Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[C:10]([CH3:12])([CH3:11])[O:9][C:8](=[O:13])[N:7]([CH2:14][CH3:15])[C:6]=2[CH:16]=1.[F:18][C:19]([F:33])([F:32])[O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][C:22]=1B(O)O.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:14]([N:7]1[C:6]2[CH:16]=[C:2]([C:26]3[CH:25]=[C:24]([CH:23]=[CH:22][C:21]=3[O:20][C:19]([F:18])([F:32])[F:33])[CH:27]=[O:28])[C:3]([CH3:17])=[CH:4][C:5]=2[C:10]([CH3:12])([CH3:11])[O:9][C:8]1=[O:13])[CH3:15]
Reactant: CCN1C(=O)OC(C)(C)c2cc(C)c(Br)cc21
Reactant: O=Cc1ccc(OC(F)(F)F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCN1C(=O)OC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OC(F)(F)F)cc21
Temperature: 80 °C
Yield: 51.4 %

Procedure:
A round bottom flask was charged with 0.5 g (1.67 mmol) of Compound 14D, 0.58 g (2,5 mmol) of 2-trifluoromethoxy-5-formylphenylboronic acid and 0.083 g of tetrakis(triphenylphosphine)palladium(0). The flask was sealed with a septa and 8.5 mL of toluene and 2.5 mL of ethanol was added. The resulting solution was stirred to dissolve the reactants and then 1.7 mL of 2M K2CO3 was added via syringe. The reaction mixture was heated to 80° C. for 4 hours. After cooling, the reaction mixture was partitioned between ethyl acatate (20 mL) and water (8 mL). The water layer was further extracted (2×10 mL) and the combined organic layers were washed with water (10 mL) followed by brine (10 mL), dried over magnesium sulfate, filtered and excess solvent removed on the rotary evaporator. The crude product was purified by flash chromatography (EtOAc/Hexanes; gradient 20% to 40%) to give 0.35 g (52%) of 3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-7-yl)-4-trifluoromethoxy-benzaldehyde as yellow solid. MS (electrospray): mass calculated for C21H20F3NO4, 407.13; m/z found 408 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.[CH3:32][N:33]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53](O)=[O:54])=[CH:48][CH:47]=1)[CH2:34][CH:35]([OH:44])[CH:36]([OH:43])[CH:37]([OH:42])[CH:38]([OH:41])[CH2:39][OH:40]>>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:53](=[O:54])[CH2:52][C:49]3[CH:48]=[CH:47][C:46]([CH2:45][N:33]([CH3:32])[CH2:34][CH:35]([OH:44])[CH:36]([OH:43])[CH:37]([OH:42])[CH:38]([OH:41])[CH2:39][OH:40])=[CH:51][CH:50]=3)=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: CN(Cc1ccc(CC(=O)O)cc1)CC(O)C(O)C(O)C(O)CO
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Product: CN(Cc1ccc(CC(=O)NCc2ccc(C3C(CCC(O)c4ccc(F)cc4)C(=O)N3c3ccc(F)cc3)cc2)cc1)CC(O)C(O)C(O)C(O)CO

Procedure:
The synthesis was carried out analogously to Example XVe), starting with 70 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one and 114 mg of (4-{[methyl-(2,3,4,5,6-pentahydroxyhexyl)-amino]-methyl}-phenyl)-acetic acid. This gave the product of molecular weight 747.84 (C41H47F2N3O8+); MS (ESI) 748.35 (M+H+).
Reaction SMILES: [NH2:1][C:2](=O)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[NH:7][CH:6]=1)=O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[NH2:1][CH2:2][CH2:3][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[NH:7][CH:6]=1
Reactant: NC(=O)C(=O)c1c[nH]c2ccc(OCCCCc3ccccc3)cc12
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCCc1c[nH]c2ccc(OCCCCc3ccccc3)cc12
Temperature: 25 °C
Yield: 32.8 %

Procedure:
A suspension of the 3-(2-amino-1,2-dioxoethyl)-5-(4-phenylbutyloxy)indole (0.4 g, 1.3 mmol) and LiAIH4 (0.32 g, 8.44 mmol) in dry THF (30 ml) was heated at reflux for 3 days under nitrogen. After allowing the reaction mixture to cool to room temperature, the excess LiAIH4 was decomposed by the addition of a saturated solution of sodium potassium tartrate (3 ml) at 0° C. The precipitated material was removed by filtration and the flitrate was dried (MgSO4). The solvent was removed under reduced pressure to afford an oily product. The oil was purified by column chromatography using a solvent system of CH2Cl2/MeOH (90:10) to provide 3-(2-aminoethyl)-5-(4-phenylbutyloxy)indole (32.8% yield) as an oil. The oil was taken up in anhydrous Et2O (5 ml) and added to a saturated ethereal solution of oxalic acid. The resultant oxalate salt was collected by filtration, washed with anhydrous Et2O (2×10 ml), and recrystallized from MeOH/Et2O to afford a tan solid; mp 130°-132° C. Analytically calculated formula C20H24N2O. (COOH)2.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].C1(N=C=NC2CCCCC2)CCCCC1.[Cl:21][C:22]1[C:27](O)=[CH:26][C:25]([N:29]2[C:34](=[O:35])[CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[N:31]([CH3:40])[C:30]2=[O:41])=[C:24]([F:42])[CH:23]=1>C(Cl)Cl>[C:1]([O:5][C:27]1[CH:26]=[C:25]([N:29]2[C:34](=[O:35])[CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[N:31]([CH3:40])[C:30]2=[O:41])[C:24]([F:42])=[CH:23][C:22]=1[Cl:21])(=[O:4])[C:2]#[CH:3]
Reactant: C#CC(=O)O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C#CC(=O)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.68 g of propiolic acid in 5 ml of methylene chloride is added dropwise at 0° C. while stirring during 5 minutes to a solution of 2.18 g of N,N'-dicyclohexylcarbodiimide in 10 ml of methylene chloride and the mixture is stirred at 0° C. for 15 minutes. solution of 1.5 g of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 10 ml of methylene chloride is added dropwise while stirring during 20 minutes and the mixture is stirred at 0° C. for 2 hours. Insoluble constituents are filtered off under suction and the filtrate is evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using ethyl acetate/n-hexane (1:7) as the eluent. There is obtained 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl -4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorophenyl propiolate. 1H-NMR (CDCl3. 400 MHz: 7.40 ppm (d,1H), 7.21 ppm 1(d,1H), 6.36 ppm (s,1H), 3.56 ppm (d,3H). 3.15 ppm (s,1H),
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([NH:12][C@@H:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=[O:15])([O:10][CH3:11])=[O:9].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:17](=[O:19])[CH2:18][C@@H:13]([NH:12][C:8]([O:10][CH3:11])=[O:9])[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@@H]1CC(=O)OC1=O
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)N[C@H](CC(=O)c1ccc(Br)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of bromobenzene (373 g) and (R)-2-carbomethoxyaminosuccinic anhydride (1) (90.51 g) in dichloromethane (260 ml) was cooled in ice, and aluminum chloride (174.34 g) was added over 1 minute (exothermic!). The dark red mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. The mixture was poured onto crushed ice, and concentrated hydrochloric acid was added slowly with stirring. Diethylether was added and the mixture was stirred until all of the red-brown material disappeared. The layers were separated, and the aqueous was extracted twice more with diethylether. The combined ether extracts were washed with water and extracted with aqueous sodium carbonate. The combined extracts were washed with diethylether, cooled in ice, and acidified with conc. hydrochloric acid. The acid was extracted 3 times with diethylether. The combined extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave the title compound as a foam, 149.6 g. [α]D =-41° (25° C., CH3OH, c=1.0352).
Reaction SMILES: Cl/[C:2](/[CH3:13])=[CH:3]\[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:20](/[C:2](/[CH3:13])=[CH:3]\[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C/C(Cl)=C/C(=O)Nc1ccccc1
Reactant: Oc1ccccc1
Product: C/C(=C/C(=O)Nc1ccccc1)Oc1ccccc1

Procedure:
3-chlorocrotonanilide [formed from aniline and β-chloro-crotonyl chloride] was reacted with phenol in a basic media to obtain 3-phenoxy-crotonanilide melting at 145° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:8][C:7]=12.[C:17]1([N:23]2[C:27]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][N:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([N:31]3[CH2:32][CH2:33][N:28]([C:27]4[N:23]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[N:24]=[N:25][N:26]=4)[CH2:29][CH2:30]3)=[O:14])=[CH:9][NH:8][C:7]=12
Reactant: O=C(O)C(=O)c1c[nH]c2c(Br)ncc(F)c12
Reactant: c1ccc(-n2nnnc2N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
2-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (5.0 g, 17.5 mmol) was dissolved in DMF (100 mL) and treated with 1-(1-phenyl-1H-tetrazol-5-yl)piperazine (4.0 g, 17.5 mmol), Hunig's base (9.2 mL, 52.6 mmol) and TBTU (5.6 g, 17.5 mmol) and the reaction mixture was stirred at rt for 18 h. Solvent was removed in vacuum and water was added. A white solid precipitated out and it was collected by filtration and recrystallized twice with MeOH to afford the title compound (4.58 g) as a white solid. The mother liquid was concentrated and purified using silica gel (CH2Cl2 to 5% MeOH/CH2Cl2) to afford more title compound (1.8 g). 1HNMR (500 MHz, DMSO) δ 8.47 (s, 1H), 8.16 (s, 1H), 7.70-7.59 (m, 5H), 3.67 (m, 2H), 3.44 (m, 2H), 3.37 (m, 2H), 3.20 (m, 2H). LCMS: m/e 499 (M+H)+, ret time 1.50 min (method 1).
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[C:9]([C:12]#[N:13])(=O)[CH3:10]>>[C:12]([C:9](=[N:6]/[C:3](=[C:2](\[NH2:1])/[C:7]#[N:8])/[C:4]#[N:5])[CH3:10])#[N:13]
Reactant: N#C/C(N)=C(/N)C#N
Reactant: CC(=O)C#N
Product: CC(C#N)=N/C(C#N)=C(\N)C#N
Reaction time: 0.17 h

Procedure:
A mixture of 16 g of diaminomaleonitrile and 12.6 g of acetyl cyanide was stirred with a glass rod whereby an exothermic reaction occurred and the resulting reaction mixture turned into a yellow-colored mixture. After allowing the mixture to stand for 10 minutes, the mixture was washed with small amount of cooled methanol and dried under reduced pressure to obtain 22.65 g (95.9% yield) of crude crystals of α-cynoethylidenediaminomaleonitrile which was found to have a purity sufficient to be used in subsequent reactions. For analysis, a sample of the above crystals was then repeatedly recrystallized from a mixture of methanol and water (3:2 by volume) to obtain α-cyanoethylidenediaminomaleonitrile having a melting point of 220°-221° C as milky white fine crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:11]([OH:13])=O)[CH2:7][C@H:8]([OH:10])[CH:9]=1)=[O:4].[C:14]([O:18][C:19]([C@@:21]1([NH2:26])[CH2:23][C@H:22]1[CH:24]=[CH2:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:11](=[O:13])[NH:26][C@:21]2([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:23][C@H:22]2[CH:24]=[CH2:25])[CH2:7][CH:8]([OH:10])[CH:9]=1)=[O:4]
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC(C)(C)C
Reactant: COC(=O)C1=C[C@@H](O)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CC(O)C=C1C(=O)OC)C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
To an ice cooled solution of 28 (50 mg, 37 mmol) and (1R,2S)-1-amino-2-vinyl-cyclopropane carboxylic acid tert-butyl ester in DMF (5 mL), DIPEA (47 mmol) and HATU (47 mmol) were added. After two hours the solution was concentrated and purified using column chromatography (toluene/ethyl acetate 3:1). This gave the title compound as a slightly yellow oil (50 mg, 38%).
Reaction SMILES: [OH:1]O.[CH3:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12]>O.C(O)(=O)C>[CH3:3][S:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:1]
Reactant: CSc1ccccc1S(N)(=O)=O
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)c1ccccc1S(N)(=O)=O
Reaction time: 0.75 h

Procedure:
14.8 g of hydrogen peroxide (0.13 mol), 30% strength in H2O, were added dropwise at from 25° to 30° C. to a suspension of 26.5 g 6f 2-(methylthio)benzenesulfonamide (0.13 mol) and 2.1 g of Na2WO4 ·2H2O in 88 ml of glacial acetic acid. Stirring was carried out for 45 minutes at 25° C., the reaction mixture was poured onto 400 ml of water and the precipitate was filtered off with suction. It was washed with water and dried under reduced pressure from a water pump at 40° C. 24.3 g (85% of theory) of the title compound were thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]#[C:19][Si](C)(C)C)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO.C(OCC)(=O)C>[C:18]([C:17]1[CH:16]=[N:15][N:5]2[CH:6]=[C:7]([C:9]3[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=3)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=12)#[CH:19]
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C#C[Si](C)(C)C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0.10 M solution of 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-3-[(trimethylsilyl)ethynyl]pyrazolo[1,5-a]pyridine (788 mg, 2.43 mmol) in tetrahydrofuran and methanol (1:1, v/v) was added potassium carbonate (336 mg, 2.43 mmol). The reaction mixture was stirred at ambient temperature for two hours, and then diluted with ethyl acetate. The mixture was washed with saturated aqueous ammonium chloride and brine. The organic layer was separated, and the aqueous layer was back extracted with ethyl acetate three times. The combined organic layers was dried over sodium sulfate, filtered and concentrated to give 3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine. LRMS (ESI) calculated for C14H13N4O [M+H]+, 252.1; found 253.0.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[NH2:11])[CH:7]=[CH:8][CH:9]=1)[CH2:2][CH3:3].[CH3:17][N:18]=[C:19]=[O:20]>C(#N)C>[CH3:17][NH:18][C:19]([NH:11][N:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:5]=1)=[O:20]
Reactant: CCCc1cccc(N(N)CC(=O)OC)c1
Reactant: CN=C=O
Solvent: CC#N
Product: CCCc1cccc(N(CC(=O)OC)NC(=O)NC)c1

Procedure:
Methyl [1-(3-propylphenyl)hydrazino]acetate (700 mg) was dissolved in acetonitrile (10 ml) under nitrogen at room temperature. Methyl isocyanate (0.69 ml) was added to the solution which was then heated at 80° for 85 min. The solvent was removed in vacuo and the residue was dissolved in ether (10 ml). Hexane (20 ml) was added to precipitate a solid which was filtered off to give the title compound (677 mg), m.p. 76°-77°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[C:11]1([CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CCc1ccccc1)N1CCC(O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCN(C(=O)CCc2ccccc2)CC1
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
To 1.68 mL of oxalyl chloride (19.2 mmol) in 35 mL of CH2Cl2 at −78° C. was added 2.73 mL (38.5 mmol) of dry DMSO in 5 mL of CH2Cl2. After the addition, 3.6 g (15.4 mmol) of 1-(3-phenylpropionyl)-4-hydroxypiperidine 134 in 5 mL of Cl2Cl2 was added, and the mixture was stirred for 5 min in the cold. 10.73 mL (77 mmol) of triethylamine in 5 mL of CH2Cl2 was added, and the mixture was allowed to come to room temperature. The mixture was quenched with saturated aqueous ammonium chloride solution. The organic phase was washed with water twice, with saturated brine, dried, and evaporated under vacuum to give 3.2 g (89%) of 1-(3-phenylpropionyl)-4-ketopiperidine (135). GC/MS showed 100% purity with a molecular ion of 231.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][CH2:18][N:17]([S:21]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=4[O:31][CH3:32])(=[O:23])=[O:22])[C:16]=3[CH:33]=2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[Cl-].[NH4+].[N-:36]=[N+:37]=[N-:38].[Na+].Cl>CN(C)C=O>[NH:36]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]3[CH:13]=[CH:14][C:15]4[O:20][CH2:19][CH2:18][N:17]([S:21]([C:24]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=5[O:31][CH3:32])(=[O:23])=[O:22])[C:16]=4[CH:33]=3)=[O:11])=[CH:7][CH:8]=2)=[N:2][N:38]=[N:37]1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C#N)cc3)cc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(-c4nnn[nH]4)cc3)cc21

Procedure:
A microwave tube was charged with a solution of 4-(5-chloro-2-methoxybenzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (4-cyano-phenyl)-amide (50 mg, 0.10 mmol) in dimethylformamide (2.0 mL). Ammonium chloride (102 mg, 1.9 mmol) and sodium azide (121 mg, 1.9 mmol) were added and the tube was sealed under an argon atmosphere and irradiated in a microwave oven at a temperature of 155° C. for 35 min. The mixture was then acidified with HCl 1N and extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate and evaporated. The crude was resuspended in dichloromethane and sonicated. Filtration yielded 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide as a white solid, 35 mg (64%), MS (ISP): m/e=525.0, 527.0 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:25][C@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Yield: 20.5 %

Procedure:
To a mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (200 mg, 0.539 mmol) and tert-butyl (1R,2S)-2-aminocyclohexylcarbamate (173 mg, 0.808 mmol) in ACN (5 mL) was added N,N-diisopropylethylamine (0.141 mL, 0.808 mmol). The reaction mixture was heated in a sealed vial at 100° C. for several hours after which additional amine (0.5 eq) was added. The mixture was heated overnight and the solvent was subsequently removed in vacuo. The residue was dispersed in DMSO and MeOH (1/1) and the resulting mixture was filtered. The filtrate was purified via preparative HPLC. The fractions were collected and dried in vacuo to give the title compound as a tan solid (60.7 mg, 21%). [M+H] calc'd for C27H34ClFN4O5, 550. found, 550
Reaction SMILES: FC(F)(F)C(O)=O.CC(OC([N:15]1[CH:24]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH:28]2[C:32]#[N:33])=[O:26])[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:36][CH3:37])=[C:20]([O:34][CH3:35])[CH:21]=2)[CH2:16]1)=O)(C)C>C(#N)C>[CH3:35][O:34][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:36][CH3:37])[CH2:16][NH:15][CH:24]([C:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[C:32]#[N:33])=[O:26])[CH2:23]2
Reactant: COc1cc2c(cc1OC)CN(C(=O)OC(C)(C)C)C(C(=O)N1CCCC1C#N)C2
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1OC)CC(C(=O)N1CCCC1C#N)NC2
Yield: 105.9 %

Procedure:
Trifluoroacetic acid (1.2 mL, 15.6 mmol) was added to a solution of the title A compound, 3-(2-cyano-1-pyrrolidinyl)carbonyl-3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinecarboxylic acid 1,1-dimethylethyl ester [Diastereomer B] (196 mg, 0.47 mmol) in acetonitrile (9 mL) at room temperature overnight. The mixture was then concentrated under vacuum. The residue was taken up in another portion of acetonitrile (8 mL) and concentrated again under vacuum. The brown oily residue was triturated with ether to form a solid which was collected and washed with ether and dried under vacuum to give 157 mg (78%) of the title compound as a yellow solid, 88% pure by HPLC, m.p. 153-154° C. (dec). 1H NMR (CD3OD, 300 MHz): 6.85 (s, 1H), 6.8 (s, 1H), 4.85 (dd, 1H), 4.55 (dd, 1H), 4.35 (2, 2H), 3.8 (s, 6H), 3.6-3.8 (m, 2H), 3.4 (dd, 1H), 3.1 (dd, 1H), 2.1-2.4 (m, 4H). MS: 316 (MH+ for free amine).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCOC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2CCOC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
930 mg (2.0 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)propanoate (mixture of racemic diastereomers) were hydrolysed with TFA according to General Method 6A. Yield: 974 mg (purity 94%, quant.)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][N:22]([CH3:34])[C:23]([NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)=[O:24])([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:33][C:28]1[CH:27]=[C:26]([NH:25][C:23](=[O:24])[N:22]([CH2:21][C:11]2([C:14]3[CH:15]=[CH:16][C:17]([I:20])=[CH:18][CH:19]=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH3:34])[CH:31]=[C:30]([Cl:32])[CH:29]=1
Reactant: CN(CC1(c2ccc(I)cc2)CCN(C(=O)OC(C)(C)C)CC1)C(=O)Nc1cc(Cl)cc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CC1(c2ccc(I)cc2)CCNCC1)C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.8 %

Procedure:
To a solution of 4-[3-(3,5-dichloro-phenyl)-1-methyl-ureidomethyl]-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.218 g, 0.35 mmol) in CH2Cl2 (4.5 mL) at 0° C. was added TFA (1.5 mL, to give a 25% v/v solution). The reaction mixture was warmed to room temperature and stirred for 4 h. The solvent was removed by rotary evaporation and the residue was dissolved in EtOAc (25 mL) and washed with 10% aqueous NaHCO3 (2×25 mL). The organic extracts were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give 3-(3,5-dichloro-phenyl)-1-[4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-1-methyl-urea (˜0.19 g, 100%).