Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(O)=O.[CH3:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH2:20][CH2:21][NH:22][CH2:23][C@H:24]2[O:28][C:27](=[O:29])[N:26]([C:30]3[CH:31]=[CH:32][C:33]4[S:34][CH2:35][C:36](=[O:40])[NH:37][C:38]=4[N:39]=3)[CH2:25]2)[C:10]1=[O:41]>CN(C=O)C.CCOCC>[CH3:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH2:20][CH2:21][N:22]([CH2:23][C@H:24]2[O:28][C:27](=[O:29])[N:26]([C:30]3[CH:31]=[CH:32][C:33]4[S:34][CH2:35][C:36](=[O:40])[NH:37][C:38]=4[N:39]=3)[CH2:25]2)[C:1](=[O:3])[CH3:2])[C:10]1=[O:41]
Reactant: Cn1c(=O)n(CCNC[C@@H]2CN(c3ccc4c(n3)NC(=O)CS4)C(=O)O2)c(=O)c2ccccc21
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O=CO
Product: CC(=O)N(CCn1c(=O)c2ccccc2n(C)c1=O)C[C@@H]1CN(c2ccc3c(n2)NC(=O)CS3)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
Acetyl chloride (0.009 ml) was added to a solution of the compound of Example 55 (56 mg) and TEA (0.017 ml) in DMF (2 ml). The mixture was stirred at rt overnight. The reaction mixture was partitioned between water and EA/MeOH 9:1. The aq. layer was extracted with EA/MeOH 9:1 and the combined org. layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting material was purified by CC (EA/MeOH 19:1) and afforded, after stirring in ether, a slightly yellow solid (175 mg; 42% yield).
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1.[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)=[O:28]
Reactant: c1cc(-c2noc(C3CCNCC3)n2)ccn1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)N1CCC(c2nc(-c3ccncc3)no2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of pyridine (18 μl, 0.22 mmol) and 4-(5-piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine (Example 51, 50 mg, 022 mmol) in CH2Cl2 (4 ml) was treated with 3,3-dimethylbutanoyl chloride (58 mg, 0.43 mmol). The reaction was stirred at rt for 18 h then quenched with saturated aqueous NaHCO3 (1 ml). The organic phase was separated, evaporated and the residue purified by flash chromatography (IH-EtOAc, 1:1 to 0:1) to afford the title compound: RT=3.1 min, m/z (ES+)=329.3 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([O-:13])=[O:12]>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N+:9]([O-:10])=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cccc(NO)c1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(C=[N+]([O-])c2cccc(CO)c2)c1
Yield: 69.8 %

Procedure:
The reaction of hydroxylamine 91 (1.36 g, 10 mmol) with 3-nitrobenzaldehyde (57) (1.51 g, 10 mmol) afforded, after workup, a light yellow solid. The crude product was recrystallized from acetone/petroleum ether to obtain 1.90 g (6.98 mmol, 70%) of 92 as a pale yellow crystalline solid: mp 177°-179° C.; IR (Nujol) 3220, 1570, 1530, 1350, 1040, 800 cm-1 ; 1H NMR (Me2SO-d6) δ 4.58 (d, J=5.6 Hz, 2H), 5.39 (t, J=4.8, 2H), 7.45-9.53 (m, 9H); 13C NMR (Me2SO-d6) δ 62.91, 119.87, 120.25, 122.98, 125.19, 128.68, 129.42, 130.47, 132.40, 132.94, 135.30, 144.73, 148.26, 148.73. Anal. Calcd for C14H12N2O4 : C, 61.76; H, 4.41. Found: C, 61.99; H, 4.52.
Reaction SMILES: C(O[C@@H](C1C(C)=CC2N=C(C3C=CC4N(C)N=NC=4C=3)SC=2C=1C1C=CC(Cl)=CC=1)C(O)=O)(C)(C)C.[C:37]([O:41][C@@H:42]([C:48]1[C:67]([CH3:68])=[CH:66][C:51]2[N:52]=[C:53]([C:55]3[CH:60]=[CH:59][N:58]4[C:61]([CH3:65])=[N:62][C:63]([CH3:64])=[C:57]4[CH:56]=3)[S:54][C:50]=2[C:49]=1[C:69]1[CH:74]=[CH:73][C:72]([Cl:75])=[CH:71][CH:70]=1)[C:43]([O:45]CC)=[O:44])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C@@H:42]([C:48]1[C:67]([CH3:68])=[CH:66][C:51]2[N:52]=[C:53]([C:55]3[CH:60]=[CH:59][N:58]4[C:61]([CH3:65])=[N:62][C:63]([CH3:64])=[C:57]4[CH:56]=3)[S:54][C:50]=2[C:49]=1[C:69]1[CH:70]=[CH:71][C:72]([Cl:75])=[CH:73][CH:74]=1)[C:43]([OH:45])=[O:44])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccn4c(C)nc(C)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: Cc1cc2nc(-c3ccc4c(c3)nnn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-c3ccn4c(C)nc(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
Prepared in a manner similar to (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)benzo[d]thiazol-6-yl)acetic acid, but using (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethylimidazo[1,5-a]pyridin-7-yl)-5-methylbenzo[d]thiazol-6-yl)acetate instead of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)benzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C29H29ClN3O3S: 534.1 (M+H+); Found: 534.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.33 (s, 1H), 8.28 (d, J=7.7 Hz, 1H), 7.87 (s, 1H), 7.76-7.65 (m, 2H), 7.60 (d, J=6.4 Hz, 3H), 5.27 (s, 1H), 2.86 (s, 3H), 2.65 (s, 3H), 2.62 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]12[CH2:19][C:18](=[O:20])[CH:17]=[C:6]1[C:7]1[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10]([O:15]C)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:5]12[CH2:19][C:18](=[O:20])[CH:17]=[C:6]1[C:7]1[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10]([OH:15])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCc3cc(OC)ccc3C1=CC(=O)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC12CCc3cc(O)ccc3C1=CC(=O)C2
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of 3a-butyl-7-methoxy-3,3a,4,5-tetrahydro-2H-cyclopenta[α]naphthalen-2-one (598 mg, 2.2 mmol) in anhydrous CH2Cl2 (22 mL) was placed under a N2 atmosphere, cooled in a dry ice-acetone bath (−78° C.), and stirred while 1M BBr3 in CH2Cl2 (6.6 mL, 6.6 mmol) was added dropwise over 4 minutes. After stirring at −78° C. for 5 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 160 minutes. Additional 1M BBr3 in CH2Cl2 (1.4 mL) was added and the mixture was stirred at room temperature for 60 minutes. The mixture was diluted with EtOAc, washed with 1N HCl, 5% NaHCO3, water, and brine, dried over MgSO4, filtered, and evaporated under vacuum to give an orange-red solid. The crude product was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40S (4×7 cm) silica gel column, eluting successively with 5:1, 2:1, and 1:1 hexane-EtOAc followed by EtOAc. The product-containing fractions were evaporated under vacuum to afford 3a-butyl-7-hydroxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as a solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:9][C:8](=O)[CH2:7][CH2:6][CH:5]([C:11]2[N:12]([CH3:19])[N:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[O:4]1)[CH3:2].[CH3:20][C:21]([S@:24]([NH2:26])=[O:25])([CH3:23])[CH3:22].[BH4-].[Na+]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH2:1]([CH:3]1[CH2:9][CH:8]([NH:26][S:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25])[CH2:7][CH2:6][CH:5]([C:11]2[N:12]([CH3:19])[N:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[O:4]1)[CH3:2]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CCC1CC(=O)CCC(c2c([N+](=O)[O-])cnn2C)O1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCC1CC(NS(=O)C(C)(C)C)CCC(c2c([N+](=O)[O-])cnn2C)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-ethyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-one (120 mg, 0.45 mmol) in THF (3 mL) was added (R)-2-methylpropane-2-sulfinamide (70 mg, 0.58 mmol) followed by titanium(IV) ethoxide (0.30 mL, 1.12 mmol). The reaction mixture was heated at reflux for 4 hr then allowed to cool to room temperature. The crude solution was added dropwise to a solution of sodium borohydride (69 mg, 1.80 mmol) in THF (3 mL) at −60° C. The reaction mixture was warmed to 0° C., quenched with MeOH (3 mL) and brine (50 mL), and stirred at room temperature for 18 hr. The mixture was filtered through Celite® washing with EtOAc (200 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (150 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-10% MeOH/DCM) gave N-(2-ethyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl)-2-methyl-propane-2-sulfinamide as a mixture of diastereomers (ratio 5:2) as a colourless solid (118 mg, 71% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.03 and 8.02 (2s, 1H), 5.60-5.51 (m, 1H), 4.08 and 4.06 (2s, 3H), 3.83-3.66 (m, 2H), 3.62-3.50 (m, 1H), 3.22 and 3.15 (d, J=6.2 and 4.0 Hz, 1H), 2.11-1.96 (m, 4H), 1.76 (s, 1H), 1.63-1.54 (m, 2H), 1.28-1.15 (m, 9H), 0.91 (td, J=7.4, 2.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][C:8]([O:10]CC)=[O:9])=[O:5].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:16]=[C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NCC(=O)OCC)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NCC(=O)O)c(F)c1

Procedure:
A mixture of 26.4 g. of ethyl N-[2-fluoro-4-(hexadecylamino)benzoyl]glycinate, 110 ml. of 1 N sodium hydroxide solution; and 100 ml. of ethanol is stirred at ambient temperature for 2 hours and then partially evaporated. The aqueous solution is washed with diethyl ether, acidified with 6 N hydrochloric acid, and filtered. The white solid is dried in vacuo and recrystallized from acetone to yield N-[2-fluoro-4-(hexadecylamino)benzoyl]glycine.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH2:12][C:13]([OH:15])=O)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:16]([C@H:23]1[CH2:27][NH:26][C@H:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:33][CH:32]=2)=[O:29])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C@H:23]1[CH2:27][N:26]([C:13](=[O:15])[CH2:12][C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]=2[CH3:2])[C@H:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)=[CH:33][CH:32]=2)=[O:29])[CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: Cc1[nH]c2ccccc2c1CC(=O)O
Agent: Cl
Product: Cc1[nH]c2ccccc2c1CC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 36.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2-methyl-1H-indol-3-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 37, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(2-methyl-1H-indol-3-yl)acetyl)pyrrolidine-2-carboxamide (12.2 mg, 36.2%). 1H-NMR (400 MHz, DMSO-D6): σ 10.78 (s, 1H), 9.91 (s, 1H), 7.53 (m, 2H), 7.41 (d, 1H), 7.15 (m, 8H), 6.94 (m, 6H), 4.59 (m, 1H), 3.67 (m, 2H), 3.54 (m, 1H), 3.33 (m, 1H), 3.19 (t, 1H), 2.87 (s, 2H), 2.60 (m, 2H), 2.24 (s, 3H). MS (EI) for C35H32FN3O3: 562.8 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23](OC)=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[Cl:22])[CH2:12][CH2:13][N:7]21.[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=4[Cl:22])[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH2:23][OH:24])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCN3c1c(C)cc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(Cl)c1N1CCn2c1nc1c(Cl)ccc(CO)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.3 %

Procedure:
To a solution of methyl 8-chloro-1-(2,4-dichloro-6-methylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole-5-carboxylate (200 mg, 0.487 mmol) in tetrahydrofuran (10 mL) was added lithium tetrahydroborate (53 mg, 2.43 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 days. Aqueous ammonium chloride was added to the reaction mixture at 0° C. and the mixture was concentrated in vacuo. The precipitated solid was collected by filtration, washed with water, 2-propanol and diisopropyl ether to give the title compound (165.9 mg, 0.43 mmol, 89%) as a colorless solid.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])=[N:13][C:12]=1[CH2:23][CH2:24][CH3:25])=[O:10].[CH3:26][O:27][CH2:28][CH2:29][N:30]([CH3:38])[C:31]1[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=1>>[CH3:26][O:27][CH2:28][CH2:29][N:30]([CH3:38])[C:31]1[N:32]=[CH:33][C:34]([NH:37][C:9]([C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:13][C:12]=2[CH2:23][CH2:24][CH3:25])=[O:10])=[CH:35][N:36]=1
Reactant: COCCN(C)c1ncc(N)cn1
Reactant: CCCc1nc(-c2ccccc2Br)oc1C(=O)ON1C(=O)CCC1=O
Product: CCCc1nc(-c2ccccc2Br)oc1C(=O)Nc1cnc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 50 above, 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was prepared from 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd for C21H24BrN5O3 (m/e) 474, obsd 475 (M+H).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:5]([C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4]1.[OH:19][CH2:20][CH2:21][NH:22][CH3:23].Cl>C1(C)C(C)=CC=CC=1.CCOCC.C(O)(C)C>[OH:19][CH2:20][CH2:21][N:22]([CH2:2][C:3]1[C:4]2[CH:5]3[CH2:6][CH2:7][CH:8]([C:13]4[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:9]=2[CH:10]=[CH:11][CH:12]=1)[CH3:23]
Reactant: CNCCO
Reactant: ClCC1CC2c3ccccc3C1c1ccccc12
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CC(C)O
Solvent: CCOCC
Product: CN(CCO)Cc1cccc2c1C1CCC2c2ccccc21
Temperature: 25 °C

Procedure:
11-Chloromethyl-9,10-dihydro-9,10-ethanoanthracene (45 gm) was combined with 2-hydroxyethylmethylamine (45 gm) in xylene (300 ml) and the mixture heated to reflux for 17 days. The mixture was cooled to room temperature and extracted with 1 N hydrochloric acid (3×100 ml). The combined acid solutions were washed with ether (100 ml), made basic with the addition of 50% sodium hydroxide solution and the mixture extracted with ether (3×100 ml). The combined ether solutions were dried over magnesium sulfate and the ether removed on a rotary evaporator. The residue was distilled (220° C. at 7 mm Hg) to yield a colorless oil. The material was dissolved in ether (200 ml) and treated with 6 N hydrochloric acid in isopropyl alcohol (2 ml). The resulting precipitate was filtered and washed with ether to provide the product. Analytical data are reported in Table I.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][C:8](=[O:41])[C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([C:16]2[CH2:20][CH2:19][CH2:18][C:17]=2[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[F:40])[CH:10]=1)[CH3:6]>>[CH2:5]([O:7][C:8](=[O:41])[C:9]1[C:14]([NH:15][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=[C:11]([C:16]2[CH2:20][CH2:19][CH2:18][C:17]=2[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[F:40])[CH:10]=1)[CH3:6]
Reactant: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3F)CCC2)ccc1N
Reactant: CC(=O)Cl
Product: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3F)CCC2)ccc1NC(C)=O

Procedure:
Prepared by general procedure E but using acetyl chloride instead of propionyl chloride and (3-{2-[5-trifluoromethyl-2-(2,4-difluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoic acid ethyl ester instead of 5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acid methyl ester.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7].C(O)C.[BH4-].[Na+]>O>[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:6]([OH:7])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CCCCCCC(=O)c1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCCCC(O)c1ccco1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 85g (0.337 mol) of ethyl 7-(2-furoyl)heptanoate (Example 3) in 500 ml of abs. ethanol is added 12.75g (0.337 mol) of sodium borohydride in small portions during 20 min. at 20°-35° C. The mixture is stirred at ambient temperature for 3.5 hr., poured into 2.5 l of water, and extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give a pale yellow oil (85.8g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:11]1([C@H:17]([NH2:19])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OC(C)C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:9])[CH2:10][NH:19][C@@H:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:18])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: Brc1ccc([C@H]2CO2)cc1
Solvent: CC(C)OC(C)C
Product: C[C@@H](NC[C@@H](O)c1ccc(Br)cc1)c1ccccc1
Temperature: 80 °C
Yield: 64.4 %

Procedure:
A mixture of (2S)-2-(4-bromophenyl)oxirane (55.0 g) and (R)-1-phenylethylamine (98.2g, 810 mmol) was heated at 80° C. for 6 hours. Addition of isopropyl ether (200 ml) to the residue after distillation of excess phenethylamine and successive filtration yielded (1S)-1-(4-bromophenyl)-2-((1R)-1-phenylethylamino)ethanol (57.0 g) as white crystals. Further crystallization was performed by the concentration of the filtrate in vacuo and cooling the residue in refrigerator. Filtration of the crystal with isopropyl ether (30 ml) yielded additional title compound (5.60 g) as crystals (72.4% yield, 3 steps).
Reaction SMILES: [NH2:1][C:2]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[CH:19][C:18]([F:30])=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.CCN(C(C)C)C(C)C.[S:40](Cl)(=[O:43])(=[O:42])[NH2:41].[Cl-].[NH4+]>C(Cl)Cl>[F:30][C:18]1[CH:19]=[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[C:2]([NH:1][S:40](=[O:43])(=[O:42])[NH2:41])=[C:3]([CH:17]=1)[O:4][C:5]1[CH:6]=[C:7]([NH:11][S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])[CH:8]=[CH:9][CH:10]=1
Reactant: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2N)c1
Reactant: NS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 34.7 %

Procedure:
244 mg N-(3-{2-amino-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}-phenyl)ethanesulfonamide (0.448 mmol, 1 eq.) were dissolved in 10 mL DCM, treated with 0.781 mL DIPEA (4.5 mmol, 10 eq.) and 388 mg sulfamoyl chloride (3.36 mmol, 7.5 eq.) and the resulting solution stirred at rt for four days. The reaction mixture was portioned between ammonium chloride solution and DCM, the aqueous layer reextracted with DCM, the combined organic layers dried, filtered and concentrated in vacuo. Flash column chromatography provided 97 mg of the target compound (35% yield). A second product fraction was further purified by thick layer chromatography (hexane/ethyl acetate 1:1 as eluent) yielding additional 67 mg of the target compound (22% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:23])=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=2)=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:23][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:7][C:6]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1)=[O:9]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cc(N)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(NCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
A solution of ethyl (4-{[(5-amino-2-chlorophenyl)carbonyl]amino}phenyl)acetate (300 mg, 0.90 mmol) in DMF (5 ml) was treated with potassium carbonate (152 mg, 1.1 mmol, 1.2 eq) and benzyl bromide (215 ul, 1.8 mmol, 2 eq) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate (150 ml) and washed with water (2×80 ml) and brine (80 ml). Organic layer dried over magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography (Biotage SP4, 40 g silica column) eluting with 0-25% ethyl acetate in hexanes to afford the title compound as a white solid (90 mg). MS (ES+) m/z 423 [M+H]+ (C24H2335ClN2O3). 1H-NMR (400 MHz, d6-DMSO) δ 1.18 (3H, t, J 7.2), 3.61 (2H, s), 4.07 (2H, q, J 7.2), 4.30 (2H, d, J 6), 6.62-7.65 (13H, m).
Reaction SMILES: C[O:2][CH:3]1[CH:7]=[CH:6][CH:5](OC)[O:4]1.CO.O.NN.N1[CH:20]=[CH:19][CH:18]=[CH:17]N=1>O.C(O)(=O)C>[CH3:17][C:18]1[O:2][C:3]([CH2:7][CH2:6][CH2:5][OH:4])=[CH:20][CH:19]=1
Reactant: COC1C=CC(OC)O1
Reactant: c1ccnnc1
Agent: NN
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1ccc(CCCO)o1
Temperature: 25 °C

Procedure:
Under nitrogen with stirring 5-methyl-2- 3- 2, 6-dimethyl-4-(2-methyl-tetrazol-5-yl) phenoxy!-propyl!-2,5-dimethoxy-2,5-dihydrofuran (820 mg, 1.8 mmol), 0.8 mL of methanol, and 1.5 mL of 1% aqueous acetic acid solution were combined at room temperature, refluxed for 10 min, and then cooled to room temperature. To the above solution was added hydrazine hydrate (0.26 mL) over a 2 min period, and the mixture was allowed to reflux for 1 h, and cooled to room temperature. The mixture was diluted with water, the aqueous layer was extracted with methylene chloride, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to afford 180 mg (29 %) of 3,methyl-6- 3- 2,6-dimethyl-4-(2-methyltetrazol-5-yl)-phenoxy!propyl !-pyridazine (Formula I; R1, R2 =3,5-dimethyl, R3 =6-methyl, R4 =hydrogen, R5 =2-methyltetrazol-5-yl), m.p. 114°-115° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])C.Cl>[OH-].[Na+]>[O:22]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:17]1[C:18]([CH2:19][O:20][CH3:21])=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8][C:9]=1[NH:10]2)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(Oc4ccccc4)c3c2c1COC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COCc1c(C(=O)O)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101 %

Procedure:
7.7 g of 5-phenoxy-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester is heated with 70 ml of 2N sodium hydroxide solution until a clear solution is produced (2 hours). Then, it is carefully acidified with 4N hydrochloric acid and afterwards stirred for 15 minutes at room temperature. After suctioning off and drying over P2O5 and KOH at 80° C., 7.2 g (100% of theory) of 5-phenoxy-4-methoxymethyl-beta-carboline-3-carboxylic acid is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][N:3]=1.[CH2:8]=[O:9]>>[CH3:7][N:6]1[C:2]([CH3:1])=[N:3][N:4]=[C:5]1[CH2:8][OH:9]
Reactant: Cc1nncn1C
Reactant: C=O
Product: Cc1nnc(CO)n1C
Temperature: 90 °C
Yield: 82 %

Procedure:
A mixture of 3,4-dimethyl-4H-1,2,4-triazole (2.3 g, 23.7 mmol) and formalin (5 mL) was heated to 90° C. overnight. The mixture was concentrated to give crude product. The crude product was purified by silica gel chromatography (dichloromethane/methanol=200:1 to 15:1) to give the title compound (2.48 g, yield 82%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm); 2.31 (s, 3H), 3.52 (s, 3H), 4.52-4.54 (d, J=5.2 Hz, 2H), 5.49-5.51 (t, J=5.2 Hz, 1H). LC-MS (ESI) m/z: 128 (M+1)+