Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[C:17]([CH2:18][CH2:19][O:20][CH3:21])=[N:16][O:15][N:14]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8].C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:27](=[O:28])[O:12][N:11]=[C:10]2[C:13]2[C:17]([CH2:18][CH2:19][O:20][CH3:21])=[N:16][O:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COCCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 70 °C
Yield: 100.3 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-N′-hydroxy-4-(2-methoxyethyl)-1,2,5-oxadiazole-3-carboximidamide (2.5 g, 7.9 mmol) was dissolved in THF (44 mL) followed by addition of N,N-carbonyldiimidazole (1.5 g, 9.5 mmol). The reaction was heated to 70° C. for 1.5 h. The reaction solution was concentrated and purified by silica gel chromatography (20% ethyl acetate/hexane) to give the desired product (2.7 g, 99%). MF═C13H10ClFN4O4; LCMS calculated for C13H11ClFN4O4 (M+H)+: m/z=341.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10]N=2)[CH:5]=[CH:4][N:3]=1.[ClH:14].O.[CH:16](O)(C)C>[Pd]>[ClH:14].[N:11]1[CH:12]=[CH:13][C:8]([CH:6]2[NH:7][C:2]([NH2:1])=[N:3][CH2:4][CH2:5]2)=[CH:16][CH:10]=1
Reactant: Nc1nccc(-c2ccncn2)n1
Reactant: CC(C)O
Agent: [Pd]
Agent: Cl
Solvent: O
Product: NC1=NCCC(c2ccncc2)N1
Yield: 27 %

Procedure:
To a solution of 5 g (29.2 mmoles) of 2-amino-4-(4-pyrimidyl)-pyrimidine (Journal of Medicinal Chemistry (1978), 21(7), 623-8) in 30 ml of a 6N solution of hydrochloric acid in isopropanol was added 5 ml of water and 0.2 g of palladium on carbon catalyst (10% wt/wt). The suspension was hydrogenated under 40 psi pressure at 50° C. temperature during 8 h. The catalyst was removed by filtration and the solvent evaporated under reduced pressure. Isopropanol was added and the resulting solution was refiltered and the solvent removed by evaporation under reduced pressure to give 2.0 g (27%) of compound as a white powder which was used as such.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>O1CCCC1>[C:36]([O:28][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[C:24]([F:25])([F:26])[F:27])(=[O:38])[CH3:37]
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (84.1 mg, 0.187 mmol) and triethylamine (33.8 μL, 0.242 mmol) in tetrahydrofuran (1.0 mL) was added acetyl chloride (15.9 μL, 0.224 mmol) at 0° C. After 1 h, triethylamine (18.2 μL, 0.131 mmol) and acetyl chloride (8.0 μL, 0.112, mmol) was added. After 1 h, the reaction mixture was quenched with water, concentrated in vacuo, and purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (93.2 mg, 0.187 mmol, 100%). Analytically pure material was obtained by recrystallization from ethyl acetate/hexane.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[CH3:25][CH:26]([O:28][CH2:29][C:30](O)=[O:31])[CH3:27].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C1COCC1.C(N(CC)CC)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:30](=[O:31])[CH2:29][O:28][CH:26]([CH3:27])[CH3:25])=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: CC(C)OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)OCC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (300 mg), (1-methylethoxy)acetic acid (119 mg), 1H-benzotriazol-1-ol (136 mg) and triethylamine (0.291 ml) in THF (4.2 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (192 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (384 mg).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:28]1[CH2:30][CH2:29]1)[O:5][C:6]1[CH:27]=[CH:26][C:9]2[C:10]3[N:14]([CH2:15][CH2:16][O:17][C:8]=2[CH:7]=1)[CH:13]=[C:12]([C:18]1[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=1)[N:11]=3.[NH3:32]>CO>[CH:28]1([CH:4]([O:5][C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH:13]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[N:11]=4)[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[C:3]([NH2:32])=[O:2])[CH2:29][CH2:30]1
Reactant: COC(=O)C(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C1CC1
Reactant: N
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(OC(C(N)=O)C3CC3)cc1OCC2
Yield: 50 %

Procedure:
A solution of cyclopropyl-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-acetic acid methyl ester (0.068 g, 0.16 mmol) and 7M ammonia in methanol (20 mL) was stirred at RT for 18 h then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in ethyl acetate) to give 549 (0.033 g, 50%). LCMS: RT=3.52 min, [M+H]+=409. 1H NMR 400 MHz (DMSO-d6): δ 8.28 (1 H, d, J=8.97 Hz), 7.89 (1 H, d, J=0.64 Hz), 7.85 (1 H, s), 7.54 (1 H, s), 7.25 (1 H, s), 6.73 (1 H, dd, J=8.99, 2.59 Hz), 6.49 (1 H, d, J=2.57 Hz), 5.89-5.88 (1 H, m), 4.52-4.44 (4 H, m), 3.97 (1 H, d, J=8.20 Hz), 1.48 (3 H, d, J=1.16 Hz), 1.46 (3 H, d, J=1.16 Hz), 1.26-1.25 (1 H, m), 0.61-0.54 (3 H, m), 0.44-0.43 (1 H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14]CC)=[O:13])[C:6]=2[CH:23]=1.[Br:24][C:25]1[C:26]([O:36][CH3:37])=[C:27]([C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:28]([OH:30])=O>>[Br:24][C:25]1[C:26]([O:36][CH3:37])=[C:27]([C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:23]=1)=[O:30]
Reactant: COc1ccc(Br)c(OC)c1C(=O)O
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Product: COc1ccc(Br)c(OC)c1C(=O)Nc1ccc2ncn(C(CC(=O)O)c3ccccc3)c2c1

Procedure:
Using the procedure of Preparation 21, the title compound (24 mg) was prepared from ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and 3-bromo-2,6-dimethoxybenzoic acid, and purified by RP-HPLC. [LCMS (Method A, Mobile Phase I) RT=4.43 min, MH+ 526].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:18][C:17](=O)[C:12]2[C:13]([CH3:16])=[CH:14][O:15][C:11]=2[CH2:10]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:18]/[C:17](=[N:24]\[NH:23][C:20]([NH2:22])=[NH:21])/[C:12]2[C:13]([CH3:16])=[CH:14][O:15][C:11]=2[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1coc2c1C(=O)CC(c1c(Cl)cccc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1c(Cl)cccc1Cl)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 119.6 %

Procedure:
To a mixture of 6-(2,6-dichlorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.42 g) and aminoguanidine hydrochloride (157 mg) were added ethanol (30 ml) and 6N hydrochloric acid (0.12 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2,6-dichlorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 44) (0.33 g).
Reaction SMILES: [CH2:1]([N:9]1[C@@H:17]2[C@@H:12]([C:13]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:14]=3[CH2:15][CH2:16]2)[CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:23]([N:25]([CH2:28]C)[CH2:26]C)C.CC(N(C)Cl)=[O:32].O>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:23][N:25]([CH3:28])[C:26](=[O:32])[O:22][C:18]1[C:14]2[CH2:15][CH2:16][C@H:17]3[C@H:12]([CH2:11][CH2:10][N:9]3[CH2:1][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:13]=2[CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)N(C)Cl
Reactant: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCc1ccccc1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)C(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCc1ccccc1
Yield: 92.2 %

Procedure:
2.69 g (0.00917 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-phenethyl-1H-benzo[e]indol-6-ol were dissolved in 90 ml of toluene. 0.974 g (1.34 ml, 0.00963 mol) of triethylamine and 112 mg (917 mmol, 0.1 eq.) of 4-dimethylaminopyridine were added thereto in succession and then 0.88 ml (0.00963 mol) of dimethyl chloroformamide were added dropwise thereto. The mixture was boiled under reflux for 5 hours, then cooled, poured into water and extracted with CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3 and NaCl solutions, dried with Na2SO4, filtered and concentrated. By chromatography of the residue over silica gel with dichloromethane/isopropyl alcohol and crystallization of the product in hexane/ethyl acetate there were obtained 3.08 g (92%) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-phenethyl-1H-benzo[e]indol-6-yl dimethylcarbamate as yellowish crystals with m.p. 98°-102°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH:19]([OH:21])[CH3:20]>O.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]([CH2:18][CH:19]([OH:21])[CH3:20])[N:4]=1
Reactant: COc1n[nH]cc1[N+](=O)[O-]
Reactant: CC(O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nn(CC(C)O)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 33.6 %

Procedure:
To a suspension of 3-methoxy-4-nitro-1H-pyrazole (2.00 g, 14.0 mmol, 1.00 eq) and cesium carbonate (13.7 g, 41.9 mmol, 3.0 eq) was added 1-bromo-2-propanol (2.70 mL, 22.4 mmol, 1.60 eq, 70% purity) and the reaction mixture was heated at 60° C. After 3.5 hr, an additional portion of 1-bromo-2-propanol (2.70 mL, 22.4 mmol, 1.60 eq, 70% purity) was added. After a further 12 hr, the reaction mixture was cooled to ambient temperature and diluted with water (100 mL) and EtOAc (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (4×50 mL). The combined organics were washed with water (50 mL) and brine (50 mL), dried (Na2SO4), concentrated, and purified via flash chromatography on silica gel eluting with a gradient of 0-50% EtOAc in heptane to give the title compound (945 mg, 34% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.09 (s, 1H), 4.32-4.22 (m, 1H), 4.06 (s, 3H), 4.05 (dd, J=5.0, 13.0 Hz, 1H), 3.87 (dd, J=8.0, 13.0 Hz, 1H), 2.60 (br. s., 1H), 1.29 (d, J=6.4 Hz, 3H). m/z (APCI+) for C7H12N3O4 201.9 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:28])[NH:15][C@@H:16]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[F:27])[CH2:17][CH2:18][OH:19])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29]COC(C)=O>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:28])[NH:15][C@@H:16]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[F:27])[CH2:17][CH2:18][O:19][CH3:29])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)N[C@H](CCO)c1cccc(Cl)c1F
Product: COCC[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)OC(C)(C)C)c1cccc(Cl)c1F

Procedure:
was prepared according to Scheme B9 (Step B) from (1R,3S,5R)-3-[(R)-1-(3-chloro-2-fluoro-phenyl)-3-hydroxy-propylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester. TLC, Rf (EtOAc)=0.82; MS (UPLC/MS): 427.4/429.4 [M+H]+, 471.4 [M+HCOO]−; tR (HPLC conditions a): 3.71 min.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:15]3[CH:16]=[C:17]([CH2:19][CH3:20])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([O:23]CC)=[O:22])[CH:11]=2)=[CH:7][CH:6]=1)=[O:4].O[Li].O>CO.O>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:15]3[CH:16]=[C:17]([CH2:19][CH3:20])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([OH:23])=[O:22])[CH:11]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CCOC(=O)c1cc(Oc2ccc(C(=O)N(C)C)cc2)c2cc(CC)oc2c1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CCc1cc2c(Oc3ccc(C(=O)N(C)C)cc3)cc(C(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A suspension of ethyl 4-{4-[(dimethylamino)carbonyl]phenoxy}-2-ethyl-1-benzofuran-6-carboxylate (400 mg, 1.0 mmol) and LiOH.H2O (200 mg, 4.7 mmol) in MeOH (20 mL) and water (2 mL) was stirred for 4 hr at room temperature. TLC (petroleum ether/EtOAc 4:1) indicated the reaction was complete. The reaction mixture was concentrated to dryness and poured into water (30 mL). The aqueous layer was acidified to pH˜2 with conc. HCl and extracted with EtOAc (20 mL×3). The organic layer was washed with brine (25 mL×2), dried over Na2SO4 and concentrated to afford the desired product (350 mg, 99%) as a yellow solid.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>C(OCC)C>[C:1]([NH:5][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A 1 L three-necked round-bottomed flask was charged with diethylether (500 mL), tert-butylamine (11.3 mL, 105 mmol), and triethylamine (14.9 mL, 105 mmol). To this vigorously stirred solution at 0° C. was slowly added pivaloyl chloride (8.9 mL, 100 mmol) and the resultant white slurry was stirred for 18 h at ambient temperature. This slurry was then filtered with a water aspirator pump and the volatile components of the filtrate were removed under reduced pressure. The resultant crystalline solid was sublimed at 55° C./0.05 Torr to afford LtBu,tBuH as white crystals (15.41 g, 98%): mp 116-118° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[O:4][N:3]=1.[CH2:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])[CH:12]([CH3:14])[CH3:13]>>[CH2:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:8](=[O:10])[CH2:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: Cc1cc(CC(=O)O)on1
Product: Cc1cc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)on1

Procedure:
Following General Procedure I above, and using (3-methyl-isoxazol-5-yl)acetic acid (CAS# 19668-85-0) and alanine iso-butyl ester (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:12]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[NH:19][S:20]([NH2:23])(=[O:22])=[O:21])#[N:11].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.O>[C:10]([C:12]1[CH:17]=[C:16]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:14][C:13]=1[NH:19][S:20]([NH2:23])(=[O:22])=[O:21])#[N:11]
Reactant: N#Cc1cc(Br)ccc1NS(N)(=O)=O
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(-c2ccccc2)ccc1NS(N)(=O)=O
Reaction time: 0.08 h

Procedure:
In a 2 mL microwave vial, phenyl boronic acid (75 mg, 0.6 mmol), N-(2-cyano-4-bromophenyl)sulfamide (Example 83b) (137 mg, 0.5 mmol), and potassium carbonate (400 mg, 1.5 mmol) were dissolved in DME/Water mixture (1.5 mL, DME/Water 4:1). The solution was degassed by bubbling N2 gas into the reaction solution for 5 minutes and Palladium tetrakis triphenylphospine (25 mg, 0.025 mmol) was added. The reaction was placed in a microwave reactor for 5 minutes at 150° C. The crude reaction was dissolved in water and washed with ethyl acetate. The aqueous solution was evaporated under vacuum to give N-(2-Cyano-4-phenylphenyl)sulfamide.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[N:18]=[C:17]2[CH2:19][CH2:20][CH2:21][C:16]2=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[N+:18]([O-:9])=[C:17]2[CH2:19][CH2:20][CH2:21][C:16]2=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc2c(n1)CCC2
Solvent: ClCCl
Product: [O-][n+]1c(Cl)ccc2c1CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of m-chloroperbenzoic acid 70% (520.9 mg, 2.113 mmol) in 5 mL of CH2Cl2 was added drop wise to a stirring solution of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (295 mg, 1.921 mmol) in 3 mL of CH2Cl2 and the resulting solution was allowed to stir at room temperature overnight. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 and the CH2Cl2 layer was separated. The aqueous phase was then extracted with CH2Cl2 (3×), and the combined organic extracts were washed with brine and then dried over anhydrous Na2SO4. After removing solvent at reduced pressure, the residue was purified by preparative TLC (eluting with 70% EtOAc/Hexane) to afford the title compound (I-1a).
Reaction SMILES: [CH2:1]([Mg]I)[CH3:2].[Br:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=O)=[C:8]([F:16])[CH:7]=1.[NH4+].[Cl-]>C(OCC)C.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[Br:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]2([OH:12])[CH2:2][CH2:1]2)=[C:8]([F:16])[CH:7]=1
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: CC[Mg]I
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(c2ccc(Br)cc2F)CC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 27.5 %

Procedure:
To a stirred solution of Ti(OiPr)4 (44.68 mL, 141.63 mmol, 1 eq) in diethyl ether (250 mL) was added freshly prepared ethyl magnesium iodide (212.44 mL, 424.89 mmol, 3 eq) in diethyl ether (220 mL) at −78° C. for 45 min. The reaction mixture was stirred for 90 min at −78° C., then methyl 4-bromo-2-fluorobenzoate (33.0 g, 141.63 mmol, 1.0 eq) was added and the mixture allowed to stir at RT for 16 h. Saturated aqueous NH4Cl (30 mL) was added and the mixture passed through celite pad. The ether layer was separated, washed with 1 N HCl (250 mL), brine (500 mL), water (750 mL), dried over MgSO4 and the solvent evaporated. The resulting residue was purified by CC using PE/EtOAc (19:1) as eluent to get 1-(4-bromo-2-fluorophenyl)cyclopropanol (9.01 g, 28%; TLC system: PE/EtOAc (9:1), Rf: 0.3).
Reaction SMILES: [C:1]([C:4](=[CH:10][CH2:11][CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:2][C:1]1[O:3][C:11]([CH3:12])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCC=C(C(C)=O)C(=O)OCC
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(C)oc1C
Yield: 83.2 %

Procedure:
A mixture of 3.41 g (0.02 mole) ethyl 2-acetyl-2-pentenoate and 3.57 g (0.02 mole) N-bromosuccinimide in 50 ml of carbon tetrachloride was heated at reflux for 2 hours. After cooling, the succinimide was removed by filtration and the solution concentrated in vacuo. Distillation gave 2.8 g (83%) of ethyl 2,5-dimethyl-3-furoate, bp 96 °-100° C. (18 mm).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12]O)=[CH:2]1.[Br:14]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1CCCCC1>O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][Br:14])=[CH:2]1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCc1c[nH]c2ccccc12
Solvent: C1CCCCC1
Solvent: C1COCCO1
Product: BrCCCc1c[nH]c2ccccc12
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a solution of 2 g (11.41 mmol) of 3-(1H-indol-3-yl)propanol in 40 ml of dioxane was added at room temperature 5.3 g (12.55 mmol) of dibromotriphenylphosphorane and the resulting solution was stirred during 18 h. An excess of cyclohexane was added and the resulting precipitate was filtered and discarded. The solvent was evaporated to dryness to give 2.7 g (99%) of product as an oil which was used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)[CH3:12]>>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH2:11][CH3:12])=[CH:15][C:16]=2[N+:21]([O-:23])=[O:22])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(F)nc1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Product: CCOc1ccc(NC(=O)c2ccc(F)nc2)c([N+](=O)[O-])c1

Procedure:
To the solution of KMnO4 (284 mg, 1.8 mmol) in H2O (50 mL) was added 2-fluoro-5-methylpyridine (100 mg, 0.9 mmol) at room temperature. The reaction mixture was then heated to 100° C. for 4 h. The resulting precipitate was filtered and discarded. The aqueous solution was washed with 3:2, hexane: ethyl acetate (2×20 mL), acidified with 2N HCl, then extracted with ethyl acetate (3×20 mL). The organic extracts were combined and washed with H2O and brine, dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to give 6-fluoronicotinic acid (30 mg) as a white solid. The title compound was prepared from 6-fluoronicotinic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 11.09 (bs, 1H), 8.88 (d, J=2.4, 1H), 8.81 (d, J=9.3, 1H), 8.42-8.35 (m, 1H), 7.74 (d, J=3.3, 1H), 7.33-7.29 (m, 1H), 7.13-7.10 (m, 1H), 4.11 (q, J=7.2, 2H), 1.47 (t, J=7.2, 3H).
Reaction SMILES: C(O[C@H]1C[C@@H](O)C=C1)(=O)C.[CH2:11]1[CH2:16][CH2:15][CH:14]([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23]CC2)CC1>C(Cl)Cl>[N:19]1([C:18]2[CH:11]=[CH:16][CH:15]=[CH:14][N:17]=2)[CH2:20][CH2:25][CH2:24][CH2:23]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(=O)O[C@@H]1C=C[C@H](O)C1
Solvent: ClCCl
Product: c1ccc(N2CCCC2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.1 mmol of the cyclopentenol, 3.1 mmol of DCC and 0.1 mmol of PP are dissolved in CH2Cl2 in a 100 ml flask fitted with a CaCl2 tube, 3.1 mmol of the carboxylic acid are added at 0°-5° C. with ice cooling, and the mixture is stirred at room temperature for 24 hours. The precipitated urea is filtered off, the solvent is removed by evaporation, and the crude product is recrystallized a number of times from ethanol.
Reaction SMILES: C([O-])=O.[NH4+].[N:5]([C@@:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=2)[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[OH:14])=[N+]=[N-]>CO.[Zn]>[NH2:5][C@@:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=2)[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[OH:14]
Reactant: [N-]=[N+]=N[C@@]1(c2cccc(Br)c2)CCOC[C@@H]1O
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: N[C@@]1(c2cccc(Br)c2)CCOC[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
Ammonium formate (16.9 g) and zinc (5.25 g) were added to a solution of (±)-(3R*,4R*)-4-azido-4-(3-bromophenyl)tetrahydropyran-3-ol (16.0 g) in methanol (250 mL). The mixture was stirred at room temperature overnight, and then the excess of methanol was evaporated under reduced pressure. The residue was diluted with an ammonium chloride solution, and the aqueous layer was extracted with chloroform. The organic layer was washed with an ammonium chloride solution and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (10.9 g).