)=[O:3]
Reactant: CC(=O)c1ccc2c(c1)CCC2
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: O=C(CBr)c1ccc2c(c1)CCC2
Reaction time: 23 h
Yield: 94.2 %

Procedure:
To a solution of 5-acetylindan (500 mg, 3.1 mmol) in dichloromethane-methanol (2:1, 15 ml) was added tetrabutylammonium tribromide (1.64 g, 3.4 mmol) was added at room temperature. After 23 h, the mixture was concentrated and the residue was partitioned between diethyl ether (50 ml) and water (50 ml). The organic layer was separated and washed with water (50 ml), brine (50 ml), and dried (MgSO4). Removal of solvent gave 698 mg (56%) of the title compound as white solids.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:10]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[C:35]([OH:37])=[O:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[NH:12][C:13]([CH2:20][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[C:35]([OH:37])=[O:36])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncccc2Cl)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncccc2Cl)=NC1c1ccc(F)cc1Br
Yield: 40.4 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(3-chloropyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.81 g, 1.53 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.36 g, 40%). The compound was characterized by the following spectroscopic data: