Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[S:11]([F:16])([F:15])([F:14])([F:13])[F:12].[NH2:17][C:18]1[CH:34]=[CH:33][C:21]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:31][CH3:32])=[O:30])[CH:24]=2)=[CH:20][CH:19]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:17][C:18]2[CH:34]=[CH:33][C:21]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:31][CH3:32])=[O:30])[CH:24]=3)=[CH:20][CH:19]=2)=[O:10])=[CH:4][C:3]=1[S:11]([F:16])([F:12])([F:13])([F:14])[F:15]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C=Nc1ccc(Br)c(S(F)(F)(F)(F)F)c1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Br)c(S(F)(F)(F)(F)F)c3)cc2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
The crude 1-bromo-4-isocyanato-2-(pentafluoro-λ6-sulfanyl)benzene obtained above was dissolved in DCM (70 mL). 4-(4-aminophenoxy)-N-methylpicolinamide (1.54 g, 6.34 mmol, 0.8 eq) was added at room temperature under N2. The mixture was stirred at room temperature for about 30 min, a lot of solid precipitated. DCM (30 mL) was added and made the mixture stirred at room temperature for 18 hrs. The solid was filtrated, washed with DCM (50 mL), dried under high vacuum to afford 2.6 g (yield 72%) of the title compound as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:8]([NH2:9])=[CH:7][CH:6]=1.Cl.[N:16]([O-])=O.[Na+]>C(OCC)(=O)C.CO.O>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]=[N:16][NH:12][C:10]=2[CH:11]=1
Reactant: Nc1ccc(OCCBr)cc1[N+](=O)[O-]
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: BrCCOc1ccc2nn[nH]c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.6 %

Procedure:
Raney nickel (10.95 g) was washed with water (4×300 ml) then with methanol (4×300 ml). The catalyst was suspended in 450 ml of methanol and 4-(2-bromoethoxy)-6-nitroaniline (5.08 g, 19.46 mmol) was added. The reaction mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 1.5 h. After removal of the catalyst by filtration, the filtrate was evaporated to give a black residue. The black residue was redissolved in a mixture of ethyl acetate (200 ml) and methanol (50 ml). Etheral HCl solution (1N, 40 ml) was added slowly to precipitate the diamine as the hydrochloride salt. The purple solid was collected and dissolved in a mixture of acetic acid (25 ml) and water (50 ml). The reaction mixture was cooled to 5° C. in an ice-bath. A solution of sodium nitrite (1.75 g, 25.36 mmol) in 10 ml water was added slowly into the reaction mixture. The mixture was heated at 80° C. for 3 h. The solid was collected by filtration and washed with water (3×30 ml). The solid was dissolved in THF and dried over magnesium sulphate, filtered and concentrated. The residue was chromatographed on silica gel eluted with 50% ethyl acetate in hexanes to give 2.15 g of 6-(2-bromoethoxy)-1H-benzotriazole as a white solid. 1H NMR (CDCl3) 7.86 (1h, d, J=9.03), 7.11-7.05 (2H, m), 4.34 (2H, t, J=6.10), 3.67 (2H, t, J=6.10).
Reaction SMILES: [CH3:1][C:2]([CH3:41])([S:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH:12]=2)[N:7]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:6]=1[CH2:34][C:35]([CH3:40])([CH3:39])[C:36](O)=[O:37])[CH3:3]>C1COCC1>[CH3:3][C:2]([CH3:41])([S:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH:12]=2)[N:7]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:6]=1[CH2:34][C:35]([CH3:40])([CH3:39])[CH2:36][OH:37])[CH3:1]
Reactant: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12
Solvent: C1CCOC1
Product: CC(C)(CO)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reaction time: 18 h
Yield: 72.2 %

Procedure:
To a solution of 3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionic acid (2.57 g, 4.4 mmol) in THF (20 mls) was added borane dimethyl sulfide complex (1.06 g, 14.0 mmol) dropwise. Upon completion of addition, the reaction was stirred for 18 hrs. It was then quenched slowly and dropwise with aqueous sat'd NaHCO3 (30 mls). The THF was stripped off in vacuo and the aqueous residue was extracted with ethylacetate (3×50 mls). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 1:1) to afford 1.82 g (72%) of 3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropanol as a white foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.[NH2:28][OH:29]>CO>[OH:29][NH:28][C:21]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:27])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[O:15])=[CH:26][CH:25]=1)=[O:22]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: NO
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(C(=O)NO)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of methyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamido)benzoate 3 (0.200 g, 0.5 mmol) in MeOH (2 mL) was added an hydroxylamine solution (1.76 M, 2 mL) in MeOH and the reaction mixture was stirred 1 h at RT under magnetic stirring. The reaction mixture was adjusted to pH=5, concentrated and the residue was partitioned between EtOAc and H2O. The organic layer was dried with Na2SO4 and the product was crystallized by dissolving the mixture at 80° C. in CH3CN to give N-(4-(hydroxycarbamoyl)phenyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamide EHT 3741 (0.070 g, 35% yield) as a pale red solid.
Reaction SMILES: [C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)[CH3:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:38].C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)C>[ClH:38].[C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:43])[NH2:27])=[CH:22][CH:21]=4)[CH3:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C#N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 74 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 74% of theory, C29H32N6O3 (512.6); EKA mass spectrum: (M+H)+=513; (M+H+Na)++=268; (M+2H)++=257.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:43])[CH2:10][NH:11][C:12]([CH2:14][C@H:15]1[CH2:26][CH2:25][C:24]2[S:23][C:22]3[C:17](=[C:18]([O:27][CH:28]4[CH2:33][CH2:32][CH:31]([N:34](C)[C:35](=O)OC(C)(C)C)[CH2:30][CH2:29]4)[N:19]=[CH:20][N:21]=3)[C:16]1=2)=[O:13])(C(C)(C)C)(C)C.Cl>ClCCl>[OH:8][C@H:9]([CH3:43])[CH2:10][NH:11][C:12](=[O:13])[CH2:14][C@H:15]1[CH2:26][CH2:25][C:24]2[S:23][C:22]3[C:17](=[C:18]([O:27][CH:28]4[CH2:29][CH2:30][CH:31]([NH:34][CH3:35])[CH2:32][CH2:33]4)[N:19]=[CH:20][N:21]=3)[C:16]1=2
Reactant: C[C@H](CNC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)NC[C@@H](C)O)CC4)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-([[(2R)-2-[(tert-butyldimethylsilyl)oxy]propyl]carbamoyl]methyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (60 mg, 0.09 mmol, 1.00 equiv) in dichloromethane (2 mL) was added hydrogen chloride (6 N) (1 mL). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (50 mg) was purified by preparative HPLC under the following conditions: column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 50 mL NH4CO3 and CH3CN (5.0% CH3CN up to 43.0% in 12 min, up to 95.0% in 2 min, down to 5.0% in 2 min); detector: 254/220 nm. This resulted in 22 mg (55%) of N-[(2R)-2-hydroxypropyl]-2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetamide as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([F:14])=[CH:7][C:6]=1[Br:15])([CH3:3])[CH3:2]>C(OCC)(=O)C.[C].[Pd]>[Br:15][C:6]1[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:10][C:9]([NH2:11])=[C:8]([F:14])[CH:7]=1
Reactant: CC(C)Oc1cc([N+](=O)[O-])c(F)cc1Br
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(N)c(F)cc1Br
Yield: 95.5 %

Procedure:
Then, 60 g (0.22 mol) of 2-bromo-4-fluoro-5-nitrophenyl isopropyl ether was dissolved in 300 ml of ethyl acetate, to which 1.0 g of 10% palladium-carbon was added, and the hydrogenation was effected under an atmosphere of hydrogen. After completion of the reaction, the palladium-carbon was removed by filtration, and the filtrate was concentrated, which afforded 52 g (0.21 mol) of 4-bromo-2-fluoro-5-isopropoxyaniline.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:17]([CH3:26])[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(OCC)(=O)C>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:26][N:17]1[CH:18]=[C:19]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:16]1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Yield: 91.3 %

Procedure:
To a solution of 4-[3-(4-Benzyloxy-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyridine (1.28 g) in ethanol (50 ml)/ethyl acetate (50 ml) in a parr bottle was added Palladium hydroxide (500 mg). The parr bottle was charged to 40 psi on a shaker for 6 h. The reaction mixture was filtered and concentrated. MPLC biotage chromatography eluting with methanol (1-7%)/chloroform provided the title compound (860 mg, 91%). 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 8.39 (d, J=5.8 Hz, 2 H), 7.15 (m, 4H), 6.72 (d, J=8.7 Hz, 1H), 3.84 (s, 3H); MS: (M+H m/z=252.2).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]([CH:28]([CH3:30])[CH3:29])=[CH:16][C:15]=1[N:31]1[C:35]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42]O)=[CH:38][CH:37]=2)=[CH:34][N:33]=[N:32]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C(Cl)Cl.CN(C=O)C>[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:17]([CH:28]([CH3:30])[CH3:29])=[CH:16][C:15]=1[N:31]1[C:35]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:38][CH:37]=2)=[CH:34][N:33]=[N:32]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)c1cc(-n2nncc2-c2ccc(CO)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1cc(-n2nncc2-c2ccc(CN3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
TEA (160 μl, 1.17 mmol) and MsCl (90 μl, 1.17 mmol) were added to a solution of {4-[3-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-3H-[1,2,3]triazol-4-yl]-phenyl}-methanol (200 mg, 0.39 mmol) in DCM (5 ml) at 0° C. The solution was stirred for 30 minutes at 0° C. and for 12 hours at RT. The solvent was removed under reduced pressure and the reaction crude was dissolved in DMF (3 ml). Morpholine (1.17 mmol) and TEA (160 μl, 1.17 mmol) were added and the reaction mixture was stirred for 12 hours at RT. After standard work-up with AcOEt (4×30 ml) and washing with H2O (2×30 mL) and brine (2×30 ml), the solvent was evaporated under reduced pressure and the crude reaction mixture was purified by column chromatography (PE/AcOEt:20/80) to obtain the desired adduct as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[NH:9][C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:9][C@@H:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH3:12])[C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)=[CH:6][CH:7]=1
Reactant: CC[C@@H](NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1ccccc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC[C@@H](NC(c1ccc(F)cc1)c1cccc(N)c1)c1ccccc1

Procedure:
Following a reaction and purification procedure similar to those described in Example (59b), 2.70 g of N-[(4-fluorophenyl)-(3-nitrophenyl)methyl]-N-[(R)-1-phenylpropyl]amine [prepared as described in step (a) above], 4.06 g of nickel chloride hexahydrate and 1.18 g of sodium borohydride were reacted, to obtain 778 mg of isomer A and 615 mg of isomer B of the title compound as yellow oils, respectively.
Reaction SMILES: [CH3:1][C:2]12[CH2:8][C:6]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=3)([CH2:7]1)[C:5](=[O:18])[N:4]([CH2:19][CH2:20][CH3:21])[C:3]2=[O:22].[H][H]>[Pd].C(OCC)(=O)C>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]23[CH2:8][C:2]([CH3:1])([CH2:7]2)[C:3](=[O:22])[N:4]([CH2:19][CH2:20][CH3:21])[C:5]3=[O:18])=[CH:14][CH:13]=1
Reactant: CCCN1C(=O)C2(C)CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCN1C(=O)C2(C)CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
1.0 g of 5% palladium-on-carbon catalyst is added to a solution of 10.0 g of 5-methyl-1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione in 200 ml of ethyl acetate and the whole is hydrogenated under normal pressure and at 30°-35° in a hydrogen atmosphere. When the absorption of hydrogen is complete, the reaction mixture is diluted with 100 ml of methylene chloride and freed of catalyst by filtration over HYFLO Super-Cel®. The solvent is evaporated off in vacuo, and the residue is recrystallised from an ethyl acetate/n-hexane mixture, yielding the title compound in the form of white crystals having a melting point of 135°-136°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][N:10]=[N+]=[N-])=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C1COCC1.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][NH2:10])=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NCCCc1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NCCCc1ccncc1
Reaction time: 24 h

Procedure:
A solution of 2-4 (7.3 g, 41.2 mmol) in H2O (100 mL) and THF (200 mL) was treated with triphenylphosphine (43.3 g, 165 mmol) and the resulting slurry was stirred vigorously for 24 h. The solution was diluted with EtOAc and washed with 10% KHSO4. The aqueous layers were combined and basified to pH13 with 1N NaOH and extracted repeatedly with CH2 Cl2. The CH2Cl2 layers were combined, dried with brine and concentrated to give 2-5 as a yellow oil.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1C1C=CC=CC=1.Br[C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=1.IC1C=CC=CC=1>>[F:38][C:37]([F:40])([F:39])[C:35]1[CH:34]=[CH:33][N:32]=[C:31]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[CH:36]=1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Reactant: FC(F)(F)c1ccnc(Br)c1
Agent: Cl
Solvent: Ic1ccccc1
Product: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3cc(C(F)(F)F)ccn3)c(=O)c2)cc1

Procedure:
4-[3-(4'-Trifluoromethyl-2-oxo-2H-[1,2']bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2-bromo-4-trifluoromethylpyridine for the iodobenzene in Step 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[Br:10].[OH-].[K+].IC.[C:15](OCC)(=O)C>CC1CCCO1.[Cl-].[Na+].O>[Br:10][C:3]1[CH:4]=[C:5]([CH2:8][O:9][CH3:15])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: OCc1ccc(Cl)c(Br)c1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Solvent: CI
Product: COCc1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a stirred solution of 4-chloro-3-bromophenyl-methanol (cited in Amgen patent WO03099776) (900 mg, 4.06 mmol) in 2-methyl-tetrahydrofuran (15 ml) was added potassium hydroxide (912 mg, 16.3 mmol) and the resulting suspension was stirred at room temperature for 30 minutes. Iodomethane (1.01 ml, 4.00 mmol) was then added and the reaction was stirred for 16 hours at room temperature. LCMS indicated incomplete reaction. Potassium hydroxide (912 mg, 16.3 mmol) was added and the resulting mixture stirred for 5 minutes before adding further iodomethane (4.04 ml, 16 mmol) and stirring was continued for 3 hours at room temperature. Ethyl acetate (60 ml) and saturated brine solution (30 ml) were added and the layers were separated. The organic extract was further washed with saturated brine solution (2×30 ml) then dried over anhydrous MgSO4 (s), filtered and evaporated in vacuo to afford the crude title compound as a yellow oil (901 mg, 94%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:26][O:27][CH3:28])=[C:10]([C:19](OC(C)(C)C)=[O:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:26][O:27][CH3:28])=[C:10]([CH2:19][OH:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(C(=O)OC(C)(C)C)c(COC)nc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCn1ncc2c(-c3cncc(C)c3)c(CO)c(COC)nc21
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 64.9 %

Procedure:
To a stirred solution of tert-butyl 1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (100 mg) in toluene (2.5 ml) was added 1N diisobutylaluminum hydride in toluene (0.92 ml) at −78° C. and the reaction mixtrue was stirred at −78° C. for 1.5 hour. Another 1N diisobutylaluminum hydride in toluene (0.4 ml) was added at −78° C. and the reaction mxitrue was stirred at −78° C. for 2.5 hours. Another 1N diisobutylaluminum hydride in toluene (0.52 ml) was added at −78° C. and the reaction mxitrue was stirred at −78° C. for 1 hour. The reaction mixture was quenched with brine, filtrated through celite pad, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (2:1) to give [1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (53 mg) as a light yellow oil.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH:13]1[C:23]2[C:24]3[C:16](=[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:18][C:19]=3[CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:12][CH:13]1[C:23]2[C:24]3[C:16](=[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:18][C:19]=3[CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
A portion (470 mg) of the crude compound obtained in Example 126 was suspended in methylene chloride (4 ml) and to the suspension was added trifluoroacetic acid (4 ml). The mixture was stirred for 1 hour at room temperature. The reaction mixture was made basic with saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate/methanol=9:1) to yield 100 mg (41%) of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([OH:19])=O)[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:27][C:28]([F:42])([F:41])[C:29]1[C:30]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:31][CH:32]=[CH:33][CH:34]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([N:38]3[CH2:39][CH2:40][N:35]([C:30]4[C:29]([C:28]([F:42])([F:27])[F:41])=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:36][CH2:37]3)=[O:19])[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: COc1cccc(S(=O)(=O)N2CC(C(=O)O)N(c3ccccc3)C2=O)c1
Product: COc1cccc(S(=O)(=O)N2CC(C(=O)N3CCN(c4ncccc4C(F)(F)F)CC3)N(c3ccccc3)C2=O)c1

Procedure:
In analogy to example 1, (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid (step 4 of example 1) was reacted with 1-[3-(trifluoromethyl)pyrid-2-yl]-piperazine to give the title compound as a colorless solid. MS: 589.8 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:14]([OH:16])=O)[CH:3]=1.[CH2:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][NH2:32])[CH2:26][CH2:25]1)=[O:23])[CH2:18][CH2:19][CH3:20].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:17]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:30](=[O:33])[CH2:31][NH:32][C:14]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][C:8]([CH3:13])=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)=[O:16])[CH2:28][CH2:29]1)=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: Cc1cc2nc(C(=O)O)cc(O)c2cc1C
Reactant: CCCCOC(=O)N1CCN(C(=O)CN)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)c3cc(C)c(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 100 mg of 4-Hydroxy-6,7-dimethyl-quinoline-2-carboxylic acid and 164 mg of 4-(2-Amino-acetyl)-piperazine-1-carboxylic acid butyl ester in 1 ml of DMF, 70 mg of HOBT and 88 mg of EDC was added and the reaction mixture was stirred for 4 h at RT. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the isolated crude product was pure enough for the next reaction step. Yield: 250 mg.
Reaction SMILES: C(OC([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:26].CO>CO>[ClH:26].[CH3:23][N:22]([CH3:24])[C:21]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH2:19][CH2:20][NH:8][CH2:9][C:10]1=2)=[O:25]
Reactant: CN(C)C(=O)n1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)n1c2c(c3ccccc31)CCNC2
Reaction time: 8 h
Yield: 82 %

Procedure:
A 434 mg (1.26 mmol) portion of 2-t-butoxycarbonyl-9-dimethylcarbamoyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole was dissolved in 10 ml of methanol, and the solution was mixed with 1 ml of 10% hydrochloric acid-methanol and stirred overnight. The solvent was removed by evaporation under a reduced pressure and the resulting residue was recrystallized from methanol-ethyl acetate to obtain 291 mg (82% in yield) of 9-dimethylcarbamoyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole hydrochloride.