Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([F:59])=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]3[CH2:50][CH2:49][N:48](C(OC(C)(C)C)=O)[C@@H:47]([CH3:58])[CH2:46]3)[CH:39]=2)[CH:37]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([NH:30][CH2:31][C:32]3[CH:37]=[C:36]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]5[CH2:50][CH2:49][NH:48][C@@H:47]([CH3:58])[CH2:46]5)[CH:39]=4)[C:35]([F:59])=[CH:34][CH:33]=3)=[O:26])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)O
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(F)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
A mixture of 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (80 mg, 0.19 mmol), 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (82 mg, 0.19 mmol), HBTU (87 mg, 0.23 mmol) and Et3N (0.13 mL, 0.96 mmol) in DCM (3 mL) was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were then washed with water followed by a brine wash. The organic layer was then concentrated under vacuum to give a crude residue: LC-MS m/z 799 (M+H)+. The crude residue was dissolved in 25% TFA in DCM (2 mL) and stirred at RT for 2 h. It was purified with a Gilson HPLC (with 0.1% TFA condition) eluting with 10 to 70% CH3CN in water at a flowrate of 20 mL/min. The fractions were combined and then converted to the free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]butanediamide as a solid (59 mg, 44%). LC-MS m/z 699 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[NH:27][CH:28]=[CH:29][C:22]=34)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.C(OC([N:39]1[CH2:42][CH2:41][C@H:40]1[C:43](O)=[O:44])=O)(C)(C)C>>[NH:39]1[CH2:42][CH2:41][C@H:40]1[C:43]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[NH:27][CH:28]=[CH:29][C:22]=34)[CH:6]=2)[C:2]([CH3:31])([CH3:1])[CH2:3]1)=[O:44]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reactant: CC1(C)CNc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21
Product: CC1(C)CN(C(=O)[C@@H]2CCN2)c2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21

Procedure:
The titled compound was prepared from N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)amino]nicotinamide (Example 16) and (2S)-azetidine-1,2-dicarboxylic acid-1-tert-butyl ester by the method described in Example 13. MS (ES+): 496 (M+H). Calc'd. for C28H29N7O2—495.58.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:24])[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[CH:10]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:26][C:27](OCC)=[O:28]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:24])[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[CH:10]([C:18]3[CH2:23][CH2:22][N:21]([CH:27]([OH:28])[CH3:26])[CH2:20][CH:19]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)C(c1ccncc1)CC2(O)c1ccc(F)cc1
Reactant: CCOC(=O)CBr
Solvent: CC(C)=O
Product: Cc1ccc2c(c1)C(C1=CCN(C(C)O)CC1)CC2(O)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
3-(4'-Fluorophenyl)-3-hydroxy-6-methyl-1-(4-pyridyl)indane (Example 8) (9.0 g) was refluxed with ethyl bromoacetate (5.0 g) in acetone (50 ml) for 3 hrs. The reaction mixture was cooled in a refrigerator overnight and the precipitated pyridinium bromide filtered off. Yield: 7.8 g (56.9%). MP: 177°-78° C. This bromide (7.0 g) was dissolved in methanol (50 ml), cooled to 0° C., and NaBH4 (3.0 g) was added during 1 hour under stirring. The reaction mixture was poured into NH4Cl (10 g) in 1 liter of H2O and finally extracted with ethyl acetate (2×150 ml). The combined organic phases were dried (MgSO4) and the ethyl acetate evaporated. The remaining oil (1-(1-ethylcarboxymethyl-1,2,3,6-tetrahydropyrid-4-yl)-3-(4'-fluorophenyl)-3-hydroxy-6-methylindane) was dissolved in dry tetrahydrofuran (25 ml) and added dropwise to a suspension of LiAlH4 (1.8 g) in dry tetrahydrofuran under ice cooling. The mixture was refluxed for two hours, hydrolysed by careful addition of H2O (5 ml) in tetrahydrofuran (100 ml). The precipitate was filtered off, and the solvent evaporated leaving the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:16][C:17]([O:19]C)=[O:18].[Cl:21][C:22]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:23]=1[CH:24]=[CH:25][C:26](O)=[O:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:10][CH2:11][N:12]([C:26](=[O:27])/[CH:25]=[CH:24]/[C:23]3[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:22]=3[Cl:21])[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)C=Cc1cccc(Cl)c1Cl
Reactant: COC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Product: O=C(O)CC1CC2(CCN(C(=O)/C=C/c3cccc(Cl)c3Cl)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared employing a procedure analogous to that described in Example 1 using methyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate and 2,3-dichlorocinnamic acid followed by a procedure analogous to that described in Example 2. LC-MS Method 1 tR=1.98, min, m/z=480; 1H NMR (CDCl3) 1.52 (d, 2H), 1.71 (m, 2H), 2.40 (m, 1H), 2.49 (m, 1H), 2.65-3.10 (4H), 3.32 (m, 1H), 3.62 (m, 1H), 4.13 (d, 1H), 4.79 d, 1H), 6.88 (d, 1H), 7.05-7.30 (4H), 7.46 (d, 1H), 7.52 (d, 1H), 8.00 (d, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(=O)(O)[O-].[Na+].[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>C(OCC)(=O)C.CC(C)=O.O>[C:33]1([NH:39][C:40](=[O:41])[NH:1][CH:2]([C:21]2[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=2)[C:3]([NH:5][CH:6]2[C:19](=[O:20])[N:8]3[CH:9]([C:14]4[NH:18][N:17]=[N:16][N:15]=4)[C:10]([CH3:12])([CH3:13])[S:11][C@H:7]23)=[O:4])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)S[C@@H]2C(NC(=O)C(N)c3ccc(O)cc3)C(=O)N2C1c1nnn[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)S[C@@H]2C(NC(=O)C(NC(=O)Nc3ccccc3)c3ccc(O)cc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a stirred solution of 0.78 g. (0.002 mole) of 6-(2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 40 ml. of 1:1 acetone-water, the pH of which has been adjusted to 6.0 by the addition of sodium bicarbonate solution, is added 0.238 g. (0.002 mole) of phenyl isocyanate, at ambient temperature. Stirring is continued at ambient temperature for a further 30 minutes, and then 50 ml. of ethyl acetate is added. The pH of the aqueous phase is lowered to 1.5 with 1 N hydrochloric acid, and then the organic layer is removed, dried and evaporated to dryness in vacuo. The residue is re-dissolved in a small volume of ethanol, to which 0.2 ml. of triethylamine is then added. The resulting solution is added dropwise to 200 ml. of ether, with vigorous stirring, and then the solid which precipitates is filtered off. This affords 0.8 g. (66% yield) of 6-(2-[3-phenylureido]-2-[p-hydroxyphenyl] acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as its triethylamine salt, m.p. 165°-170° C. (dec.). The infrared spectrum of the product (KBr disc) shows absorptions at 1790 cm-1 (β-lactam) and 1670 cm-1 (amide I). The NMR spectrum (DMSO-d6 /D2O) shows absorptions at 7.60-6.70 ppm (multiplet, 9H, aromatic hydrogens), 5.80-5.50 ppm (multiplet, 3H, C-5 and C-6 hydrogens, and side-chain methine hydrogen), 5.05 ppm (singlet, 1H, C-3 hydrogen), 3.05 ppm (quartet, 6H, N--CH2CH3), 1.55 ppm (singlet, 3H, C-2 methyl hydrogen), 1.10 ppm (triplet, 9H, N-CH2CH3) and 0.95 ppm (singlet, 3H, C-2 methyl hydrogens).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:3]=1.[O:17]=[C:18]1[CH2:26][C:25]2[C:20](=[CH:21][C:22]([C:27]#[N:28])=[CH:23][CH:24]=2)[NH:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C(#N)CCC.ClCCl.CO.C(OCC)C>[ClH:1].[OH:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[C:2]1[CH:3]=[C:4]([O:8][CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:5]=[CH:6][N:7]=1)=[CH:24][CH:23]=[C:22]([C:27]#[N:28])[CH:21]=2
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Reactant: Clc1cc(OCCN2CCOCC2)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCCC#N
Solvent: CCOCC
Product: N#Cc1ccc2c(-c3cc(OCCN4CCOCC4)ncn3)c(O)[nH]c2c1
Temperature: 160 °C
Yield: 19.1 %

Procedure:
A mixture of 4-{2-[(6-chloropyrimidin-4-yl)oxy]ethyl}morpholine (0.116 g, 0.47 mmol), 2-oxoindoline-6-carbonitrile (0.075 g, 0.47 mmol) and cesium carbonate (0.46 g, 1.42 mmol) in butyronitrile (3 mL), was heated in a microwave oven at 160° C. for 10 min. The crude product was purified using preparative HPLC (XTerra®PrepMS C8 column 10 μm, 30×150 mm; 0.1 M NH4OAc buffer/acetonitrile, (80:20-20:80), as the eluent). The acetonitrile was evaporated and the remaining aqueous phase was extracted with chloroform and evaporated in vacuo to give a yellow solid. The solid was dissolved in dichloromethane/methanol, (9:1), and treated with HCl in diethyl ether (1 M) at 0° C. The resulting yellow crystals were collected by filtration, washed with diethyl ether, and dried to obtain 0.036 g (17% yield) of the title compound: 1H NMR (D2O, 400 MHz) δ 8.31 (s, 1H), 7.15 (dd, J=8, 2 Hz, 1H), 6.96 (d, J=8 Hz, 1H), 6.93 (d, J=2 Hz, 1H), 6.01 (s, 1H), 4.67 (m, 2H), 4.17 (m, 2H), 3.94 (m, 2H), 3.75 (m, 2H), 3.66 (m, 2H), 3.40 (m, 2H); MS (ESP) m/z 366 (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[C:9](\[CH2:13][CH3:14])/[C:10]([OH:12])=[O:11])=[C:6]([O:15]C)[C:5]([O:17][CH3:18])=[C:4]([O:19][CH3:20])[C:3]=1[O:21]C>CCOCC>[CH3:20][O:19][C:4]1[C:3](=[O:21])[C:2]([CH3:1])=[C:7](/[CH:8]=[C:9](\[CH2:13][CH3:14])/[C:10]([OH:12])=[O:11])[C:6](=[O:15])[C:5]=1[O:17][CH3:18]
Reactant: CC/C(=C\c1c(C)c(OC)c(OC)c(OC)c1OC)C(=O)O
Solvent: CCOCC
Product: CC/C(=C\C1=C(C)C(=O)C(OC)=C(OC)C1=O)C(=O)O

Procedure:
Compound 10c was prepared from 9c (0.010 g, 0.033 mmol) as described above for 10a to give 0.003 g (0.010 mmol, 32%) of the product as a red solid following flash chromatography (1:1 Et2O:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:3]1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[O:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([NH:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:5]=2)=[O:9])[CH2:26][CH2:27]1
Reactant: Cc1onc(-c2ccccn2)c1CNc1cc(C(=O)O)n(C)n1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccn2)c1CNc1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 96 %

Procedure:
As described for example 160c, 1-methyl-3-((5-methyl-3-(pyridin-2-yl)isoxazol-4-yl)methylamino)-1H-pyrazole-5-carboxylic acid (14 mg; 44.7 μmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (17 mg, 96%) which was obtained as a white solid. MS: m/e=397.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCC[CH2:16]1.CC(C)([O-])C.[K+].IC>C(OC)(C)(C)C>[CH3:16][N:11]1[CH:12]=[CH:13][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH2:9][C:10]1=[O:14]
Reactant: O=C1CC=C(c2ccccc2)C=CN1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CI
Product: CN1C=CC(c2ccccc2)=CCC1=O
Temperature: -30 °C
Yield: 100 %

Procedure:
The 5-phenyl-1,3-dihydro-azepin-2-one (168.5 g, 911.3 mmol) is combined with tetrahydrofuran (1300 mL) and the solution cooled to about −30° C. Potassium tertiary-butoxide (107.4 g, 956.9 mmol) is added in one portion. Exotherm is observed warming the reaction contents to −12° C. Upon subsiding of the exotherm, the contents are allowed to re-cool to −25° C. and iodomethane (113.5 mL, 1.823 moL) is added providing a slight exotherm. The reaction contents are allowed to warm to room temperature and stirred. After 10 hours the reaction mixture is diluted with methyl tertiary-butyl ether (1300 mL) and extracted with saturated ammonium chloride solution (2×250 mL), water, and saturated aqueous sodium chloride solution. The combined aqueous layers are back extracted with methyl tertiary-butyl ether (200 mL). The methyl tertiary-butyl ether extracts are combined, dried over MgSO4 and filtered. The solution is concentrated via rotary evaporation to provide the title compound (185 g, 100%) as a brown powdery residue. The material is used directly, without purification, in the next step.
Reaction SMILES: ClC1C=C(Cl)C=CC=1CNC(C1C(=O)NN=C(C2C=CN=CC=2)C=1)=O.[O:26]=[C:27]1[C:32]([C:33]([OH:35])=O)=[CH:31][C:30]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)=[N:29][NH:28]1.C(Cl)(=O)C(Cl)=O.[Cl:48][C:49]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:50]=1[NH2:51]>C(N(CC)CC)C.CN(C)C=O.ClCCl>[Cl:48][C:49]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:50]=1[NH:51][C:33]([C:32]1[C:27](=[O:26])[NH:28][N:29]=[C:30]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[CH:31]=1)=[O:35]
Reactant: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: Nc1ccc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Yield: 199.4 %

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.036 g of 2,4-dichloroaniline and 0.19 cm3 of triethylamine, 0.16 g of N-(2,4-dichlorophenyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a cream-colored solid melting above 260° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1)#[N:2].[CH:12]1([CH2:15][N:16]2[C:24]3[N:23]=[C:22]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][CH3:33])=[CH:28][CH:27]=4)[NH:21][C:20]=3[C:19](=[O:34])[N:18]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])[C:17]2=[O:43])[CH2:14][CH2:13]1>CN(C)C1C=CN=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:32]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][C:22]3[NH:21][C:20]4[C:19](=[O:34])[N:18]([CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[F:42])[C:17](=[O:43])[N:16]([CH2:15][CH:12]5[CH2:14][CH2:13]5)[C:24]=4[N:23]=3)=[CH:27][CH:28]=2)[CH3:33])=[O:9])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: CN(C)c1ccncc1
Product: CN(C(=O)c1ccc(C#N)nc1)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1

Procedure:
This compound was prepared by a method similar to that described in example 79 except that 6-cyanonicotinic acid (Lancaster) was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid, the reaction was performed using 0.66 equivalents of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione and 0.68 equivalents of 4-dimethylaminopyridine was added as the final reagent to the reaction mixture. The product was purified by chromatography using silica gel eluted with 5:95 hexanes/ethyl acetate followed by crystallization from acetonitrile. MS, m/z(M+)=564.2161.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:33])([CH3:32])[C:13]([N:15]1[CH2:27][C:26](=O)[C:25]2[C:24]3[C:23]([C:29]([O-])=[O:30])=[CH:22][CH:21]=[CH:20][C:19]=3[NH:18][C:17]=2[CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.C1C2NC3C=CC=C4C(=O)[NH:51][N:52]=C(C=2C=34)CC1>>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]([CH3:33])([CH3:32])[C:13](=[O:14])[N:15]1[CH2:16][C:17]2[NH:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:29](=[O:30])[NH:51][N:52]=[C:26]([C:25]=2[C:24]=34)[CH2:27]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N1CC(=O)c2c([nH]c3cccc(C(=O)[O-])c23)C1
Reactant: O=C1NN=C2CCCc3[nH]c4cccc1c4c32
Agent: NN
Solvent: O
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
The target product was prepared from 2-(2-(((benzyloxy)carbonyl)amino)-2-methylpropanoyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and hydrazine hydrate according to the procedure similar to that for Compound 1. 1H NMR (DMSO-d6) δ 11.8 (s, 1H), 10.2 (s, 1H), 7.18-7.55 (m, 8H), 4.82-4.91 (m, 4H), 4.43-4.55 (m, 2H), 1.25 (s, 6H). MS (ESI) m/e [M+1]+ 446.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[CH2:54](Br)[CH:55]=[CH2:56]>C(O)C>[NH:1]([CH2:56][CH:55]=[CH2:54])[C@H:2]([C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C=CCN[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C

Procedure:
H-Tyr(But)-Gly-Gly-Phe-Leu-OBut (2.0 g., 3 mM) was dissolved in ethanol (90 ml.). To the solution were added sodium bicarbonate (0.378 g., 4.5 mM) and allyl bromide (0.387 ml., 4.5 mM). The solution was stirred and refluxed for 20 hours. The solvent was then evaporated in vacuo and the residue dissolved in a mixture of ethyl acetate (120 ml.) and water (80 ml.). The two phases were separated and the organic phase was washed with saturated brine (80 ml.) and dried (Na2SO4). The solvent was evaporated in vacuo to give a gum-like residue which was chromatographed using the dry column chromatography technique with ethyl acetate/methanol 90:10 v/v as eluent. The product band was eluted from the column with ethyl acetate/methanol 85:15 v/v. The solvent was evaporated in vacuo from the eluate to give allyl-Tyr(But)-Gly-Gly-Phe-Leu-OBut having Rf 0.48 (t.l.c. on silica gel; ethyl acetate/methanol 90:10 v/v).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:16]#[N:17].[Na+].O>CS(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:16]#[N:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1CCCCN1Cc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1CCCCN1Cc1ccccc1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
(RS)-1-Benzyl-2-bromomethylpiperidine, D31 (4.2 g) was dissolved in dry dimethylsulphoxide (15 ml) and treated with sodium cyanide (5.0 g). The solution was then stirred at 85° C. under argon for 18 h. The reaction solution was then poured into water (300 ml) and extracted with dichloromethane (2×200 ml). The organic solution was dried (MgSO4) and the solvent removed in vacuo. Chromatography (silica gel, diethyl ether/petroleum ether mixtures) afforded the title compound (3.3 g).
Reaction SMILES: [CH3:1][NH2:2].Cl[S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=1)[O:13][CH2:12][CH2:11][CH2:10]2)(=[O:6])=[O:5]>>[CH3:1][NH:2][S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=1)[O:13][CH2:12][CH2:11][CH2:10]2)(=[O:6])=[O:5]
Reactant: CN
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCC2
Product: CNS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCC2

Procedure:
207 g of a 40% aqueous solution of methylamine were introduced into a 1-liter round-bottomed flask and 123 g of finely ground 6-chlorosulphonylchroman-8-carboxylic acid were then added in portions, while maintaining the temperature between 0° C. and 5° C., by cooling.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@@:8]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:16])[CH2:10][CH2:9]1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[N:28]([CH2:6][CH2:7][C@@:8]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:16])[CH2:10][CH2:9]1)=[N+:29]=[N-:30]
Reactant: C[C@H](N1CC[C@](CCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](N1CC[C@](CCN=[N+]=[N-])(c2ccc(F)cc2)OC1=O)C(C)(C)C
Yield: 92.4 %

Procedure:
To a solution of 2-((S)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methanesulfonate (273 mg, 0.68 mmol) in DMF (5 mL) was added NaN3 (133 mg, 2.04 mmol), and the mixture was refluxed overnight. The reaction was quenched with H2O, and the pH of the mixture was adjusted to >9 with 1N aq NaOH. The mixture was extracted with EtOAc (3×). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated to give (S)-6-(2-azidoethyl)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (219 mg, 93%). 1H NMR (CDCl3): 0.61-0.69 (s, 9H), 1.02-1.08 (d, 3H), 1.98-2.14 (m, 3H), 2.23-2.32 (m, 1H), 2.51-2.61 (m, 1H), 2.91-3.02 (m, 1H), 3.06-3.13 (m, 1H), 3.41-3.52 (m, 1H), 4.33-4.42 (m, 1H), 6.98-7.03 (m, 2H), 7.21-7.24 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].CCOCC.[CH3:16][N:17]([CH3:25])[CH2:18][CH2:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21]>O>[CH:22]1([C:20]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)([OH:21])[CH2:19][CH2:18][N:17]([CH3:25])[CH3:16])[CH2:24][CH2:23]1
Reactant: COc1ccc(Br)cc1
Reactant: CN(C)CCC(=O)C1CC1
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C(O)(CCN(C)C)C2CC2)cc1
Temperature: 25 °C

Procedure:
The Grignard reagent prepared from 86 g. (0.46 mole) of 4-bromoanisole and 11.2 g. (0.46 mole) of magnesium metal in 200 ml. of dry ether was cooled to -20° C. and treated dropwise with 30 g. (0.23 mole) of cyclopropyl 2-dimethylaminoethyl ketone in 100 ml. of dry ether. After addition the mixture was allowed to warm to room temperature, then hydrolyzed with water and worked up as described in Preparation I. The oily product was distilled at 110°-115° C./0.1 mm.; the yield of free base was 16 g. (28%).