Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[CH2:5][C:6]1([OH:25])[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7]1)C.NN.Cl.[N:30]([O-])=O.[Na+].[CH3:34][OH:35]>C(Cl)(Cl)Cl.C1C=CC=CC=1>[O:35]=[C:34]1[NH:30][CH2:5][C:6]2([CH2:7][C@@H:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10]2)[O:25]1
Reactant: O=N[O-]
Reactant: CO
Reactant: CCOC(=O)CC1(O)C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)[C@@H]1CC2(CNC(=O)O2)CN1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
(2S)-di-tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxypyrrolidine-1,2-dicarboxylate (A1) (1.58 g, 4.42 mmol, 1 eq.) was diluted in methanol (6 mL). To this mixture, hydrazine (0.417 mL, 13.26 mmol, 3 eq.) was added. The reaction was stirred at room temp. overnight then concentrated. To the residue, 0.5 N HCl (22.1 mL, 11.05 mmol, 2.5 eq.) was added and the mixture was sonnicated until the residue dissolved in the acid. The solution was cooled in an icewater bath. A 1.0 M solution of NaNO2 (5.3 mL, 5.3 mmol, 1.2 eq.) was added slowly and stirred for 15 min. A 1:1 benzene:chloroform mixture was added, the organic layer was separated and added slowly to refluxing benzene (2×). The reaction was refluxed for 1 hr then concentrated. Chromatography using DCM and 20% MeOH in DCM gave 0.978 g (2.86 mmol) of (8S)-di-tert-butyl 2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-7,8-dicarboxylate (B1) as a 4:1 (5S,8S:5S,8R) mixture of the diastereomers. 1H NMR (300 MHz, DMSO) 7.63 (m, 1H), 4.29-4.09 (m, 1H), 3.65-3.39 (m, 4H), 2.5-2.0 (m, 2H), 1.43-1.18 (m, 18H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][C:13]3[N:17]=[CH:18][C:19]([C:21]4[O:25][N:24]=[C:23]([C:26](Cl)=[O:27])[N:22]=4)=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:38]1([NH2:43])[CH2:42][CH2:41][CH2:40][CH2:39]1.C([O-])(O)=O.[Na+]>ClCCCl>[CH:38]1([NH:43][C:26]([C:23]2[N:22]=[C:21]([C:19]3[CH:18]=[N:17][C:13]4[O:14][CH2:15][CH2:16][N:11]([S:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)(=[O:10])=[O:9])[C:12]=4[CH:20]=3)[O:25][N:24]=2)=[O:27])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(Cl)c1noc(-c2cnc3c(c2)N(S(=O)(=O)c2ccc(F)cc2)CCO3)n1
Reactant: NC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(NC1CCCC1)c1noc(-c2cnc3c(c2)N(S(=O)(=O)c2ccc(F)cc2)CCO3)n1
Reaction time: 72 h
Yield: 32.7 %

Procedure:
To a suspension of 5-(1-(4-fluorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-1,2,4-oxadiazole-3-carbonyl chloride (21 mg, 0.049 mmol) in DCE (5 mL) was added DIPEA (21 μL, 120 μmol) to form a clear solution. To that solution was added cyclopentyl amine (40 μL, 0.099 mmol) and saturated aqueous NaHCO3 (1 mL). The reaction was stirred for 72 hours. LCMS analysis of the reaction mixture indicated consumption of starting material. The reaction was extracted with DCM (3×2 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography to provide N-cyclopentyl-5-(1-(4-fluorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-1,2,4-oxadiazole-3-carboxamide (7.7 mg, 0.016 mmol, 32.2%) as a white solid. LCMS (+ESI) m/z=474.1 [M+H]+; 1H-NMR (CDCl3) δ 8.90 (d, 1H), 8.87 (d, 1H), 7.75 (m, 2H), 7.21 (m, 2H), 6.97 (m, 1H), 4.47 (m, 1H), 4.09 (dd, 2H), 3.92 (dd, 2H), 2.13 (m, 2H), 1.82-1.52 (m, 6H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)(C)C)(C)C)[CH:46]([O:58][CH:59]([CH3:61])[CH3:60])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2]>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:58][CH:59]([CH3:60])[CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:66])[CH3:67])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC(C)C)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 69.1 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(tert-butyldimethyl-siloxy)-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos18-ene-2,3,10,16-tetraone (130 mg) in acetonitrile (4 ml) was added a solution of 2% HF in aqueous acetonitrile (70 μl), and the mixture stirred at room temperature. After 5.5 hours, the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate solution and the organic phase dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol) gave the title compound (80 mg).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17](=[O:24])[NH:16][C:15]3[CH:25]=[CH:26][CH:27]=[N:28][C:14]2=3)=[O:12])[CH2:6][CH2:5]1.S(Cl)([Cl:31])=O>C(Cl)(Cl)Cl>[ClH:31].[ClH:31].[Cl:31][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17](=[O:24])[NH:16][C:15]3[CH:25]=[CH:26][CH:27]=[N:28][C:14]2=3)=[O:12])[CH2:6][CH2:5]1
Reactant: O=C1Nc2cccnc2N(C(=O)CN2CCN(CCO)CC2)c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=C1Nc2cccnc2N(C(=O)CN2CCN(CCCl)CC2)c2ccccc21
Yield: 25 %

Procedure:
Compound 25 (110 mg, 0.22 mmol) was refluxed for 1 h with thionyl chloride (1 mL) in chloroform (4 mL). The volatile material was removed in vacuo, and the residue was basified with aqueous Na2CO3 (pH 10) and washed immediately with ether to completely remove the non polar impurity (TLC CHCl3 /CH3OH/NH4OH: 9/1/0.1, Rf 0.4). The product was extracted into CHCl3 from the cold aqueous phase and the combined CHCl3 layers were concentrated in vacuo and acidified using ether/HCl. The precipitate was dried in vacuo to yield 29 mg of 26 (25%) as a white solid: mp 188°-190° C.; 1H NMR (D20, HCl salt) δ 3.00-4.00 (m, 14 H), 7.50-7.70 (m, 3 H), 7.70-7.90 (m, 3 H), 8.40 (s, 1 H); MS (CI/NH3) m/e 400 (MH+), 212 (base), 364, 338. FAB mass spectroscopy showed peaks at mass 438 (M+ K), 422 (M+ Na), 400 (M+ H), 364, 329, 307, 289, 211, 154, and 136. The salt was stable upon storage at -20 ° C. for at least 6 months.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:18](=[O:19])[N:17]([CH2:20]C=C)[C:16](=[O:23])[C:15]([CH3:24])=[N:14]1.BrCC=C.IC.ClC1C(OC(C)C)=CC(N2C(=O)N(CCCF)C(=O)C=N2)=C(F)C=1.ClC1C(OC(C)C)=CC(N2C(=O)NC(=O)C=N2)=C(F)C=1.ClCCCF>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:18](=[O:19])[N:17]([CH3:20])[C:16](=[O:23])[C:15]([CH3:24])=[N:14]1
Reactant: C=CCn1c(=O)c(C)nn(-c2cc(OC(C)C)c(Cl)cc2Cl)c1=O
Agent: CC(C)Oc1cc(-n2ncc(=O)[nH]c2=O)c(F)cc1Cl
Agent: CC(C)Oc1cc(-n2ncc(=O)n(CCCF)c2=O)c(F)cc1Cl
Agent: FCCCCl
Solvent: C=CCBr
Solvent: CI
Product: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2Cl)c(=O)n(C)c1=O

Procedure:
Compound 16, 2-[2,4-dichloro-5-(1-methylethoxy)phenyl]-6-methyl-4-(2-propenyl)-1,2,4-triazine-3,5(2H,4H)-dione, was also prepared by the method of Example IV using 3-bromo-1-propene rather than iodomethane in Step D. Similarly, Compound 50, 2-[4-chloro-2-fluoro-5-(1-methylethoxy)phenyl]-4-(3-fluoropropyl)-1,2,4-triazine-3,5(2H,4H)-dione, was prepared by treating Compound 17 (Example II D) with 1-chloro-3-fluoropropane.
Reaction SMILES: [F:1][CH2:2][C:3]([NH2:11])([CH2:6][CH2:7][CH2:8][O:9][CH3:10])[C:4]#[N:5].C(N(CC)CC)C.[C:19](Cl)(=[O:29])[C:20]1[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:22](Cl)=[O:23]>C(Cl)Cl>[F:1][CH2:2][C:3]([N:11]1[C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]2[C:19]1=[O:29])([CH2:6][CH2:7][CH2:8][O:9][CH3:10])[C:4]#[N:5]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: COCCCC(N)(C#N)CF
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a solution of 2-fluoromethyl-2-amino-5-methoxy-valeronitrile (1.62 g, 10 mmol) and triethylamine (2.02 g, 20 mmol) in methylene chloride (30 mL), cooled to -20° C., is added phthaloyldichloride (2.03 g, 10 mmol) in methylene chloride (10 mL). The mixture is allowed to warm up to room temperature overnight. After washing with water, 1 N HCl, water again, and drying (Na2SO4), the solvent is removed under reduced pressure to give 2.4 g (83%) of crude material. This is purified by chromatography on silica (ethyl acetate/petroleum ether 3:7).
Reaction SMILES: [CH:1]([Mg]Br)=[CH:2][CH2:3][CH3:4].[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH3:18])=[C:12]([CH2:14][CH:15]=[O:16])[CH:13]=1.[Cl-].[NH4+]>C1COCC1>[CH3:18][O:17][C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:13][C:12]=1[CH2:14][CH:15]([OH:16])[CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: CCC=C[Mg]Br
Reactant: COc1ccc(F)cc1CC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(O)Cc1cc(F)ccc1OC
Yield: 75.3 %

Procedure:
To a solution of 1-butenylmagnesium bromide (0.5 M in THF, 9 mL, 4.5 mmol) at 0° C. was added a solution of 5-fluoro-2-methoxyphenylacetaldehyde (635 mg, 3.8 mmol) in THF (10 mL) dropwise for 15 min. Then the reaction mixture was poured in to a solution of saturated ammonium chloride (40 mL) in a separatory funnel. The organics were extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine (50 mL) and dried over sodium sulfate. The solvent was removed in vacuo and crude product thus obtained was purified by flash column chromatography (12.5% EtOAc in hexane, Rf=0.18) to give the product as an oil (642 mg, 74%).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]([C:19](=[O:34])[C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH3:18])[CH:5]=1.O.O[Li].O.Cl>O1CCOCC1.CCOC(C)=O>[F:33][C:30]([F:31])([F:32])[C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=1)[C:19]([N:17]([CH3:18])[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([OH:35])=[O:2])=[O:34]
Reactant: COC(=O)c1ccc(C)c(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)O)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-{3-[(3,5-bis-trifluoromethyl-benzoyl)-methyl-amino]-pyridin-4-yl}-4-methyl-benzoic acid methyl ester (33 mg, 66.5 μmol, example 83) in dioxane (1 mL) was added water (2 mL) and LiOH.H2O (3.49 mg, 83.1 μmol). The reaction mixture was stirred at room temperature for 2 hours and then poured on 20 mL 1M aqueous HCl and 20 mL EtOAc. The layers were separated and the aqueous layer extracted a second time with 20 mL EtOAc. The combined organic layers were washed with 20 ml brine, dried over MgSO4, filtered and concentrated under vacuum. Colorless solid (32 mg, 99%). MS (ESI): m/z=483.113 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C@H:26]([O:63][CH3:64])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:61][CH3:62])[C@@H:36]([CH3:60])[C:37]([NH:39][C@H:40](/[CH:48]=[CH:49]/[C:50]1[CH:55]=[CH:54][C:53]([C:56]([O:58][CH3:59])=[O:57])=[CH:52][CH:51]=1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:70][CH2:71][CH2:72][C:73]([OH:75])=[O:74].C([BH3-])#N.[Na+]>>[C:73]([CH2:72][CH2:71][CH2:70][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C@H:26]([O:63][CH3:64])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:61][CH3:62])[C@@H:36]([CH3:60])[C:37]([NH:39][C@H:40](/[CH:48]=[CH:49]/[C:50]1[CH:51]=[CH:52][C:53]([C:56]([O:58][CH3:59])=[O:57])=[CH:54][CH:55]=1)[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:75])=[O:74]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccc(C(=O)OC)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccc(C(=O)OC)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
The title compound was synthesized by analogy with the synthesis process of Example 1 by reacting 45 mg (47 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-3-{[(2S,3E)-4-[4-(methoxycarbonyl)phenyl]-1-phenylbut-3-en-2-yl}amino)-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetic acid salt (intermediate 23) with a 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[CH2:15]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[CH2:16][CH3:17]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:13][CH:14]=1)[C:8](=[O:10])[N:22]([C:21]1[CH:23]=[CH:24][C:18]([CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=1)[C:11]2=[O:12])([O-:3])=[O:2]
Reactant: CCCc1ccc(N)cc1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: CC(=O)O
Product: CCCc1ccc(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)cc1
Temperature: 25 °C

Procedure:
A solution of 95% 4-nitrophthalic acid anhydride (4.22 g, 20.7 mmol) and 4-propylaniline (2.81 g, 20.7 mmol) in acetic acid (86 ml) was refluxed by heating for 24 hours. The reaction solution was cooled to room temperature, and then added to ice water, and the deposited crystals were collected by filtration, and washed with water. The resulting crystals were purified by recrystallization (ethanol) to obtain 5-nitro-2-(4-propyl-phenyl)-isoindole-1,3-dione as pale yellow scaly crystals (5.89 g, yield: 91.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:6]3=[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[CH:3]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[ClH:1].[CH2:27]([O:26][C:24]([N:14]1[CH2:15][CH2:16][C:6]2[C:7](=[N:8][C:9]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:13]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: Clc1ccc2nc3c(c(-c4ccccc4)c2c1)CCNCC3
Product: CCOC(=O)N1CCc2nc3ccc(Cl)cc3c(-c3ccccc3)c2CC1
Product: Cl
Yield: 65 %

Procedure:
9-Chloro-1,2,4,5-tetrahydro-11-phenyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 9-chloro-1,2,4,5-tetrahydro-11-phenyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][NH:13]2)=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[N:8]=1.I[CH2:24][CH:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH2:24][CH:25]([CH3:27])[CH3:26])=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[N:8]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Cn1cnc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
An N,N-dimethylformamide (5 ml) suspension of 2-chloro-6-((S)-3-methylmorpholin-4-yl)-9H-purine (839 mg, 3.31 mmol), 1-iodo-2-methylpropane (730 mg, 3.97 mmol), and potassium carbonate (594 mg, 4.30 mmol) was stirred at 50° C. for 4 hours. The reaction mixture was returned to room temperature. Ethyl acetate was added to the reaction mixture and the resulting mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (hexane:ethyl acetate=7:3) to give the title compound (868 mg, 85%) as an amorphous substance.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][C:4]=2[CH:3]=1.C(O)(=O)/C=C\C(O)=O.ClC1[N:36]=[N:35]C2CCNCC=2C=1.C1(CCC(Cl)=O)C=CC=CC=1>C(O)C>[NH:35]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][C:4]=2[CH:3]=1)[NH2:36]
Reactant: Clc1cc2c(nn1)CCNC2
Reactant: O=C(CCc1ccccc1)N1CCc2nnc(Cl)cc2C1
Agent: O=C(Cl)CCc1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: NNc1cc2c(nn1)CCN(C(=O)CCc1ccccc1)C2

Procedure:
The 3-chloro-5,6,7,8-tetrahydro-6-(3-phenylpropionyl)pyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 28.6 g of 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 31.5 g of 3-phenylpropionyl chloride. M.P. 134°-137° from 95% ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([O:21]CC)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CCOC(=O)Cc1ccc2nc(Nc3ccccc3C)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
In THF-methanol (1:1, 20 ml) was dissolved ethyl 2-(2-methylphenylamino)-6-benzothiazolylacetate (907 mg, 2.78 mmol). To the resulting solution was added 1.0M-NaOH (8.34 ml, 8.34 mmol), followed by stirring overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was acidified with 1.0N HCl. The crystals thus obtained were collected by filtration under reduced pressure, washed with water and dried at 60° C. under reduced pressure, whereby 2-(2-methylphenylamino)-6-benzothiazolylacetic acid (675 mg, 81%) was obtained as a white crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[NH:19][C:18](=O)[CH2:17][O:16][C:15]([CH:26]([CH3:28])[CH3:27])([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)[C:14]=3[CH:29]=2)[CH:9]=1)[C:5]#[N:6].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[NH:19][C:18](=[S:39])[CH2:17][O:16][C:15]([CH:26]([CH3:28])[CH3:27])([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)[C:14]=3[CH:29]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: CC(C)C1(c2cccs2)OCC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)C1(c2cccs2)OCC(=S)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared by heating a mixture of 3-fluoro-5-(5-isopropyl-2-oxo-5-thien-2-yl-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)benzonitrile and Lawesson's reagent at reflux in toluene generally according to example 10. 1H-NMR (DMSO-d6) δ 12.09 (s, 1H), 8.1 (s, 1H), 7.96 (d, J=10.1 Hz, 1H), 7.88 (m, 2H), 7.83 (dd, J=8.5, 1.8 Hz, 1H), 7.48 (dd, J=4.9, 0.66 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.03 (d, J=2.6 Hz, 1H), 7.00 (m, 1H), 4.48 (d, J=14.1 Hz, 1H), 4.37 (d, J=14.1 Hz, 1H), 2.96 (m, 1H), 0.93 (d, J=6.7 Hz, 3H), 0.87 (d, J=6.5 Hz, 3H); MS (ES) m/z 421 (M−H)−.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[CH:15]=[C:14]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:18]=2)[NH:13][N:12]=1)=O.[NH3:33].[OH2:34]>CN(C=O)C.O1CCOCC1>[C:9]([C:11]1[CH:15]=[C:14]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:18]=2)[NH:13][N:12]=1)(=[O:34])[NH2:33]
Reactant: O=C(ON1C(=O)CCC1=O)c1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Reactant: N
Reactant: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: NC(=O)c1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-(2-phenyl-quinazolin-4-ylamino)-1H-pyrazole-3-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (270 mg, 0.63 mmol) in DMF (20 ml) was added a solution of ammonia in 1,4-dioxane (0.5 M, 10 ml). The resulting mixture was stirred at room temperature for 24 h. After concentration of the solvents, the residue was added to water (20 ml). The resulting precipitate was collected to afford III-100 (168 mg, 80%)as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 7.77-7.51 (m, 6H), 7.86 (br s, 2H), 8.11 (m, 1H), 8.50 (m, 2H), 8.63 (m, 1H), 10.52 (s, 1H), 11.25 (s, 1H); EI-MS 331.1 (M+H); HPLC-Method A, Rt 2.52 min.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].[CH3:17][NH:18][O:19][CH3:20].CN1CCOCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1>[CH3:20][O:19][N:18]([CH3:17])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CNOC
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 87.3 %

Procedure:
2-Nitro-4-trifluoromethyl-benzoic acid (2.753 mg, 11.7 mmol) in THF was reacted with N,O-dimethylhydroxy amine (1.277 g, 13.1 mmol), NMM (3 ml) and DMTMM (3.34 g) at room temperature overnight. The reaction mixture was quenched by adding H2O. The mixture was extracted with ethyl acetate (50 ml×3). The combined organic layer was washed 1M NaHCO3 (50 ml×2), 3% HCl (50 ml×2) and brine (50 ml), and then dried over MgSO4. The filterate was concentrated in vacuo to yield the title compound (2.84 g, 87%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Reactant: FC(F)(F)c1nnc(Cl)s1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4nnc(C(F)(F)F)s4)CC2)C3)CC1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole following a procedure analogous to that described for Example 79. LC (method 7): tR=1.46 min; Mass spectrum (ESI+): m/z=516 [M+H]+.