Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)=O.[CH2:25]([NH2:28])[CH2:26][NH2:27]>C(O)C>[N+:22]([C:18]1[CH:17]=[C:16]([C:14]2[C:3]3[CH:4]=[C:5]([C:8]4[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=4)[CH:6]=[CH:7][C:2]=3[NH:28][CH2:25][CH2:26][N:27]=2)[CH:21]=[CH:20][CH:19]=1)([O-:24])=[O:23]
Reactant: NCCN
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1cc(-c2ccncc2)ccc1F
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C2=NCCNc3ccc(-c4ccncc4)cc32)c1
Temperature: 180 °C
Yield: 56.2 %

Procedure:
A 5 mL microwave tube was charged with [2-fluoro-5-(4-pyridinyl)phenyl](3-nitrophenyl)methanone (100 mg), ethanol and ethylenediamine (100 mg) then heated to 180° C. for 600 s using microwave irradiation. The reaction was concentrated to dryness and residue was taken up in water then extracted with methylene chloride. The extracts were dried over magnesium sulfate, filtered and concentrated to an oil. Silica gel purification followed by trituration with ether provided 5-(3-nitrophenyl)-7-(4-pyridinyl)-2,3-dihydro-1H-1,4-benzodiazepine (60 mg) as a yellow powder. H1 NMR (d6-dmso): 8.42 (d, 2H), 8.28 (s, 1H), 8.27 (d, 1H), 7.84 (d, 1H), 7.66 (m, 2H), 7.38 (d, 2H), 7.26 (s, 1H), 6.92 (d, 1H), 6.79 (br s, 1H), 4.00 (m, 2H), 3.60 (m, 2H). Mass (ES+)=345.3 (100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.[C:13]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C@H:21]1[CH2:22]O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([O:12][CH2:22][CH:21]2[CH2:24][CH2:25][CH2:26][N:20]2[C:18]([O:17][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:19])=[N:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: COC(=O)c1cnc(O)c(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OCC2CCCN2C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 70 °C
Reaction time: 13 h
Yield: 39.7 %

Procedure:
To a stirred solution of methyl 3-chloro-2-hydroxypyridine-5-carboxylate (300 mg, 1.599 mmol), N-tert-butoxycarbonylprolinol (321.9 mg, 1.599 mmol), and Ph3P (503 mg, 1.919 mmol) in THF (3 mL) was slowly added DIAD (378 μl, 1.919 mmol) at room temp, and the mixture was stirred for 13 hr at 70° C. The mixture was concentrated and the residue was chromatographed on silica-gel with n-hexane-EtOAc (3:1, v/v) as eluent to give 235.6 mg (40%) methyl 3-chloro-2-[[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate as a pale yellowish oil. 1H-NMR (400 MHz, CDCl3) δ1.46 (s, 9H), 1.87 (m, 1H), 2.05 (br s, 3H), 3.43 (br s, 2H), 3.92 (s, 3H), 4.17, 4.26 (br s each, 1H), 4.45-4.51 (m, 1H), 4.50 (s, 1H), 8.21 (s, 1H), (s, 1H), 8.67 (d, J=2.0 Hz, 1H); MS (FAB) m/z 371 (M++1).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NCc1ccccn1
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CNCc1ccccn1

Procedure:
The product was made from D-glucose and 2-aminomethyl-pyridine comparable as in Example A. A resin-like, yellow product was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([Cl:27])=[N:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1.[H-].[Na+].[NH4+].[Cl-]>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([Cl:27])=[N:22][CH:23]=[N:24]3)=[CH:19][CH:18]=2)[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncnc2cc(CBr)ccc12
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(Cl)ncnc3c2)C(=O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-oxopiperazine-1-carboxylic acid tert-butyl ester (3.93 g, 19.6 mmol) and 7-bromomethyl-4-chloroquinazoline, EXAMPLE 7, (5.0 g, 19.6 mmol) in 150 mL of THF and 15 mL of DMF at 0° C. is added a 60% dispersion in mineral oil of NaH (0.79 g, 19.6 mmol). The solution is stirred at 0° C. for 0.5 hours and then is allowed to warm to ambient temperature. After 4 hours, the solution is poured into a saturated solution of NH4Cl. The layers are separated and the organic layer is washed with H2O, and saturated NaCl, dried over MgSO4, filtered and concentrated. The title compound is obtained as a white solid (5.1 g, 13.4 mmol). MS (FAB) m/z 377, 379, (M+H), chlorine pattern.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cncc(Br)c1
Product: Nc1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and 5-bromo-pyridin-3-ylamine (example B.44) (156 mg, 0.9 mmol) according to general procedure II. Obtained as a light brown solid (40 mg, 9%). MS (ISN) 506.1 [(M+OAc)−]; mp 216–217° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]([CH2:13][CH2:14][CH2:15][O:16]C3CCCCO3)=[CH:7][C:6]=2[C:5]=1[C:23]([O:25][CH3:26])=[O:24])([O-:3])=[O:2]>Cl.CO>[OH:16][CH2:15][CH2:14][CH2:13][C:8]1[NH:9][C:10]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[C:6]=2[CH:7]=1
Reactant: COC(=O)c1c([N+](=O)[O-])ccc2[nH]c(CCCOC3CCCCO3)cc12
Agent: Cl
Solvent: CO
Product: COC(=O)c1c([N+](=O)[O-])ccc2[nH]c(CCCO)cc12
Yield: 77.7 %

Procedure:
Methyl 5-nitro-2-[3-(tetrahydropyran-2-yloxy)-propyl]-1H-indole-4-carboxylate (Intermediate 22, 0.650 g) was dissolved in a solution of hydrogen chloride in methanol (1.25M, 18 ml) and the resultant mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and aqueous potassium carbonate solution (10%). The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give methyl 2-(3-hydroxypropyl)-5-nitro-1H-indole-4-carboxylate (0.388 g) as a dark orange gum.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([O:19][C:20]2[CH:42]=[CH:41][C:23]3[C:24]4[N:28]([CH2:29][CH2:30][O:31][C:22]=3[CH:21]=2)[CH:27]=[C:26]([C:32]2[N:33]([CH:38]([CH3:40])[CH3:39])[N:34]=[C:35]([CH3:37])[N:36]=2)[N:25]=4)[CH3:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH3:43][C:44]([CH3:46])=O>CO.[Pd]>[CH:38]([N:33]1[C:32]([C:26]2[N:25]=[C:24]3[C:23]4[CH:41]=[CH:42][C:20]([O:19][CH:17]([CH:14]5[CH2:15][CH2:16][N:11]([CH:44]([CH3:46])[CH3:43])[CH2:12][CH2:13]5)[CH3:18])=[CH:21][C:22]=4[O:31][CH2:30][CH2:29][N:28]3[CH:27]=2)=[N:36][C:35]([CH3:37])=[N:34]1)([CH3:39])[CH3:40]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)C4CCN(C(=O)OCc5ccccc5)CC4)cc2OCC3)n(C(C)C)n1
Reactant: CC(C)=O
Agent: [Pd]
Solvent: CO
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)C4CCN(C(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 42 %

Procedure:
To a solution of 4-{1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]ethyl}piperidine-1-carboxylic acid benzyl ester from Example 11 (60 mg, 0.10 mmol) in acetone (2 mL) and MeOH (0.5 mL) was added 10% Pd/C (50 mg). The reaction mixture was stirred at RT under a hydrogen atmosphere for 48 h. The suspension was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 216 (20 mg, 42%). LCMS: RT 3.03 min [M+H]+ 379.2. 1H NMR (CDCl3, 400 MHz): δ 8.39 (1H, d, J=8.96 Hz), 7.56 (1H, s), 6.70 (1H, dd, J=8.98, 2.55 Hz), 6.52 (1H, d, J=2.51 Hz), 5.99-5.84 (1H, m), 4.51-4.34 (4H, m), 4.19 (1H, m), 3.00-2.78 (2H, m), 2.77-2.63 (1H, m), 2.41 (3H, s), 2.18-2.05 (3H, m), 1.95-1.85 (1H, m), 1.77-1.67 (1H, m), 1.56 (6H, d, J=8.76 Hz), 1.52-1.32 (2H, m), 1.28 (3H, d, J=8.24 Hz), 1.05 (6H, d, J=6.54 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([OH:19])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:22]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([O:19][CH3:22])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2ccc(Br)c(O)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(Br)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Temperature: 25 °C
Yield: 100.6 %

Procedure:
To 220 mg (0.67 mmol) of 5-bromo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 0.42 mL (6.7 mmol) of iodomethane, 185 mg (1.34 mmol) of K2CO3 and 2 mL of DMF. The mixture was stirred at room temperature over night. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent gave 230 mg (100% yield) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.[CH:17]1([C:20]2[NH:24][N:23]=[C:22]([NH2:25])[CH:21]=2)[CH2:19][CH2:18]1>C(O)CCC>[CH:17]1([C:20]2[NH:24][N:23]=[C:22]([NH:25][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)[N:3]=3)[CH:21]=2)[CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1cnc(-c2ccccn2)nc1Cl
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCCCO
Product: O=[N+]([O-])c1cnc(-c2ccccn2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 90 °C
Yield: 77325.3 %

Procedure:
To 4-chloro-5-nitro-2-(pyridin-2-yl)pyrimidine (1.42 g, 0.006 mmol, 1 equiv.) in BuOH (20 mL) was added 5-cyclopropyl-1H-pyrazol-3-amine (1.23 g, 0.01 mmol, 1.6 equiv.) After heating at 90° C. for 4 h. the reaction mixture was filtered to produce N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitro-2-(pyridin-2-yl)pyrimidin-4-amine (1.5 g, 79%). LC-MS (m/z)=324 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ0.74-0.77 (m, 2H), 0.97-1.02 (m, 2H), 1.93-2.00 (m, 1H), 7.00 (s, 1H), 7.60-7.63 (m, 1H), 8.03-8.06 (m, 1H), 8.43 (d, J=7.6 Hz, 1H), 8.84 (d, J=4.0 Hz, 1H), 9.37 (s, 1H), 10.24 (s, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[CH:5]=O.[CH3:12][N:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:19]2[N:13]([CH3:12])[C:14](=[O:15])[NH:16][C:17]2=[O:18])[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10]
Reactant: CN1CC(=O)NC1=O
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Product: CN1C(=O)NC(=O)C1=Cc1cc(Br)c(O)c(Br)c1
Yield: 72.7 %

Procedure:
Prepared according to the procedure described in Example 99 using 3,5-dibromo-4-hydroxybenzaldehyde (8.4 g, 30 mmoles) and 1-methyl hydantoin (3.5 g, 30 mmoles) to afford the pure product (8.2 g), mp 271°-277° C.
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]1[CH:10]=[C:11]([C@H:33]([NH:35][S@@](C(C)(C)C)=O)[CH3:34])[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25]1)[N:18]=2>CO>[F:8][C:9]1[CH:10]=[C:11]([C@H:33]([NH2:35])[CH3:34])[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][CH2:26]1)[N:18]=2
Reactant: C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](N)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrogen chloride 4.0 M in 1,4-dioxane (0.04 mL, 0.2 mmol) was added to a solution of (R)-N-((R)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-ethyl)-2-methylpropane-2-sulfinamide (0.0301 g, 0.06 mmol) in MeOH (5 mL). The yellow reaction mixture was allowed to stir at ambient temperature for 18 h. The crude reaction mixture was concentrated in vacuo and purified by silica gel chromatography to afford (R)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethanamine. MS (ESI) m/z: calculated: 389.1; Observed: 390.1 (M++1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[CH3:22][N:23]([CH3:30])[CH2:24][CH2:25][CH2:26][C:27](O)=[O:28].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:22][N:23]([CH3:30])[CH2:24][CH2:25][CH2:26][C:27](=[O:28])[N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)CCCC(=O)O
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4C(=O)CCCN(C)C)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (48.0 mg, 0.14 mmol) (Intermediate 10.1), 4-(dimethylamino)butyric acid hydrochloride (36.3 mg, 0.21 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (54.9 mg, 0.29 mmol), 4-dimethylaminopyridine (122.5 mg, 1.00 mmol), and dichloromethane (8 ml) is stirred for 24 h at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to render 50.4 mg (94%) of the respective amide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 92% purity, tR 6.27 min (tR(SM) 6.61 min).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([N:15]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:16][CH3:17])[C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([O:11]C)=O.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(O)C.CS(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([N:15]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:16][CH3:17])[C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([NH:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31])=[O:11]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
Aqueous NaOH (0.126 g, 3.09 mmol) was added to a solution of methyl 5-bromo-3-(cyclopentyl(ethyl)amino)-2-methylbenzoate (0.7 g, 2.06 mmol) in ethanol (5 mL) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and the aqueous layer acidified using dilute HCl to pH 6 and citric acid to pH 4. The product was extracted using ethyl acetate. Combined organic layers were dried and concentrated to give the crude acid (0.5 g, 75%). The acid (0.5 g, 1.53 mmol) was then dissolved in DMSO (5 mL) and 3-(amino methyl)-4,6-dimethylpyridin-2(1H)-one (0.467 g, 3.07 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.19 g, 2.30 mmol) was added to it and stirring was continued for overnight. After completion of the reaction, the reaction mixture was poured into ice, extracted with 10% MeOH/DCM. Combined organic layers were dried and concentrated, then the product was purified by column chromatography to afford 5-bromo-3-(cyclopentyl(ethyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.3 g, 42%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH:17]=3)[CH2:13][C:12]2=[O:30])[CH:6]=1)C.[BH4-].[Na+].O>CCO>[CH:25]1([O:24][C:18]2[CH:17]=[C:16]([CH:14]3[CH2:15][N:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][OH:3])[CH:6]=4)[C:12](=[O:30])[CH2:13]3)[CH:21]=[CH:20][C:19]=2[O:22][CH3:23])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)c1cccc(N2CC(c3ccc(OC)c(OC4CCCC4)c3)CC2=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C2CC(=O)N(c3cccc(CO)c3)C2)cc1OC1CCCC1

Procedure:
A solution of 3-[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]benzoic acid ethyl ester (20 mg, 0.05 mmol) in EtOH (0.5 mL) was added NaBH4 (5 mg, 0.135 mmol)). The mixture was stirred at r.t. for 12 h when water (1 mL) was added to quench the reaction. The mixture was poured into water (4 mL) and extracted twice with EtOAc. The combined organic layer was concentrated and purified by preparative LC-MS.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:4]([N+:20]([O-:22])=[O:21])[C:5](OS(C(F)(F)F)(=O)=O)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([F:29])[CH:35]=2)=[C:4]([N+:20]([O-:22])=[O:21])[C:3]=1[C:23]#[C:24][Si:25]([CH3:26])([CH3:27])[CH3:28]
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1-c1cccc(F)c1
Temperature: 80 °C
Yield: 87.5 %

Procedure:
A solution of methyl 5-chloro-3-nitro-2-{[(trifluoromethyl)sulfonyl]oxy}-4-[(trimethylsilyl)ethynyl]benzoate (9.3 g, 20 mmol) and (3-fluorophenyl)boronic acid (4.3 g, 30 mmol) in toluene (200 mL) was treated with water (200 mL) saturated with sodium bicarbonate (3.4 g, 40 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, treated with tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.0 mmol), degassed with nitrogen for 10 minutes, and heated at 80° C. for 6 hours. The reaction mixture was cooled to 20° C. and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to a crude residue. The crude material was diluted with dichloromethane and adsorbed onto 36 g of silica gel. Purification by flash column chromatography using ethyl acetate in hexanes (0%-40%) gave the desired product (7.1 g, 86%). LCMS for C19H18ClFNO4Si (M+H)+: m/z=406.1; Found: 405.7.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[CH3:17])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:42]1([CH2:47][C:48](O)=[O:49])[CH:46]=[N:45][N:44]=[N:43]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:15][C:14]([NH:16][C:48](=[O:49])[CH2:47][N:42]3[CH:46]=[N:45][N:44]=[N:43]3)=[N:13][C:12]=2[CH3:17])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: O=C(O)Cn1cnnn1
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)Cn2cnnn2)sc1-c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 58) (0.08 g, 0.3 mmol) is added to a solution of HATU (0.113 g, 0.3 mmol) and 1-tetrazole acetic acid (0.039 g, 0.31 mmol) in DCM. Triethylamine (0.104 ml, 0.75 mmol) is then added and the reaction mixture is left to stir at room temperature overnight. The product is purified by chromatography on silica eluting with methanol—DCM (96:4) to give the titled compound.
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]1([C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH2:13][CH3:14])[CH:11]=[O:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C1COCC1>[OH:12][CH:11]([C:10]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:13][CH3:14])[C:1]#[N:2]
Reactant: [C-]#N
Reactant: CCC(C=O)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(c1ccccc1)(c1ccccc1)C(O)C#N
Temperature: 40 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
17.4 g (91.6 mmol) of p-toluenesulfonic acid H2O, and then 5.9 g (91.6 mmol) of KCN in 25 ml of water, were added at 35° C. to a solution of 19.09 g (84.8 mmol) of 2,2-diphenylbutyraldehyde in 97 ml of THF (abs.). The mixture was then stirred at 40° C. for 4 hours and at room temperature for 16 hours. The mixture was evaporated to 1/3 of the volume, water was added, and the phases were separated. The aqueous phase was then extracted three times with ethyl acetate, and the combined organic phases were washed with 10% strength sodium disulfite solution, dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed on silica gel with n-heptane/acetic acid (20:1). 19.5 g (92%) of 2-hydroxy-3,3-diphenylvaleronitrile were obtained as a pale oil.
Reaction SMILES: N(OCCC(C)C)=O.[C:9]([O:12][CH2:13][C@@H:14]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@H:16]([N:27]2[CH:35]=[N:34][C:33]3[C:28]2=[N:29][C:30](N)=[N:31][C:32]=3[Cl:36])[O:15]1)(=[O:11])[CH3:10].II.C(I)[I:41].[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.[Cu]I>[C:9]([O:12][CH2:13][C@@H:14]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@H:16]([N:27]2[CH:35]=[N:34][C:33]3[C:28]2=[N:29][C:30]([I:41])=[N:31][C:32]=3[Cl:36])[O:15]1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
Isoamyl nitrite (5 mL, 37 mmol) was added to a mixture of 5.12 g (12 mmol) [(2R,3R,4R,5R)-3,4-diacetyloxy-5-(2-amino-6-chloropurin-9-yl)oxolan-2-yl]methyl acetate (6.3), I2 (3.04 g, 12 mmol), CH2I2 (10 mL, 124 mmol), and CuI (2.4 g, 12.6 mmol) in THF (60 mL). The mixture was heated under reflux for 45 minutes and then allowed to cool to room temperature. To this solution was added 100 ml of sat. Na2S2O3 which removed the reddish color due to iodine. The aqueous was extracted 3× with chloroform, which was pooled, dried over MgSO4, and concentrated under reduced pressure. The product was then purified over a silica gel column using CHCl3—MeOH (98:2) to collect [(2R,3R,4R,5R)-3,4-diacetyloxy-5-(6-chloro-2-iodopurin-9-yl)oxolan-2-yl]methyl acetate (6.4) (80% crystallized from EtOH). 1H NMR (300 MHz, CDCl3) δ 8.20 (s, 1H H-8), 6.17 (d, J=5.41 Hz, 1H, H-1′), 5.75 (t, J=5.39 Hz, 1H, H-2′), 5.56 (t, J=5.40 Hz, 1H, H-3′), 4.38 (m, 3H, H-4′,5′), 2.14 (s, 1H, Ac), 2.11 (s, 1H, Ac), 2.10 (s, 1H, Ac).