Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].OC1CCNCC1.C([O-])(C)(C)C.[K+].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1>C1COCC1>[N+:35]([C:32]1[CH:33]=[CH:34][C:29]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[CH:30][CH:31]=1)([O-:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: OC1CCNCC1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A solution of 2.01 g (10 mmol) of N-Boc-4-hydroxypiperidine (prepared in a standard fashion starting from commercial 4-hydroxypiperidine) in 10 ml of dry THF is added dropwise to a solution of 1.23 g (11 mmol) of tBuO−K+ in 10 ml of dry THF in a three necked flask, under an inert atmosphere, cooled by an ice bath. After agitation for 30 minutes at 0° C., a solution of 1.06 ml (10 mmol) of 4-fluoronitrobenzene in 10 ml of dry THF is added dropwise. The reaction mixture is agitated for 5 hours at 23° C. and finally poured into 25 ml of a water+ice mixture. The product is extracted using 50 ml of ethyl acetate. After decantation, the organic phase is washed twice with 25 ml of water and 25 ml of salt water. The organic solution is dried over magnesium sulphate, followed by filtration and concentration of the filtrate under vacuum to produce a residue which is purified on a silica column (eluant: heptane/ethyl acetate: 8/2). The pure fractions are collected and evaporated under vacuum. The expected product is obtained in the form of a pale yellow powder with a yield of 47%. Melting point: 97-98° C.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH2:16]>CC(N(C)C)=O>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:16][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1cccc(F)c1
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccncc1NCc1cccc(F)c1
Temperature: 168 °C
Reaction time: 1.5 h
Yield: 33.2 %

Procedure:
3-Fluoroisonicotinic acid (100 mg, 0.71 mmol) and 3-fluorobenzylamine (308 μL, 2.84 mmol) were combined in DMA (3 mL) and the solution was stirred at 168° C. in a microwave for 90 min. The solution was concentrated in vacuo and purified through a short plug of silica gel chromatography (20% MeOH/DCM). The semi-pure fractions were concentrated and then taken up in water to give a white precipitate, which was collected by filtration and dried under vacuum to give 58 mg (33%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.99 (br s, 1H), 7.84 (d, 1H, J=5.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.31-7.41 (m, 2H), 7.15-7.23 (m, 2H), 4.62 (s, 2H). [M+H] calc'd for C13H11FN2O2, 247. Found 247.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12].[CH:13]1([CH2:18][CH2:19][CH2:20]O)[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH:13]1([CH2:18][CH2:19][CH2:20][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=2[O:11][CH3:12])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(CC#N)ccc1O
Reactant: OCCCC1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(CC#N)ccc1OCCCC1CCCC1
Temperature: 0 °C
Yield: 96.3 %

Procedure:
2-(4-Hydroxy-3-methoxyphenyl)acetonitrile (0.54 g, 3.31 mmol) in THF (10 mL) was treated with 3-cyclopentylpropan-1-ol (0.424 g, 3.31 mmol), triphenylphosphine (1.128 g, 4.3 mmol) and cooled in an ice bath to 0° C. DIAD (0.785 ml, 4 mmol) was added to the reaction mixture dropwise over the period of 5 min, and the reaction was left stirring slowly warming to room temperature over 18 hours. The reaction mixture was concentrated. Purification by flash chromatography (silica gel, 0-40% EtOAc/hexanes) afforded 0.871 g (96%) of 2-(4-(3-cyclopentylpropoxy)-3-methoxyphenyl)acetonitrile. MS (ESI) m/z 274 (M+H)+
Reaction SMILES: [OH-].[K+].[CH3:3][C@@H:4]1[CH2:8][CH2:7][C:6](=O)[CH:5]1[C:10]([O:12]CC)=O.[NH2:15][C:16]([NH2:18])=[S:17]>O.C(O)C>[SH:17][C:16]1[N:15]=[C:10]([OH:12])[C:5]2[C@H:4]([CH3:3])[CH2:8][CH2:7][C:6]=2[N:18]=1
Reactant: CCOC(=O)C1C(=O)CC[C@H]1C
Reactant: NC(N)=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@@H]1CCc2nc(S)nc(O)c21
Yield: 56 %

Procedure:
KOH (8.3 g, 147.9 mmol) in water (60 mL) was added to a solution of a mixture of (2R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (20 g, 117.5 mmol) and thiourea (9.2 g, 120.9 mmol) in ethanol (100 mL). The mixture was refluxed for 10 hours. After cooling, the solvent was removed, and the residue was neutralized with concentrated HCl (12 mL) at 0° C. The mixture was then extracted with DCM (3×150 mL). The solvent was removed, and the residue was purified by silica gel chromatography, eluting with hexane/ethyl acetate (2:1) to give (R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12 g, 56%). MS (APCI+) [M+H]+183.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30](Br)[CH3:31])=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:40][C:41]([F:50])([F:49])[C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1>CN(C=O)C.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[CH2:15][C@H:16]([C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([O:48][C:45]2[CH:46]=[CH:47][C:42]([C:41]([F:40])([F:49])[F:50])=[CH:43][CH:44]=2)[CH3:31])=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(Br)COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
The bromide 48.1 (80 mg, 0.16 mmol) was dissolved in DMF (2.0 mL). Cesium carbonate (200 mg, 0.62 mmol) and 4-trifluoromethylphenol (100 mg, 0.62 mmol) were added to the solution and the mixture was then heated with stirring for three hours. The reaction mixture was then cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with 1M lithium chloride solution (1×25 mL), water (1×25 mL) and brine (1×25 mL) and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue purified by medium pressure chromatography (silica, 0 to 60% EtOAc: hexanes) to obtain 48.2 (39 mg). MS ESI (pos.): m/e 595.2 (M+H).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH2:22][CH:23]([CH3:25])[CH3:24])[O:11][C:10](=[O:12])[C:9]([O:13]CC3C=CC=CC=3)=[C:8]2[OH:21])=[CH:3][CH:2]=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH2:22][CH:23]([CH3:25])[CH3:24])[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:21])=[CH:3][CH:2]=1
Reactant: CC(C)CC1(c2ccc(-c3ccccc3)cc2)OC(=O)C(OCc2ccccc2)=C1O
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: CC(C)CC1(c2ccc(-c3ccccc3)cc2)OC(=O)C(O)=C1O
Yield: 69.4 %

Procedure:
Hydrogenolysis of 350 mg of 5-[(1,1′-biphenyl)-4-yl]-4-hydroxy-3-phenylmethoxy-5-(2-methylpropyl)-2(5H)-furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provide 190 mg (69% yield) of a white powder: mp 198-199° C. dec.(CHCl3/hexanes). 1H NMR (acetone-d6) δ 7.73-7.34 (m, 9H), 2.44-2.28 (m, 1H), 1.50-0.80 (m, 8H). 13C NMR (acetone-d6) δ 169.21, 155.47, 140.81, 139.57, 129.17, 127.73, 127.18, 127.08, 126.04, 118.47, 86.01, 40.66, 23.72, 12.11, 11.87. Anal Calcd for C20H20O4+0.125 H2O: C, 73.55; H, 6.25. Found: C, 73.25; H, 6.36.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[N:9]=1.[C:22](O)(=[O:25])[CH:23]=[CH2:24]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: Nc1cccc(Nc2nccc(Sc3ccccn3)n2)c1
Reactant: C=CC(=O)O
Product: C=CC(=O)Nc1cccc(Nc2nccc(Sc3ccccn3)n2)c1
Yield: 42.9 %

Procedure:
In a procedure analogous to Example 15, reaction of N1-(4-(pyridin-2-ylthio)pyrimidin-2-yl)benzene-1,3-diamine (35 mg, 0.12 mmol) and acrylic acid (16 μL, 0.24 mmol) furnished the product (18 mg, 43%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:10](=[O:25])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH:35]([C:37]1[CH:38]=[C:39]([CH2:43][CH:44]([CH3:47])[C:45]#[N:46])[CH:40]=[CH:41][CH:42]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:1]1([NH:7][C:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:35][C:37]4[CH:38]=[C:39]([CH2:43][CH:44]([CH3:47])[C:45]#[N:46])[CH:40]=[CH:41][CH:42]=4)[CH2:16][CH2:17]3)[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:10](=[O:25])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C#N)Cc1cccc(C=O)c1
Reactant: O=C1N=C(NC2CCCCC2)C2(CCNCC2)N1c1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C#N)Cc1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Reaction time: 0.17 h

Procedure:
To a 20 mL dichloroethane solution of 0.35 g (0.92 mmol) 4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one and 0.25 mL (1.4 mmol) DIEA went 0.16 g (0.92 mmol) 3-(3-formylphenyl)-2-methylpropanenitrile (9-3). The suspension was allowed to stir for 10 min then 0.4 g (1.9 mmol) sodium triacetoxyborohydride was added and the reaction was allowed to stir at rt overnight. HPLC/MS showed no starting material so the reaction was quenched with 100 mL sat NaHCO3 and diluted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The remaining oil was purified on an Isco automated system affixed with a Biotage Flash 25(M) cartridge eluted with 5% MeOH+0.5M NH3 in CH2Cl2 at 25 mL/min over 30 min. The product eluted second.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[N:10]([CH3:14])[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a stirring suspension of 8-bromo-3-methylxanthine (prepared as described above for CT12440) (12.25 g, 50.0 mmol) and potassium carbonate (8.62 g, 62.5 mmol) in dimethylformamide (150 ml) was added methyl iodide (7.81 g, 55.0 mmol). After stirring overnight at room temperature, the mixture was poured into ice cold water (400 ml) and stirred at 0-5° C. for 1 hour. The precipitate was filtered, rinsed with water (5×25 ml) and dried under vacuum to provide 8-bromo-3,7-dimethylxanthine (12.10 g, 93% yield) as a beige solid.
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[N:50]1([C:55]2[CH:63]=[CH:62][CH:61]=[CH:60][C:56]=2[C:57](O)=[O:58])[CH:54]=[CH:53][CH:52]=[N:51]1>>[N:50]1([C:55]2[CH:63]=[CH:62][CH:61]=[CH:60][C:56]=2[C:57]([NH:16][C@H:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[NH:10][C:7]2[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=2)=[O:58])[CH:54]=[CH:53][CH:52]=[N:51]1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1ccccc1-n1cccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1cccn1

Procedure:
A solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 213 mg, 0.75 mmol), HATU (430 mg, 1.13 mmol), triethylamine (0.315 ml, 2.26 mmol) and 2-(1H-pyrazol-1-yl)benzoic acid (CAS number 55317-53-8; 156 mg, 0.83 mmol) was stirred at room temperature overnight. This was then partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5](O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S([O-])([O-])(=O)=O.[Mg+2].[CH2:23]([NH2:26])[CH2:24][NH2:25]>C1C=CC=CC=1>[NH2:25][CH2:24][CH2:23][N:26]1[CH2:2][C:3]2[C:4](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: OCc1ccccc1C(O)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: NCCN1Cc2ccccc2C1c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 127 g. (0.59 mole) of 2-hydroxymethylbenzhydrol was dissolved in 900 ml. of benzene, 80 g. of anhydrous magnesium sulfate was added and the mixture was cooled in an ice bath. Hydrogen bromide was bubbled into the stirred solution until saturation which took about 30 minutes. During this time the temperature of the solution was kept at 15°-18°. The ice bath was removed and the temperature was allowed to rise to 35° in the course of 1 hour. The mixture was heated for another hour at 40°-45° on a steam bath. During the whole time hydrogen bromide was passed into the solution to keep it saturated. The mixture was filtered and the solution was concentrated in vacuo to give a red oil which was dissolved in 200 ml. of benzene and added to 342 g. (5.7 moles) of ethylenediamine in the course of 15 minutes. During the addition the mixture was stirred and cooled to maintain a temperature of ca. 40°. The mixture was stirred at 25° for 70 minutes. Two layers were obtained and separated. The benzene layer was washed with water and concentrated in vacuo. The residual oil was dissolved in 250 ml. of ether. This solution was extracted twice with 300 ml. of cold 1N hydrochloric acid. The acidic aqueous phase was made alkaline with aqueous sodium hydroxide and extracted with 350 ml. of ether. The ethereal solution was washed with 250 ml. of water, dried and concentrated. The residue was an amber oil which crystallized on scratching. This material melted up to ca. 45°.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CC([O:29]O)(C)C.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(O)C>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:5]=[N:4][C:3]=1[CH2:14][S+:15]([O-:29])[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: CC(C)(C)OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC(C)O
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Reaction time: 30 h
Yield: 37 %

Procedure:
At room temperature, 1.307 g of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio]-1H-benzimidazole, 0.059 g of tetrabutyl ammonium bromide as an interphase transfer catalyst, and 0.157 g of Mo(acac)2 oxidation catalyst were mixed in 15 ml of IPA. Next, 1.36 g of TBHP (70% aqueous solution) was added into the mixture in about 5–10 minutes. The reaction was carried out for about 30 hours, and then 60 ml of water was added, and the reaction was continued for another one hour while stirring. Finally, the precipitate formed was filtered, water washed, and dried to obtain Lansoprazole with a yield of about 37% (HPLC purity>96%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[NH:15][N:14]=[N:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:19]=1[CH2:20]Br>CN(C=O)C.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[N:15]=[N:14][N:13]([CH2:20][C:19]3[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH3:16])[C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Reactant: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1Cn1nnc2c(-c3ccco3)nc(N)nc21
Reaction time: 1 h
Yield: 25.3 %

Procedure:
A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (606 mg, 3 mmol) in DMF (5 mL) at 0° C., was treated with CsCO3 (977 mg, 3 mmol), stirred for 1 h, treated with 2-methoxy-5-nitrobenzyl bromide (738 mg, 3 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with water (10 mL), filtered and the resulting solid purified by chromatography [SiO2; EtOAc:Heptane (2:1)] to give the title compound (279 mg, 25%) as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[C:21]([Cl:26])[CH:20]=3)=[O:16])[CH2:9]1.[N+](C1C=CC([O:36][C:37](=O)[NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]3=[O:51])=[CH:41][C:40]=2[F:52])=CC=1)([O-])=O>>[F:52][C:40]1[CH:41]=[C:42]([N:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]2=[O:51])[CH:43]=[CH:44][C:39]=1[NH:38][C:37]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[C:21]([Cl:26])[CH:20]=3)=[O:16])[CH2:9]1)=[O:36]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NC[C@H]1CCNC1)c1cc2ccc(Cl)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1cc2ccc(Cl)cc2[nH]1

Procedure:
68.3 Using general method H, 6-chloro-1H-indole-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give 6-chloro-1H-indole-2-carboxylic acid {(R)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidin-3-ylmethyl}-amide. Pale yellow solid. MS 506.1 ([M−H]−)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([OH:35])=O)=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:35])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:16]=23)[CH2:2][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c8) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: C([O:9][C:10]1[C:11]([C:27]([O:29]C)=O)=[N:12][C:13]([O:20][CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=O)C1C=CC=CC=1.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:37][C:27]([C:11]2[C:10]([OH:9])=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13]([O:20][CH2:21][C:22]([N:24]([CH3:25])[CH3:26])=[O:23])[N:12]=2)=[O:29])=[CH:34][CH:33]=1
Reactant: COC(=O)c1nc(OCC(=O)N(C)C)c2cccnc2c1OC(=O)c1ccccc1
Reactant: NCc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: CN(C)C(=O)COc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Temperature: 110 °C

Procedure:
A mixture of methyl ester from Step 1 (0.28 g, 0.68 mmol) and 4-fluorobenzylamine (0.16 mL, 1.43 mmol) in toluene (5 mL) was heated in an oil bath at 110° C. overnight. The resultant precipitate was filtered, washed with diethyl ether, and dried under vacuum. The solid was dissolved in DMSO and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as yellow solid.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:13]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=O)=[C:9]2[C:8](=[O:34])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:4])[CH3:3].[NH3:37]>O>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:13]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([NH2:37])=[O:19])=[C:9]2[C:8](=[O:34])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:4])[CH3:3]
Reactant: N
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cccc(C(=O)O)c3)n(Cc3cccc4ccccc34)nc21
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cccc(C(N)=O)c3)n(Cc3cccc4ccccc34)nc21

Procedure:
This compound was synthesized by the reaction of 3-[7-isobutyl-5-methyl-2-(1-naphthylmethyl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]benzoic acid and ammonia in water using diethyl isobutyl chloroformate as a coupling reagent Mass: 481.89 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:13]4[CH:14]=[C:15]([NH:20][C@H:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[CH3:22])[C:16]([C:18]#[N:19])=[CH:17][C:12]=4[N:11]=[CH:10]3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-:30].[K+]>CO.OO.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:13]4[CH:14]=[C:15]([NH:20][C@H:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[CH3:22])[C:16]([C:18]([NH2:19])=[O:30])=[CH:17][C:12]=4[N:11]=[CH:10]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1cc2c(cc1C#N)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@H](Nc1cc2c(cc1C(N)=O)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Temperature: 75 °C
Yield: 44 %

Procedure:
1-(5-Cyclopropyl-1H-pyrazol-3-yl)-6-[(S)-1-(4-fluorophenyl)ethylamino]-1H-benzo[d]imidazol-5-carbonitrile (Example 33; 0.30 g, 0.77 mmol) was dissolved in MeOH (10 ml), followed by addition of 25% aqueous KOH solution (0.87 ml, 3.88 mol) and 15 drops of 30% H2O2 solution. The reaction was heated at 75° C. for 48 hours. After cooling, the reaction was diluted with H2O (5 ml). The resulted solid was collected by filtration and dried under vacuum to give the title compound (0.137 g, 44%) as a white solid. NMR (400 MHz) 12.70 (s, 1H), 8.66 (d, J=4.8 Hz, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 8.03 (br, 1H), 7.42 (m, 2H), 7.24 (br, 1H), 7.13 (m, 1H), 6.80 (s, 1H), 6.00 (s, 1H), 4.57 (m, 1H), 1.95 (m, 1H), 1.47 (d, J=6.0 Hz, 3H), 1.02 (m, 2H), 0.74 (m, 2H). MS: Calcd.: 404; Found: [M+H]+ 405.