Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:7])([OH:6])[CH3:5].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10]>>[C:9](=[O:10])([O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)[O:6][C:4]([CH3:7])([CH3:5])[CH2:3][O:2][CH3:1]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCC(C)(C)O
Product: COCC(C)(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 87 %

Procedure:
1-Methoxy-2-methyl-2-propanol (3.50 ml, 30 mmol) was treated with 4-nitrophenyl chloroformate according to conditions similar to the ones described above with respect to Intermediate 2, Step 2 to provide, after purification by column chromatography over silica gel (eluting with Hexanes/EtOAc 99:1 to 70:30), 1-methoxy-2-methylpropan-2-yl 4-nitrophenyl carbonate (7.02 g, 87% yield) as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 8.26 (d, J=9.2 Hz, 2H), 7.36 (d, J=9.2 Hz, 2H), 3.56 (s, 3H), 3.43 (s, 3H), 1.57 (s, 6H).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:20]([CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]>C(Cl)Cl.C(=O)(O)[O-].[Na+].[Br-].[Zn+2].[Br-]>[CH2:1]([O:4][N:5]([C@@H:18]1[CH:19]=[C:20]([CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:47])[CH3:48])([CH3:44])[CH3:45])[C@@H:21]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[NH:22][CH2:23]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(CCO[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCON([C@@H]1C=C(CCO[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 282, 7.5 g, 10.11 mmol) in DCM (100 mL) at room temperature was added zinc bromide (6.83 g, 30.32 mmol). The reaction mixture was stirred overnight at room temperature. Another equivalent of zinc bromide was added and the reaction mixture was stirred for another 24 hours. The reaction mixture was diluted with DCM and saturated sodium bicarbonate was added. The biphasic mixture was filtered through celite to remove the solids and the layers were separated. The organics were washed once with brine, dried over magnesium sulfate, filtered and concentrated to afford an orange oil (6.49 g, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[C:5](=[O:6])[O:4][CH2:3]1.O1[CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH3:1][C:2]1([CH3:7])[C:5](=[O:6])[O:4][CH2:3]1.[CH2:9]=[CH:10][C:11](=[CH2:12])[CH3:1].[CH3:1][C:2]1([CH3:7])[C:5](=[O:6])[O:4][CH2:3]1
Reactant: C1CCOC1
Agent: CC1(C)COC1=O
Product: C=CC(=C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After 0.5 hour at 60° C., the solution was cooled to room temperature and 5.5 ml of pivalolactone was added. The resultant mixture was warmed slightly, and in about 15 minutes gelation occurred and it became too viscous to stir. It was let stand at room temperature overnight, and then was mixed with 250 ml of tetrahydrofuran. The mixture was transferred to a blender, and after being blended it was centrifuged. Extraction with THF showed no homopolyisoprene. The mixture was finally processed in a blender with about an equal volume of ethanol containing acetic acid and phenyl-β-naphthylamine antioxidant. The shredded polymer was separated on a filter and dried at room temperature under vacuum; yield, 12.5 g (80%, based on starting materials). Analysis by I. R. indicated approximately 45% pivalolactone in the polymer.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:14]([C:17]#[N:18])=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]2=[O:19])[CH2:6][CH2:5][C:4](=[O:20])[NH:3]1.[ClH:21]>CO.[Pd]>[ClH:21].[NH2:18][CH2:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:20])[NH:3][C:2]1=[O:1])[C:9]2=[O:19]
Reactant: N#Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 17 h
Yield: 99 %

Procedure:
A mixture of 2-(2,6-dioxo(3-piperidyl))-1-oxoisoindoline-4-carbonitrile (1.0 g, 3.71 mmol) and 10% Pd/C (0.2 g) in 4N HCl (20 mL) and methanol (600 mL) was hydrogenated at 50 psi for 17 hours. The mixture was filtered through celite and the filtrate was concentrated. The residue was stirred with ether (30 mL) to give 3-[4-(aminomethyl)-1-oxoisoindolin-2-yl]piperidine-2,6-dione hydrochloride (1.1 g, 99%) as a white solid: 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.64 (s, 3H), 7.79 (d, J=7.5 Hz, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.59 (t, 7.5 Hz, 1H), 5.21–5.14 (dd, J=5.0 and 13.2 Hz, 1H), 4.69 (d, J=17.4 Hz, 1H), 4.51 (d, J=17.4 Hz, 1H), 4.09 (d, J=4.9 Hz, 2H), 3.00–2.87 (m, 1H), 2.66–2.35 (m, 2H), 2.03–1.98 (m, 1H); 13C NMR (DMSO-d6) δ 172.87, 170.92, 167.77, 141.58, 132.50, 131.88, 129.39, 128.48, 123.25, 51.52, 46.19, 38.39, 31.17, 22.69.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[O:40]([C:47]1[CH:55]=[CH:54][C:50]([C:51](Cl)=[O:52])=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[O:40]([C:47]1[CH:48]=[CH:49][C:50]([C:51]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:29][CH2:30]5)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:52])=[CH:54][CH:55]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc(Oc4ccccc4)cc3)CN2C1=O
Yield: 11.9 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-phenoxybenzoyl chloride (111 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 16 mg (12%) of 18-(4-phenoxybenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 97.5% pure (HPLC), MS m/z 765 (M−H)−, HRMS: calcd. 784.3228 and found 784.3208 (M+NH4)+, mp 207-209° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:26][C:27](=[O:34])[CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.C1COCC1.O.O.[OH-].[Li+]>>[F:1][C:2]1[CH:3]=[C:4]([NH:26][C:27](=[O:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: COC(=O)CCC(=O)Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 0.5 h

Procedure:
To methyl 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-phenylamino)-4-oxobutanoate (123 mg, 0.259 mmol) was added THF/water (4:1) (2.587 m, 0.259 mmol) and lithium hydroxide hydrate (33 mg, 0.776 mmol) before it was stirred at ambient T for 30 min. The reaction mixture was concentrated, triturated with water, filtered, washed with water, and dried in a vacuum oven to give the title compound. MS (ESI) m/z: Calculated: 461.1; Observed: 462.0 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[O:13][CH2:12]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][CH:17]1[CH2:18][CH2:19][C:14]2([O:21][CH2:11][CH2:12][O:13]2)[CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sccc1N
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.5 %

Procedure:
A suspension of 3-amino-thiophene-2-carboxylic acid methyl ester (5.0 g, 31.85 mmol) in dry THF (9 mL) was treated with 1,4-cyclohexanedione monoethylene ketal (5.0 g, 32.05 mmol), followed by dibutyltin dichloride (482 mg, 1.59 mmol). After 5 min, phenyl silane (4.3 mL, 34.96 mmol) was added and the reaction mixture was stirred overnight at room temperature. After concentration, the residue was dissolved in EtOAc and washed with NaHCO3 followed by brine. The organic layer was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using 30% ethyl acetate in hexane as eluent to give 3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester (4.5 g, 47% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1.[C:32]([O:35][CH2:36][CH2:37]Br)(=[O:34])[CH3:33].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:32]([O:35][CH2:36][CH2:37][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[N:23]=[C:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OCCBr
Reactant: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2Cc2ccccc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2Cc2ccccc2OCCOC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution consisting of 2-[[2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridin-1-yl]methyl]phenol (Compound of Example 157) (41 mg), bromoethyl acetate (18 mg), N,N-dimethyl formamide (1 ml) was added potassium carbonate (19 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain [2-[[2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridin-1-yl]methyl]phenoxy]ethyl acetate (37 mg, 74%).
Reaction SMILES: C(OC(=O)C)(=O)C.C([O-])(=O)C.[NH4+:12].[C:13]1([CH2:23][C:24]([OH:26])=O)([CH2:19][C:20](O)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH2:16]1[CH2:17][CH2:18][C:13]2([CH2:23][C:24](=[O:26])[NH:12][C:20](=[O:21])[CH2:19]2)[CH2:14][CH2:15]1
Reactant: [NH4+]
Reactant: O=C(O)CC1(CC(=O)O)CCCCC1
Agent: CC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: O=C1CC2(CCCCC2)CC(=O)N1

Procedure:
reacting a mixture of acetic anhydride/ammonium acetate with 1,1-cyclohexane-diacetic acid to yield 3,3-pentamethylene glutarimide;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.FC(F)(F)C(O)=O.[F:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[C:58]=1[NH:64][C:65]([C@@H:67]1[CH2:76][C:75]2[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=2)[CH2:69][NH:68]1)=[O:66]>CN(C=O)C.CCOC(C)=O>[F:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[C:58]=1[NH:64][C:65]([C@@H:67]1[CH2:76][C:75]2[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=2)[CH2:69][N:68]1[C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]([CH3:15])[CH3:14])=[O:66]
Reactant: O=C(Nc1c(F)cccc1F)[C@@H]1Cc2ccccc2CN1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=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: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1Cc2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (60 mg, 277 μmol, Eq: 1.2) and DIEA (120 μL, 693 μmol, Eq: 3) in DMF (1 mL) was added HATU (105 mg, 277 μmol, Eq: 1.2) and the resulting solution stirred at RT for 15 min. (S)—N-(2,6-Difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide trifluoroacetate (93 mg, 231 μmol, Eq: 1.00) in DMF (1 mL) was then added and stirring was continued at rt. After 1 h, the reaction mixture was diluted with EtOAc and washed with 0.1 M NaOH, 0.1 M HCl, and brine. The organic layer was concentrated in vacuo and the residue azeotroped with n-heptanes to give tert-butyl (S)-1-((S)-3-(2,6-difluorophenylcarbamoyl)-3,4-dihydro isoquinolin-2 (1H)-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a white solid which was used without purification (130 mg), m/z=488 (M+H).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]([C:12]([NH:14][C@@H:15]([CH2:19][C:20]([F:23])([F:22])[CH3:21])[C:16](O)=[O:17])=[O:13])[CH2:2]1.ON1[C:29]2[N:30]=C[CH:32]=[CH:33][C:28]=2[N:27]=N1.CCN=C=NCCCN(C)C.Cl.C(N1CCOCC1)C>C1COCC1.CN(C=O)C>[C:29]([C:28]1([NH:27][C:16]([C@@H:15]([NH:14][C:12]([N:3]2[CH2:2][CH2:1][C:6]3([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:5][CH2:4]2)=[O:13])[CH2:19][C:20]([F:22])([F:23])[CH3:21])=[O:17])[CH2:32][CH2:33]1)#[N:30]
Reactant: On1nnc2cccnc21
Reactant: CC(F)(F)C[C@H](NC(=O)N1CCC2(CCCCC2)CC1)C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(F)(F)C[C@H](NC(=O)N1CCC2(CCCCC2)CC1)C(=O)NC1(C#N)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The crude product from example 8, (S)-2-[(3-azaspiro[5.5]undecane-3-carbonyl)amino]-4,4-difluoropentanoic acid, was dissolved in 6 ml of 2:1 THF/DMF and admixed with 161.8 mg (1.365 mmol, 1.05 eq.) of 1-amino-1-cyclopropylnitrile hydrochloride and 176.9 mg (1.3 mmol, 1 eq.) of 1-hydroxy-7-azabenzotriazole, cooled to 0° C. and admixed with 250 mg (1.3 mmol, 1 eq.) of EDCl and with 0.496 ml (3.9 mmol, 3 eq.) of N-ethylmorpholine. Subsequently, the mixture was stirred at 0° C. to RT for 2 h, THF was distilled off under reduced pressure, ethyl acetate was added and the mixture was extracted by shaking with highly dilute HCl, sat. NaHCO3 solution and sat. NaCl solution. After concentration of the organic phase, a preparative HPLC separation (Merck Hibar Purospher RP18, 250×25, Standard-Gradient of acetonitrile-water-TFA) was performed directly. Product fractions were combined and freeze-dried.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]([CH3:16])=[CH2:15])=[N:11][C:10]=1[C:17]([OH:19])=O)=O)(C)(C)C.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[N:27]1[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33]C(=O)OC(C)(C)C)[CH2:28]1>>[NH2:8][C:9]1[S:13][C:12]([C:14]([CH3:16])=[CH2:15])=[N:11][C:10]=1[C:17]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[N:27]1[CH2:32][CH2:31][CH2:30][C@H:29]([NH2:33])[CH2:28]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Reactant: C=C(C)c1nc(C(=O)O)c(NC(=O)OC(C)(C)C)s1
Product: C=C(C)c1nc(C(=O)Nc2cnccc2N2CCC[C@H](N)C2)c(N)s1

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with 5-(tert-butoxycarbonylamino)-2-(prop-1-en-2-yl)thiazole-4-carboxylic acid and (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate. Obtained the desired product as a white solid (9 mg). ESIMS m/z=359.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([C@@H:10]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]2[OH:12])=[N:4][NH:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:19](OC(=O)C)(=[O:21])[CH3:20]>CO>[OH:1][C:2]1[C:3]([C@@H:10]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]2[OH:12])=[N:4][N:5]([C:19](=[O:21])[CH3:20])[C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1[nH]nc([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1O
Solvent: CO
Product: CC(=O)n1nc([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(O)c1C(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.0 g. of 4-hydroxy-3-β-D-ribofuranosylpyrazole- 5-carboxamide in 20 cc. of anhydrous methyl alcohol was stirred and cooled to 0° C. To the cold stirred solution was added 5 cc of acetic anhydride dropwise over about 10 minutes. The reaction mixture was stirred for about 1 hour while the temperature was allowed to increase to about 25° C. The solvent was removed under reduced pressure to provide an oily residue which was dissolved in 25 cc. of 50 percent methanol-toluene. Again the solvent was removed under reduced pressure. This procedure was repeated three times to insure complete removal of any excess acylating agent. After the final solvents were totally removed, 4-hydroxy-3β-D-ribofuranosyl-N 1 -acetylpyrazole-5-carboxamide remained as a white solid.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]1([S:11]([CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]=O)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:21][C:22]([F:30])([F:29])[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CO>[C:5]1([S:11]([CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][N:26]2[CH2:27][CH2:28][CH:23]([C:22]([F:30])([F:29])[F:21])[CH2:24][CH2:25]2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(CC=O)CS(=O)(=O)c1ccccc1
Reactant: FC(F)(F)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(CCN1CCC(C(F)(F)F)CC1)CS(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
Sodium cyanoborohydride (78 mg, 1.2 mmol) was added to a stirred solution of the crude 4-benzenesulfonyl-3,3-dimethyl-butyraldehyde (240 mg, 1 mmol) and 4-trifluoromethylpiperidine (321 mg, 2.1 mmol) in methanol (4 ml). The mixture was stirred for 1 hour, quenched with sat. aqueous NaHCO3 and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified on silica (dichloromethane:methanol) to give the title product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[F:26][C:23]1[CH:22]=[N:21][C:20]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:5][CH2:4]2)=[N:25][CH:24]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncc(F)cn2)CC1
Temperature: 100 °C

Procedure:
A stirred mixture of benzyl 4-(aminomethyl)-piperidine-1-carboxylate (EXAMPLE 13, STEP 1) (10.0 g, 0.040 mol), 2-chloro-5-fluoropyrimidine (5.3 g, 0.040 mol) and cesium carbonate (26.2 g, 0.081 mol) in DMF (100 mL) was heated at 100° C. for 2 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (400 mL), washed with aqueous saturated NaHCO3 (100 mL), water (5×100 mL), and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60 (0.5 kg), eluting with 50–100% ethyl acetate in hexane to give the title compound. M.S. (M+1): 345.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[NH2:26][CH2:25][C:3]1[C:2]([NH:1][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:15][C:6]2[N:7]([CH3:14])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[C:4]=1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: COc1ccc(F)cc1-c1c(C#N)c(N)nc2c1c(=O)n(C)c(=O)n2C
Reactant: BrCCc1ccccc1
Product: COc1ccc(F)cc1-c1c(CN)c(NCCc2ccccc2)nc2c1c(=O)n(C)c(=O)n2C

Procedure:
The synthesis of title compounds started from Compound 70a (Example 64) and 1-(bromoethyl)benzene, according to procedures described in the synthesis of Compound 56. 1H NMR (400 MHz, CHLOROFORM-d) δ MS [m+H] calc'd C25H27FN5O3 464; found 464.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([NH:17][C:18]([CH3:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])=[CH:10][N:9]=2)[CH:3]=1.[C:27]([O-:30])(=[O:29])C.[K+]>CS(C)=O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[OH:14][C:12]1[C:11]([C:15]([NH:17][C:18]([CH3:26])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])=[O:16])=[CH:10][N:9]=[C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][N:5]=2)[C:27]([OH:30])=[O:29])[N:13]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)(NC(=O)c1cnc(-c2cc(Br)ccn2)nc1O)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(NC(=O)c1cnc(-c2cc(C(=O)O)ccn2)nc1O)c1ccccc1
Temperature: 120 °C

Procedure:
To the product of Example 1 (0.198 g, 0.479 mmol) in DMSO (5.0 mL) was added potassium acetate (0.188 g, 1.916 mmol), palladium(II) acetate (5.38 mg, 0.024 mmol), and dppf (0.053 g, 0.096 mmol). The reaction was stirred under a CO atmosphere and heated at 120° C. for 30 min. The reaction was diluted with EtOAc, washed with aq. HCl (1M) and concentrated. The residue was purified by preparative HPLC (Non-Polar Method). The material was further purified by flash chromatography on silica gel eluted with EtOH to afford the title compound. HPLC/MS: 379.0 (M+1); Rt=2.62 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:24]([O:26]CC)=[O:25])[CH:4]=[N:3]1.O.[OH-].[Li+]>CO.O>[CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:24]([OH:26])=[O:25])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 105.9 %

Procedure:
A mixture of ethyl 1-methyl-5-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylate (322 mg, 840 μmol) and lithium hydroxide hydrate (141 mg, 3.36 mmol) in methanol (20 ml) and water (5 ml) was stirred for 2.5 days at 25° C. The solvent was evaporated, the residue was acidified with hydrochloric acid 37% to pH=0, the precipitated solid was filtered off, washed with water and dried affording 1-methyl-5-(2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (316 mg, 106%) as an off-white solid. mp: >250° C., MS: m/z=356.4 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:24]([OH:26])=[O:25])[CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1.[N+](=[CH2:36])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:24]([O:26][CH3:36])=[O:25])[CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C(CCCN1CCOCC1)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Product: COC(=O)C(CCCN1CCOCC1)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 14, 7-chloro-2-[(1-carboxy-4-morpholinobutylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-4-morpholinobutylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.