Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43]OS(C)(=O)=O)[CH2:38][CH2:37]1)(=[O:35])=[O:34]>CN(C=O)C.O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:43][CH2:42][N:39]4[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:34])=[O:35])[CH2:37][CH2:38]4)[CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CS(=O)(=O)OCCN1CCN(S(C)(=O)=O)CC1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(c2cc(F)cc(F)c2)=C(c2cccnc2)C3=O)CC1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-5-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one (60 mg, 0.18 mmol) obtained in Step 5 of Example 128 in DMF (2 mL) was added K2CO3(75 mg, 0.54 mmol) and methylsulfonyl 2-(4-(methylsulfonyl)piperazin-1-yl)ethyl ether (77 mg, 0.27 mmol). The mixture was heated to 80° C. for 3 h and cooled to room temperature. The resulting solution was diluted with H2O (5 mL) and extracted with EtOAc (5 mL×3). The extracts were washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (2% MeOH/CH2Cl2) to afford the title compound (65 mg, 69%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([F:19])[CH:6]=1)=[O:4].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([F:19])[CH:6]=1)=[O:4])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)c1ccc(OCc2ccccc2)c(F)c1
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A solution of 2-bromo-1-[4-(benzyloxy)-3-fluorophenyl]ethanone (J. Med. Chem. 1980, 23, 738-744) (1 g) in dry DMF (2.5 mL) was cooled to 150 and treated portionwise with sodium azide (220 mg). After complete addition the reaction mixture was stirred for a further 1 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with water and the combined aqueous phase back extracted with EtOAc. The combined organic phases were washed with sat. NaHCO3(aq) three times and the combined washes back extracted with EtOAc. The combined organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with hexane-EtOAc (4:1 and 2:1) to give the title compound (810 mg). LCMS RT=3.61 min.
Reaction SMILES: Cl.[NH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC(C)=O.[C-]#N.[K+].CN(C)[C:18]1([C:23]#[N:24])[CH2:22]CC[CH2:19]1>O>[N:2]1([C:18]([CH3:22])([CH3:19])[C:23]#[N:24])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN(C)C1(C#N)CCCC1
Reactant: C1CCCNCC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C#N)N1CCCCCC1
Yield: 80 %

Procedure:
The title compound (6.6 g: 80%) was prepared from homopiperidine hydrochloride (6.7 g; 49 mmol), acetone (3.67 ml; 50 mmol), and potassium cyanide (3.25 g; 50 mmol) in water (25 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ 1.43 (6H, s), 1.50-1.65 (8H, m), 2.66 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[CH3:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2([OH:63])[CH2:62][CH2:61][NH:60][CH2:59]2)=[N:56][CH:57]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:60]3[CH2:61][CH2:62][C:58]([C:55]4[CH:54]=[CH:53][C:52]([CH3:51])=[CH:57][N:56]=4)([OH:63])[CH2:59]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Cc1ccc(C2(O)CCNC2)nc1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccc(C)cn3)C2)cc1Cl
Yield: 54.4 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-(5-methylpyridin-2-yl)pyrrolidin-3-ol dihydrochloride (10 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (9 mg). MS (ESI, pos. ion) m/z: calcd for C21H20ClN3O4: 413.1142, found 413.1143.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][CH:12]([F:15])[CH2:13][NH2:14].O>C(#N)C>[F:11][CH:12]([F:15])[CH2:13][NH:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: NCC(F)F
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccccc1NCC(F)F
Reaction time: 24 h
Yield: 95 %

Procedure:
2 ml (19 mM) of 2-Chloronitrobenzene and 2.7 ml (36 mM) of 2,2-difluoroethyl amine in 2 ml of acetonitrile were refluxed under stirring for 24 h. Water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to give 3.65 g of N-(2,2-difluoroethyl)-2-nitroaniline as an orange solid. Yield: 95%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=O)[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20]1)=[O:17]>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=[C:15]1[C:16]([N:18]([CH2:40][CH:41]([CH3:42])[CH3:43])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:20]1)=[O:17]
Reactant: COCCCCNc1ccccc1NC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Solvent: CC(=O)O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 80 °C
Reaction time: 15 h
Yield: 66.1 %

Procedure:
tert-Butyl (3S,5R)-3-{[({2-[(4-methoxybutyl)amino]phenyl}amino)(oxo)acetyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (9.11 g) was dissolved in acetic acid (50 ml), and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, the residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (5.85 g), and a fraction eluted with ethyl acetate-methanol (85:15) was concentrated under reduced pressure to give 1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide (580 mg).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9]([C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:17][C:16]1[C:11]([C:9]([NH:8][CH2:7][C:6]([OH:18])=[O:5])=[O:10])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ncccc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)c1ncccc1O
Reaction time: 5 h
Yield: 99 %

Procedure:
To a solution of [(3-hydroxy-pyridine-2-carbonyl)-amino]-acetic acid tert-butyl ester, 29, (0.070 g, 0.277 mmol) in CH2Cl2 (4 mL) is added TFA (1 mL). The resulting solution is stirred for 5 hours then concentrated under reduced pressure to afford 0.054 g (99% yield) of the desired compound as a colorless solid. 1H NMR (400 MHz, MeOD) δ ppm 8.09 (1H, d, J=3.3 Hz), 7.36-7.59 (2H, m), 4.08 (2H, s). HPLC-MS: m/z 197 [M+H]+.
Reaction SMILES: C([NH:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:8])[OH:7])=O.Cl.[CH3:24]O>>[CH3:24][O:22][C:20](=[O:21])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:9](=[O:10])[C@H:4]([CH2:5][C:6](=[O:8])[OH:7])[NH2:3]
Reactant: CO
Reactant: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O

Procedure:
A process comprising reacting N-formyl-aspartic anhydride with l-phenylalanine in glacial acetic acid to form N-formyl-α-L-aspartyl-L-phenylalanine, removing the formyl group from N-formyl-α-L-aspartyl-L-phenylalanine by hydrolysis with an aqueous solution of hydrogen chloride and esterifying the resulting α-L-aspartyl-L-phenylalanine with methanol in the presence of hydrogen chloride to form α-L-aspartyl-L-phenylalanine methyl ester and recovering the α-L-asparatyl-L-phenylalanine methyl ester.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:4][C@H:3]1[C:5](Cl)=[O:6].[NH2:8][C:9]1[S:13][N:12]=[C:11]([Br:14])[C:10]=1[C:15](=[O:17])[CH3:16].C(N(CC)CC)C>ClCCl>[C:15]([C:10]1[C:11]([Br:14])=[N:12][S:13][C:9]=1[NH:8][C:5]([C@@H:3]1[CH2:4][C@H:2]1[CH3:1])=[O:6])(=[O:17])[CH3:16]
Reactant: CC(=O)c1c(Br)nsc1N
Reactant: C[C@@H]1C[C@H]1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1c(Br)nsc1NC(=O)[C@@H]1C[C@H]1C
Yield: 82 %

Procedure:
Add a freshly prepared 1.93M solution of (1R,2R)-2-methyl-cyclopropanecarbonyl chloride (5.52; mol) in dichloromethane over 15; min to a suspension of 1-(5-amino-3-bromo-isothiazol-4-yl)-ethanone (1.17; kg, 4.93; mol) and triethylamine (859; mL, 6.16; mol) in dichloromethane (5.86; L) at room temperature and stir 4; hours. Quench the reaction with water (1; L) and separate the layers. Dry the organic layer over magnesium sulfate, filter, concentrate and purify the residue by short column silica gel chromatography (3500; g of SiO2) gradient eluting from 100:0; to 40:60 using n-hexane and ethyl acetate to give the title compound as a white solid (1230; g, 82%). MS (m/z): 303, 305; (M+1).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)(=[O:29])=[O:28])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.[CH2:46]([O:48][C:49](=[O:60])[C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][CH:58]=O)=[CH:52][CH:51]=1)[CH3:47].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:58][CH2:57][CH2:56][C:53]2[CH:54]=[CH:55][C:50]([C:49]([O:48][CH2:46][CH3:47])=[O:60])=[CH:51][CH:52]=2)=[C:15]1[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)(=[O:28])=[O:29])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1ccc(CCC=O)cc1
Reactant: O=S(=O)(Cc1ccc(Cl)c(Cl)c1)NCCc1cc2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: -10 °C
Reaction time: 4 h
Yield: 56.5 %

Procedure:
To a solution N-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)ethyl]-1-(3,4-dichlorophenyl)-methanesulfonamide (3.0 g, 5.14 mmol), triethylsilane (1.79 g, 15.4 mmol), and 4-(3-oxopropyl)benzoic acid ethyl ester (1.26 g, 6.16 mmol) in dichloromethane (30 mL) at −20 to −25° C. was added trifloroacetic acid (2.93 g, 25.7 mmol) during a period of 1 min. The mixture was warmed to −10° C. and stirred for 4 h. Saturated aqueous NaHCO3 (20 mL) was added. The mixture was extracted with EtOAc (150 mL). The organic extract was dried over Na2SO4. The solvent is evaporated. The residue is purified by column chromatography, using a mixture of heptane and EtOAc (4:1) as elute to give a white solid (2.25 g, 56%). 1H NMR (CDCl3): δ6.9-7.6 (m, Ph, CHPh2), 7.97 (d, 1H, J=1.6 Hz), 7.41 (d, 1H, J=1.9 Hz), 6.50 (d, 1H, J=8.9 Hz), 4.35 (dd, 2H, J=7.1, 14.3 Hz), 4.13 (m, 1H), 3.92 (s, 2H), 2.95 (m, 2H), 2.71 (m, 6H), 1.96 (m, 2H), 1.38 (t, 3H, J=7.1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.Cl[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:28]([CH:31]=1)[C:29]#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:29]([C:28]1[CH:31]=[C:24]([CH:25]=[CH:26][C:27]=1[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:23][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: N#Cc1cc(CCl)ccc1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCCC4)c(C#N)c3)ccc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a solution of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (40 mg, 0.139 mmol) and 5-(chloromethyl)-2-cyclohexylbenzonitrile (35.8 mg, 0.153 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (54.4 mg, 0.167 mmol). The mixture was stirred at 50° C. for 16 h. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite®. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to provide the title compound as an off-white foam (57.4 mg). LCMS m/z=485.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.24-1.34 (m, 1H), 1.43-1.53 (m, 4H), 1.50 (s, 9H), 1.80 (dd, J=12.88, 1.26 Hz, 1H), 1.89 (t, J=10.86 Hz, 4H), 2.22-2.34 (m, 1H), 2.50 (dd, J=15.73, 8.40 Hz, 1H), 2.73 (dd, J=15.79, 6.44 Hz, 1H), 2.82-2.92 (m, 1H), 2.99 (t, J=3.09 Hz, 1H), 3.65-3.75 (m, 1H), 3.95-4.04 (m, 1H), 4.07-4.16 (m, 1H), 5.06 (s, 2H), 6.09 (s, 1H), 6.85 (dd, J=8.72, 2.40 Hz, 1H), 7.08 (d, J=2.27 Hz, 1H), 7.14 (d, J=8.72 Hz, 1H), 7.37 (d, J=8.08 Hz, 1H), 7.62 (dd, J=8.15, 1.71 Hz, 1H), 7.71 (d, J=1.52 Hz, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=O)=[CH:14]2)=[O:7].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[N:21]1([C:18]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)c1cc2cccc(NC(=O)c3cccs3)c2[nH]1
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2cc(C(=O)N3CCCCC3)[nH]c12)c1cccs1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
To a mixture of 7-[(2-thienylcarbonyl)amino]-1H-indole-2-carboxylic acid (100 mg), piperidine (42 μL), 1H-1,2,3-benzotriazol-1-ol (75 mg) and N,N-dimethylformamide (4 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (94 mg) at 4° C., and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-6:4) and the obtained oil was recrystallized from diethyl ether to give the title compound (115 mg, yield 93%) as colorless prism crystals. melting point 131-132° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13](O)(=[O:15])[CH3:14]>C(OC(=O)C)(=O)C>[C:13]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:15])[CH3:14]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)Cc1csc(NC(C)=O)n1
Yield: 91 %

Procedure:
Ethyl 2-amino-4-thiazoleacetate (3.72 g 20 mmole) was taken up in acetic acid (4 mL) and acetic anhydride (4 mL), and the resulting suspension was heated at reflux for 3 hr. Concentration and flash chromatography on silica gel (5% MeOH/CH2H2) gave the title compound (4.1 g, 91%) as a white solid: MS (ES) m/e 229 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:5]([CH3:22])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)[CH:7]=[N:8][CH:9]=1.[CH3:23][C:24]1[C:28]([C:29](O)=[O:30])=[C:27]([CH3:32])[O:26][N:25]=1>>[CH3:22][C:5]1[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)=[CH:7][N:8]=[CH:9][C:4]=1[CH2:3][NH:2][C:29]([C:28]1[C:24]([CH3:23])=[N:25][O:26][C:27]=1[CH3:32])=[O:30]
Reactant: Cc1c(CN)cncc1-c1ccc2c(c1)CCC(=O)N2C
Reactant: Cc1noc(C)c1C(=O)O
Agent: Cl
Product: Cc1noc(C)c1C(=O)NCc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1C

Procedure:
In analogy to the procedure described for the preparation of example 219, 6-(5-aminomethyl-4-methyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 222) has been coupled with 3,5-dimethyl-isoxazole-4-carboxylic acid to give the title compound as an off-white solid. MS: 405.5 (M+H+).
Reaction SMILES: [NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24]([OH:26])=O)[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][NH2:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@@H:7]([C:24]([NH:45][CH2:44][C:41]1[CH:40]=[CH:39][C:38]([C:35]2[CH:36]=[CH:37][C:32]([OH:31])=[CH:33][CH:34]=2)=[CH:43][CH:42]=1)=[O:26])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccc(-c2ccc(O)cc2)cc1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: NC(=N[N+](=O)[O-])NCCC[C@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)NCc1ccc(-c2ccc(O)cc2)cc1
Yield: 48 %

Procedure:
Prepared analogously to Example 5d) from (R)-N5 -[amino(nitroimino)methyl]-N2 -(diphenylacetyl)-ornithine, 4'-hydroxy-[1,1'-biphenyl]-4-methanamine and TBTU in a yield of 48% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH:15]([CH3:14])[C:24]4[N:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH2:18][CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cccnc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ncccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-methyl-5,6,7,8-tetrahydro-[1,7]naphthyridine to provide the title compound in moderate yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([CH:16]3[CH2:32][N:20]4[C:21]5[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]4[CH2:18][CH2:17]3)=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:14]=[N:13][CH:12]=2)(O)[CH3:9])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([CH:16]3[CH2:32][N:20]4[C:21]5[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]4[CH2:18][CH2:17]3)=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:14]=[N:13][CH:12]=2)=[CH2:9])=[CH:4][CH:3]=1
Reactant: CC(O)(c1ccc(F)cc1)c1cnnn1C1CCc2c(CC(=O)O)c3ccccc3n2C1
Agent: Cl
Solvent: C1COCCO1
Product: C=C(c1ccc(F)cc1)c1cnnn1C1CCc2c(CC(=O)O)c3ccccc3n2C1
Temperature: 25 °C

Procedure:
The title compound was prepared from refluxing a solution of (7-{5-[1-(4-Fluoro-phenyl)-1-hydroxy-ethyl]-[1,2,3]triazol-1-yl}-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)-acetic acid (EXAMPLE 5) in a 1:1 mixture of Dioxane: 2M HCl for 24 h. The reaction mixture was cooled to room temperature then extracted with EA, washed with brine, dried over Na2SO4 and evaporated. Purification by Combi-flash EA/Hex 50-100% afforded the desired compound. MS (+ESI) m/z: 417.1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:33][O:32][C:5]2([O:9][CH:8]3[CH2:10][CH:11]4[CH:16]5[CH2:17][CH:18]=[C:19]6[CH2:24][CH:23]([O:25][C:26]([CH3:28])=[O:27])[CH2:22][CH2:21][C:20]6([CH3:29])[CH:15]5[CH2:14][CH2:13][C:12]4([CH3:30])[CH:7]3[CH:6]2[CH3:31])[CH2:4][CH2:3]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>Cl.N1C=CC=CC=1>[CH3:31][C:6]1[C@@H:7]2[C@:12]3([CH3:30])[C@@H:11]([CH2:10][C@@H:8]2[O:9][C:5]=1[CH2:4][CH2:3][C@H:2]([CH2:33][O:32][C:34]([CH3:35])=[O:36])[CH3:1])[C@@H:16]1[CH2:17][CH:18]=[C:19]2[CH2:24][C@@H:23]([O:25][C:26]([CH3:28])=[O:27])[CH2:22][CH2:21][C@:20]2([CH3:29])[C@H:15]1[CH2:14][CH2:13]3
Reactant: CC(=O)OC1CCC2(C)C(=CCC3C2CCC2(C)C3CC3OC4(CCC(C)CO4)C(C)C32)C1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H](C)CCC1=C(C)[C@H]2[C@H](C[C@H]3[C@@H]4CC=C5C[C@@H](OC(C)=O)CC[C@]5(C)[C@H]4CC[C@@]32C)O1
Yield: 84 %

Procedure:
Another group of workers, Dauben et al have reported a process in which diosgenin acetate is heated in acetic anhydride containing pyridine hydrochloride as catalyst which afforded pseudodiosgenin diacetate in 84% yield. (Ref:Dauben WG and Fonken GJ; J Am Chem Soc, 76, 4618, 1954).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21].O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21]
Reactant: O=c1c2cc(Cl)ccc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cc(Cl)ccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 42.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2d (200 mg, 0.587 mmol), 6-mercaptopurine monohydrate (110 mg, 0.646 mmol), K2CO3 (90 mg, 0.651 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 113 mg of a yellow crystalline solid (42%), mp 237.1-238.2° C. (decomposes). 1H NMR (DMSO-d6) δ: 13.55 (br s, 1H); 8.48 (s, 1H); 8.44 (s, 1H); 8.11 (s, 1H); 7.94 (d, J=8.3 Hz, 1H); 7.78 (d, J=8.1 Hz, 2H); 7.66 (d, J=6.7 Hz, 1H); 7.48-7.56 (m, 2H); 4.48 (s, 2H). 13C NMR (DMSO-d6) ppm: 159.8, 156.8, 153.5, 151.5, 149.6, 145.8, 143.6, 135.7, 134.0, 132.2, 132.1, 131.7, 131.5, 130.5, 130.2, 129.8, 128.8, 125.8, 121.9, 32.0. MS (ES): m/z 455.0 (M+). Anal. calcd. for C20H12Cl2N6OS.0.1C2H6O.0.6H2O(0.15KCl: C, 50.34; H, 2.89; Cl, 15.82; N, 17.44; S, 6.65. Found: C, 50.02; H, 2.63; Cl, 15.51; N, 17.39; S, 6.81.