Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH3:23])[C:20]([S:24][CH:25]5[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:36].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[C:20]([S:24]([CH:25]5[CH2:26][CH2:27][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:29][CH2:30]5)=[O:36])[C:21]([CH3:23])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)c(C)cc2OCC3)n(C(C)C)n1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)c(C)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidin-4-ylsulfanyl)-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 32 (112 mg, 0.233 mmol) in DCM (10 mL) was added TFA (90 μL, 1.165 mmol) followed by a solution of m-CPBA (44 mg, 0.256 mmol) in DCM (2 mL). The resulting mixture was stirred for 20 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 20-50% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH affording 225 as a white solid (100 mg, 87%). LCMS: RT 2.60 min [M+H]+ 497.1. 1H NMR (DMSO, 400 MHz): δ 8.72 (1H, s), 7.89 (1H, s), 7.00 (1H, s), 5.72-5.60 (1H, m), 4.62-4-47 (4H, m), 2.80 (2H, t, J=11.82 Hz), 2.72-2.57 (2H, m), 2.33 (3H, s), 2.25 (3H, s), 2.18-2.00 (2H, m), 1.81 (1H, bd, J=12.17 Hz), 1.63-1.38 (9H, m), 0.89 (6H, d, J=6.54 Hz)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[N:12][C:13]([NH:16][C:17]([NH2:19])=[S:18])=[CH:14][CH:15]=1)(=[O:9])=[O:8].Br[CH2:21][C:22](=O)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1>CN(C=O)C.CC(O)=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:22]2[N:19]=[C:17]([NH:16][C:13]3[N:12]=[CH:11][C:10]([S:7]([NH:6][C:2]4[S:1][CH:5]=[CH:4][N:3]=4)(=[O:8])=[O:9])=[CH:15][CH:14]=3)[S:18][CH:21]=2)=[CH:25][CH:26]=1
Reactant: O=C(CBr)Cc1ccc(Cl)cc1
Reactant: NC(=S)Nc1ccc(S(=O)(=O)Nc2nccs2)cn1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccs1)c1ccc(Nc2nc(Cc3ccc(Cl)cc3)cs2)nc1
Temperature: 95 °C

Procedure:
The mixture of the 6-Thioureido-pyridine-3-sulfonic acid thiazol-2-ylamide (27 mg, 0.000086 mol) and 1-Bromo-3-(4-chloro-phenyl)-propan-2-one (25 mg, 0.00010 mol) in DMF/AcOH (1:1) was heated at 95° C. for 20 min. The reaction solution was directly purified on Gilson (semi-prep, reverse phase, Phenomenex 100×21.2 mm 10 micron C18 column, 20 mL/min, Gradient 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8 TFA). Fractions were checked by LC/MS and found no pure desired product was isolated. Fractions with the desired product were combined and then dried on a lyophilizer to give the product (1126-8-P1) as a yellow powder. The product (a mixture) was purified again by chromatography (silica gel, 5% Ethyl acetate in hexanes to 100% Ethyl acetate) to give a cleaner product (1126-8-P2), which was purified by Prep TLC (25% Ethyl acetate in hexanes, then 100% Ethyl acetate) to give the final pure product (1126-8-P-3) as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.[I-].[Na+]>C(#N)C>[N:38]1([CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[NH:16][N:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: C1COCCN1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)n[nH]c12
Temperature: 60 °C
Reaction time: 0.02 h
Yield: 16.2 %

Procedure:
To a solution of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indazole-7-carboxamide (Intermediate 22) (20 mg, 0.0435 mmol) in acetonitrile (1 mL) was added K2CO3 (27 mg, 0.174 mmol), morpholine (19 uL, 0.219 mmol) and sodium iodide (0.8 mg, 0.00435 mmol). The reaction mixture was heated to 60° C. for 14 hrs. The solution was filtered and concentrated. The residue was purified by using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 80% B in 10 min, hold for 1 min where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (3.6 mg, 16%).
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14](=[O:16])[CH3:15])[CH:5]=[C:4]([Cl:17])[C:3]=1[CH3:18].[F:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[C:22]([F:29])[N:21]=1.O.N#N>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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:17][C:4]1[C:3]([CH3:18])=[C:2]([C:24]2[CH:23]=[C:22]([F:29])[N:21]=[C:20]([F:19])[CH:25]=2)[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14](=[O:16])[CH3:15])[CH:5]=1
Reactant: OB(O)c1cc(F)nc(F)c1
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1cc(Cl)c(C)c(-c2cc(F)nc(F)c2)c1-c1ccccc1
Temperature: 100 °C
Yield: 27 %

Procedure:
A biphasic solution of 1-(6-bromo-4-chloro-5-methylbiphenyl-2-yl)ethanone (0.20 g, 0.62 mmol) and (2,6-difluoropyridin-4-yl)boronic acid (0.12 g, 0.74 mmol) in 1,4-dioxane (2.0 mL) and 10% Na2CO3 in water (0.98 mL, 0.93 mmol)) was bubbled with N2 to degas. After tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) was added the mixture was bubbled with N2 for 5 min. and heated at 100° C. overnight. The mixture was cooled to room temperature and diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column, eluting with 0-30% of ethyl acetate in hexane, to give the desired product (60 mg, 30%). LCMS calculated for C20H15ClF2NO (M+H)+: m/z=358.1. found: 358.0.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]#[C:31][CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33]>C(OCC)C>[C:34]1([C:32](=[O:33])[C:31]#[C:30][C:26]2[O:25][CH:29]=[CH:28][CH:27]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: OC(C#Cc1ccco1)c1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(C#Cc1ccco1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Place pyridinium dichromate (0.75 g, 2 mmol) and methylene chloride (15 mL) under argon atmosphere and cool to 0° C. Add α-[(2-furanyl)ethynyl]-benzenemethanol (297 mg, 1.5 mmol). Stir overnight while slowly warming to room temperature. Dilute with ethyl ether and filter the chromium salts. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5]1.F[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[N:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH:15]=[CH:14]2.O>CC(N(C)C)=O>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:16]2[CH:15]=[CH:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:9][C@H:6]4[CH2:7][CH2:8][C@H:4]([NH2:3])[CH2:5]4)[CH:12]=3)[C:17]2=[O:21])=[CH:28][CH:27]=1
Reactant: COc1ccc(Cn2ccc3cc(F)ccc3c2=O)cc1
Reactant: N[C@H]1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(Cn2ccc3cc(O[C@H]4CC[C@H](N)C4)ccc3c2=O)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
106 mg (4.20 mmol) of sodium hydride (95%) were suspended in 3 mL of dimethyl acetamide and 193 mg (1.40 mmol) of (1S,3S)-3-amino-cyclopentanol (34), dissolved in 1 mL of dimethyl acetamide, were added dropwise. After 1 h, 402 mg (1.42 mmol) of 2-(4-methoxy-benzyl)-6-fluoro-2H-isoquinolin-1-one (9), dissolved in another 3 mL of dimethyl acetamide, were added. The reaction mixture was stirred at 80° C. until the reaction was complete. The mixture was poured into water, extracted three times with a mixture of dichloromethane and 2-propanol (3:1) and the combined organic layers were evaporated. Water was added and the crude product was subjected to lyophilization to remove remainders of dimethyl acetamide. The obtained crude product was purified by silica gel chromatography to yield 250 mg of the title compound (39). Rt=1.20 min (Method E). Detected mass: 365.2 (M+H+).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][NH:17][C:16](=O)[C:15]=1[N+:21]([O-:23])=[O:22]>CN(C=O)C>[Cl:3][C:16]1[C:15]([N+:21]([O-:23])=[O:22])=[C:14]([C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[Cl:6])[CH:19]=[CH:18][N:17]=1
Reactant: O=c1[nH]ccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1Cl
Temperature: 25 °C
Yield: 19 %

Procedure:
To 10 mL of POCl3 was added 4-(2,4-dichloro-phenyl)-3-nitro-1H-pyridin-2-one (1.0 g, 3.51 mmol), followed by the addition of DMF (1-2 mL) and the reaction refluxed for 5 h. The reaction mixture was cooled to room temperature and poured over ice-H2O (200 mL). The solution was extracted with EtOAc, washed with H2O, brine, dried (MgSO4), filtered, and concentrated in vacuo to give 0.20 g (19%) of 2-chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine as a brown viscous oil: crude 1H NMR (300 MHz, CDCl3): δ 8.6 (d, 1H), 7.5 (s, 1H), 7.38 (s, 1H), 7.34 (d, 1H), 7.20 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)C(C(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 80.1 g of 2-(4-nitrophenyl)-3-methylbutanoic acid, 150 ml of benzyl alcohol, 75 ml of toluene and 2 g of p-toluenesulfonic acid monohydrate was boiled under reflux, with azeotropic removal of water, for 10 hours. The toluene and excess benzyl alcohol were removed in vacuum, and the residual oil was dissolved in butyl chloride. The butyl chloride solution was washed with 6% potassium carbonate three times (acidification of the carbonate extract precipitated 5.2 g of the starting carboxylic acid), water and saturated brine. The dried (MgSO4) butyl chloride solution was evaporated to a residual oil. The oil was vacuum distilled, the bulk of it boiling at 197°-200°/0.3 Torr, providing 99 g of 2-(4-nitrophenyl)-3-methylbutanoic acid, benzyl ester as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16](/[CH:21]=[CH:22]\[C:23]4[CH:24]=[C:25]([C:33]([O:35][CH3:36])=[O:34])[C:26](=[CH:31][CH:32]=4)[C:27]([O:29][CH3:30])=[O:28])[CH:15]=3)=[C:10]([CH2:37][CH2:38][CH3:39])[CH:9]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].C(OCC)(=O)C.C(N(CC)CC)C>CO>[CH2:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([CH2:21][CH2:22][C:23]4[CH:24]=[C:25]([C:33]([O:35][CH3:36])=[O:34])[C:26](=[CH:31][CH:32]=4)[C:27]([O:29][CH3:30])=[O:28])[CH:15]=3)=[C:10]([CH2:37][CH2:38][CH3:39])[CH:9]=2)[O:4][CH2:5][CH2:6][O:7]1)[CH3:2]
Reactant: CCCc1cc(C2(CC)OCCO2)ccc1-c1cc(/C=C\c2ccc(C(=O)OC)c(C(=O)OC)c2)ccc1C
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCc1cc(C2(CC)OCCO2)ccc1-c1cc(CCc2ccc(C(=O)OC)c(C(=O)OC)c2)ccc1C
Yield: 92.8 %

Procedure:
700 mg (1.3 mmol) of dimethyl 4-{(Z)-2-[4′-(2-ethyl[1,3]dioxolan-2-yl)-6-methyl-2′-propylbiphenyl-3-yl]vinyl}phthalate are placed in 15 ml of methanol, 15 ml of ethyl acetate and 1 ml of triethylamine in a reactor. The reaction medium is degassed and 100 mg of palladium-on-charcoal (10%) and hydrogen to a pressure of 3.5 bar at 80° C. are added. The reaction medium is filtered and evaporated to give 640 mg (93%) of the expected product in the form of an oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[C:12]1[C:13]([NH:15][C:16](=[O:18])[CH:17]=1)=[O:14].[CH:19]([O:21][CH2:22][CH3:23])=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>C(Cl)Cl.N1C=CC=CC=1>[CH2:19]([O:21][CH:22]([O:9][C:6]1[C:5]([F:10])=[C:4]([F:11])[C:3]([C:12]2[C:13]([NH:15][C:16](=[O:18])[CH:17]=2)=[O:14])=[C:2]([F:1])[C:7]=1[F:8])[CH3:23])[CH3:20]
Reactant: O=C1C=C(c2c(F)c(F)c(O)c(F)c2F)C(=O)N1
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(C)Oc1c(F)c(F)c(C2=CC(=O)NC2=O)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
3 g of the 2,3,5,6-tetrafluoro-4-hydroxyphenylmaleimide obtained in Example 2 was dissolved in 20 ml of methylene chloride. Thereto was added 2.1 g of ethyl vinyl ether and 58 mg of pyridine salt of p-toluenesulfonic acid. The mixture was stirred at room temperature for 12 hours. 100 ml of ether was added. The mixture was washed with an aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent to obtain 2.8 g of an intended compound (yield: 73%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][CH:3]=1.C([Li])CCC.[B:25](OC)([O:28]C)[O:26]C.C(OC1C=CC(B(O)O)=CC=1)CCCCCCC>C1COCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([B:25]([OH:28])[OH:26])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COB(OC)OC
Reactant: CCCCCCCCCCCOc1ccc(Br)cc1
Agent: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCOc1ccc(B(O)O)cc1

Procedure:
Quantities: compound 29 (15.36 g, 0.047 mol) in anhydrous THF (200 ml), n-butyllithium (26 ml, 2.5M in hexane, 0.065 mol), trimethyl borate (9.79 g, 0.094 mol) in anhydrous THF (26 ml). The experimental procedure was as described for the preparation of compound 33.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:28]2[N:37]=[CH:36][C:35]3[C:30](=[C:31]([F:42])[CH:32]=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:34]=3)[C:29]2=[O:43])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[N:21]([CH3:25])[N:20]=2)[C:15](=[O:26])[N:14]([CH3:27])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:38]([C:33]1[CH:34]=[C:35]2[C:30](=[C:31]([F:42])[CH:32]=1)[C:29](=[O:43])[N:28]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([CH3:24])[N:21]([CH3:25])[N:20]=4)[C:15](=[O:26])[N:14]([CH3:27])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:37]=[CH:36]2)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C)n(C)n3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)nn1C
Temperature: 30 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
A mixture of 119b (150 mg, 0.26 mmol) and lithium hydroxide (61.4 mg, 2.6 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was diluted with water (5 mL). It was then extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 119 (75.0 mg, 54%) as a white solid. MS-ESI: [M+H]+ 544.3. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=5.0 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.59-7.53 (m, 4H), 7.37 (s, 1H), 5.74 (s, 1H), 4.51 (s, 2H), 4.07 (s, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 2.25 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([N:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:17][CH3:18])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: CCNc1cccnc1
Solvent: CCN(CC)CC
Product: CCN(c1cccnc1)c1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(3-pyridyl)-2-ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-(ethylamino)pyridine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([NH:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cncc(Br)c1
Product: O=C(NCc1ccccc1)c1cncc(Br)c1
Yield: 90 %

Procedure:
5-bromo-N-(phenylmethyl)pyridine-3-carboxamide was synthesized according to the procedure described above from 5-bromonicotinic acid and benzylamine. Yield 90%. 1H NMR (400 MHz, CDCl3): 8.83 (d, 1H), 8.72 (d, 1H), 8.25 (t, 1H), 7.30 (m, 5H), 6.58 (br s, 1H), 4.62 (d, 2H); MS (EI) for C13H11N2OBr: 291 (MH+).
Reaction SMILES: C([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:29])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(C)(C)C.[OH:30][C:31]1C=CC(CC(NC2C=CC=C(C3C=CC=CC=3)C=2)=O)=C[C:32]=1OC>>[C:31]([O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:8]3[CH:7]=[CH:6][CH:5]=[CH:10][CH:9]=3)[CH:12]=2)=[O:29])=[CH:21][C:22]=1[O:27][CH3:28])(=[O:30])[CH3:32]
Reactant: COc1cc(CC(=O)Nc2cccc(-c3ccccc3)c2)ccc1O
Reactant: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1O
Product: COc1cc(CC(=O)Nc2cccc(-c3ccccc3)c2)ccc1OC(C)=O

Procedure:
Instead of N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide in Example 69, the compound of Example 35 is treated in a similar manner to Example 69 to give the desired compound.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:43]1[CH2:48][CH2:47][O:46][CH2:45][CH:44]1[C:49]1[C:57]2[S:56][C:55]([NH2:58])=[N:54][C:53]=2[C:52]([O:59][CH3:60])=[CH:51][CH:50]=1>C1COCC1.C(Cl)(Cl)Cl>[O:43]1[CH2:48][CH2:47][O:46][CH2:45][CH:44]1[C:49]1[C:57]2[S:56][C:55]([NH:58][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])=[N:54][C:53]=2[C:52]([O:59][CH3:60])=[CH:51][CH:50]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)C3CCCCC3)nc12

Procedure:
From cyclohexanecarboxylic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+19.2° (c=1.05, CHCl3), ES-MS m/e (%): 377 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[C:14]([O:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:13]=[C:12]([O:23]CC3C=CC=CC=3)[CH:11]=2)=[N:6][CH:7]=1>C(O)C.[Pd]>[OH:23][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:13]=1)[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:31]
Reactant: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(OC3CCOCC3)c2)cn1
Agent: [Pd]
Solvent: CCO
Product: Cc1cnc(NC(=O)c2cc(O)cc(OC3CCOCC3)c2)cn1
Reaction time: 96 h
Yield: 90 %

Procedure:
N-(5-Methylpyrazin-2-yl)-3-[(phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide (1.70 g, 4.05 mmol) was dissolved in ethanol (40 mL) and 10% palladium on charcoal (86 mg) catalyst added under argon. The reaction was stirred under an atmosphere of hydrogen for 4 days then filtered and the filtrate concentrated in vacuo to give the desired compound as a cream-coloured solid (1.20 g). m/z 330 (M+H)+
Reaction SMILES: C([Li])CCC.[N:6]1[C:11]2[NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=[O:17])[NH:16][C:10]=2[CH:9]=[CH:8][CH:7]=1.[C:22](Cl)(=[O:27])[CH2:23][CH2:24][C:25]#[CH:26]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[O:27]=[C:22]([N:12]1[C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](=[O:17])[NH:16][C:10]2[CH:9]=[CH:8][CH:7]=[N:6][C:11]1=2)[CH2:23][CH2:24][C:25]#[CH:26]
Reactant: C#CCCC(=O)Cl
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CCCC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
22.4 ml of a 1.6 molar solution of n-butyl-lithium in n-hexane are added dropwise with stirring, at 0° C., to a suspension of 3.7 g (0.017 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in 150 ml of absolute tetrahydrofuran. After it has all been added, the mixture is stirred for a further 30 minutes and then mixed with a solution of 2.04 g (0.0175 mol) of 4-pentynoic acid chloride in 20 ml of tetrahydrofuran. The mixture is heated to 30° C. and stirred for a further hour. The reaction mixture is then poured into a saturated saline solution. The organic phase is diluted with ethyl acetate and, after being separated off, washed twice with saline solution, filtered over charcoal and evaporated to dryness in vacuo. The crude product is purified by column chromatography on silica gel using chloroform as eluant. 2.2 g (43% of theory) of colourless crystals were obtained, melting point 179°-180° C.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>>[C:1]1([CH:7]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:18]3[CH2:19][O:20]3)=[CH:13][CH:14]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCC1CO1
Reactant: CC(c1ccccc1)c1ccc(O)cc1
Product: CC(c1ccccc1)c1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-(1-phenyl-ethyl)-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.