Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.[O:2]1CCCC1.[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[N:22]([C@@H:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[CH:28]=1)[CH:25]=[CH2:26])[CH2:21][CH2:20]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C.O>[Br:33][C:29]1[CH:28]=[C:27]([C@H:24]([N:22]2[C:23]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:14][CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:20][CH2:21]2)[CH2:25][CH2:26][OH:2])[CH:32]=[CH:31][CH:30]=1
Reactant: C1CCOC1
Reactant: C=C[C@H](c1cccc(Br)c1)N1CCc2cccc(OCc3ccccc3)c21
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: OCC[C@H](c1cccc(Br)c1)N1CCc2cccc(OCc3ccccc3)c21
Temperature: 0 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A 1.0M solution of borane-tetrahydrofuran complex (BH3 --THF) in tetrahydrofuran (38.1 ml, 38.10 mmol) was added dropwise to a magnetically stirred solution of (1R)-(-)-7-benzyloxy-1-[1-(3-bromophenyl)prop-2-enyl]indoline (16.0 g, 38.1 mmol) in dry tetrahydrofuran (200 ml) under nitrogen at 0° C. The reaction mixture was heated under reflux for 8.5 h, during which time two further aliquots of 1.0M BH3 --THF in tetrahydrofuran were added (1×15.0 ml and 1×5.0 ml) until TLC inspection indicated that no further starting olefin remained. The reaction mixture was cooled to 0° C., sequentially treated with water (21.0 ml), 3M sodium hydroxide solution (21 ml) and 30% hydrogen peroxide (21.0 ml) then stirred at room temperature for 16 h. Quenched with brine (400 ml), extracted with ethyl acetate (3×200 ml), the combined organic phases were washed with brine (200 ml), dried (Na2SO4) and evaporated to yield a brown oil. Column chromatography (ethyl acetate--light petroleum (b.p. 40°-60° C.), 1:4) gave the title compound as a pink oil (11.70 g, 70%). [α]D25 -280° (c=0.011 gml-1, CHCl3); νmax (thin film)/cm-1 3391 (br. OH), 3063, 3031, 2939, 1591; δH (270 MHz) 1.89 (1H, m, 1×2-H); 2.26 (1H, m, 1×2-H); 2.69 (2H, m, indoline 2×2-H); 3.13 (1H, m, indoline 1×3-H); 3.30 (1H, bs, 1-OH); 3.43 (1H, m, indoline 1×3-H); 3.81 (2H, m, 2×1-H); 5.17 (2H, s, CH2Ph); 5.59 (1H, dd, 3-H, 3J3,2 =11.2 Hz, 3J3,2' =4.0 Hz); 6.77 (3H, m, indoline 4-H, 5-H, 6-H); 7.06 (2H, m, 5'-H,6'-H); 7.31-7.51 (7H, ArH). δC (67.8 MHz) 29.1 (2-C); 32.7 (indoline 2-C); 45.6 (indoline 3-C); 58.2 (1-C); 61.7 (3-C); 70.9 (CH2Ph); 112.2 (indoline 6-C); 118.1 (indoline 5-C); 120.6 (indoline 4-C); 122.3 (3'-C); 133.4 (indoline 3a-C); 136.7 (1'-C); 139.0 (benzyl ipso-C); 142.4 (indoline 7a-C); 145.7 (indoline 7-C). The remaining signals lie between 126.5-130.7 ppm and cannot be assigned with any certainty; m/z 439.1, 437.1 (2.69, 3.32, M+), 394.2, 392.2 (1.06, 1.09), 348.1, 346.1 (5.33, 5.60), 225.1 (18.26), 172.0, 170.0 (33.75, 34.31), 134.0 (100), 118.0 (2.79), 91.1 (67.26).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9][C:8]2[CH:25]=[CH:26][CH:27]=[N:28][C:7]1=2.I>C(O)(=O)C>[OH:17][C:14]1[CH:15]=[CH:16][C:11]2[C:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:9][C:8]3[CH:25]=[CH:26][CH:27]=[N:28][C:7]=3[N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:29])[C:12]=2[CH:13]=1
Reactant: COc1ccc2c(c1)N(CCCN(C)C)c1ncccc1N=C2c1ccccc1
Agent: I
Solvent: CC(=O)O
Product: CN(C)CCCN1c2cc(O)ccc2C(c2ccccc2)=Nc2cccnc21

Procedure:
The title compound is prepared by reacting 11-[3-(dimethylamino)propyl]-9-methoxy-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine with hydrogen iodide and glacial acetic acid.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[CH3:23])[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.C(O)C.O>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[CH3:23])[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(C)cccc2c1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(C)cccc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Temperature: 50 °C
Yield: 56.4 %

Procedure:
To a solution of ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-3,5-dimethylnaphthalen-2-yl)acetate (32 mg, 0.075 mmol) in tetrahydrofuran: ethanol:water (2:2:1, 3 mL) was added lithium hydroxide (9 mg, 0.377 mmol) and the reaction was heated to 50° C. overnight. The reaction was purified by reverse phase HPLC (Gemini, 40-100% ACN/H2O+0.1% TFA). The product was lyophilized to give a white powder (16.8 mg). 1H-NMR: 400 MHz, (CD3OD) δ: 7.86 (s, 1H), 7.54 (m, 3H), 7.29 (m, 2H), 7.16 (t, J=8.8 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 5.17 (s, 1H), 2.69 (s, 3H), 2.65 (s, 3H), 0.98 (s, 9H). LCMS-ESI− (m/z): [M−H]− calcd for C24H24ClO3: 395.15; found: 394.97.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9]2[N:13]([C:14]3[CH:19]=[C:18]([NH:20][CH3:21])[N:17]=[CH:16][N:15]=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:6][C:5]([NH2:23])=[CH:4][CH:3]=1.[CH:24]([NH:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:32](O)=[O:33])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:24]([NH:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[C:32]([NH:23][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([NH:8][C:9]2[N:13]([C:14]3[CH:19]=[C:18]([NH:20][CH3:21])[N:17]=[CH:16][N:15]=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)[CH:6]=1)=[O:33])([CH3:26])[CH3:25]
Reactant: CNc1cc(-n2nc(C)cc2Nc2cc(N)ccc2C)ncn1
Reactant: CC(C)NCc1cc(C(=O)O)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1cc(-n2nc(C)cc2Nc2cc(NC(=O)c3cc(CNC(C)C)cc(C(F)(F)F)c3)ccc2C)ncn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-methyl-N1-(3-methyl-1-(6-(methylamino)pyrimidin-4-yl)-1H-pyrazol-5-yl)benzene-1,3-diamine 39 (360 mg, 1.16 mmol, 1 eq) is dissolved in dry DMF (10 mL), followed by 3-((isopropylamino)methyl)-5-(trifluoromethyl)benzoic acid (0.504 mg, 1.02 mmol, 0.9 eq), HATU (663 mg, 1.74 mmol, 1.5 eq), and DIEA (0.5 mL, 3.49 mmol, 3 eq). The reaction mixture is stirred at room temperature for about 4 hours until the reaction is complete as evidenced by the LC/MS product peak. The reaction mixture is then quenched by NaHCO3 solution and extracted with ethyl acetate. The organic layers are combined and dried over magnesium sulfate. The solvents are removed under vacuo and the residue is purified by flash column chromatography to afford 3-((isopropylamino)methyl)-N-(4-methyl-3-(3-methyl-1-(6-(methylamino)pyrimidin-4-yl)-1H-pyrazol-5-ylamino)phenyl)-5-(trifluoromethyl)benzamide. MS: m/z [M+H+]) 553.20, 1H NMR: 11.07 (s, 1H), 10.61 (s, 1H), 9.17 (bs, 1H), 8.58 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.95 (s, 1H), 7.69 (s, 1H), 7.39 (m, 1H), 7.24 (m, 1H), 6.88 (s, 1H), 6.16 (s, 1H), 4.36 (m, 2H), 3.34-3.48 (m, 1H), 2.87 (m, 3H), 2.49 (m, 3H), 2.22 (m, 3H), 1.33-1.34 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: CCCCCCI
Agent: [H-]
Agent: [Na+]
Product: CCCCCCN(C(=O)OC(C)(C)C)n1cccc1

Procedure:
Prepared according to the N-alkylation condition used in Example 17 step a) from starting materials pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 1-iodohexane (3.0 eq.) and sodium hydride (1.3 eq.). 1H NMR (CDCl3, δ in ppm): 6.60 (m, 2H), 6.10 (m, 2H), 3.63 (t, 2H, J=7.2 Hz), 1.42 (s, 9H), 1.9-1.2 (m, 8H), 0.90 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:20])=[C:9]([NH:11][C:12]([O:14]CC(Cl)(Cl)Cl)=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[CH:33]=[N:34][C:35]([CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:36][CH:37]=2)=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:20])=[C:9]([NH:11][C:12]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:32]3[CH:33]=[N:34][C:35]([CH2:38][N:39]4[CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)=[CH:36][CH:37]=3)=[CH:24][CH:23]=2)=[O:14])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(-c2ccc(CN3CCOCC3)nc2)c2ccccc12
Reactant: Cc1ccc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(C)(C)C)cc1NC(=O)Nc1ccc(-c2ccc(CN3CCOCC3)nc2)c2ccccc12
Reaction time: 1.5 h

Procedure:
A solution of 5-t-butyl-2-methyl-1-(2,2,2-trichloroethoxycarbonyl)aminobenzene (26 mmol), 1-amino-4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalene (26 mmol), diisopropylethylamine (3.2 g, 25 mmol) and DMSO (75 mL) is heated to 55-60° C. and held for 1.5 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17](=[O:27])[N:18]3[C:23]=2[C:22]2[S:24][CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19]3)=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[O:27]=[C:17]1[C:16]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:15][C:14]([C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:13])=[C:23]2[N:18]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][S:24][C:22]=12
Reactant: CCOC(=O)C1CCN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2sccc2CC3)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2sccc2CC3)CC1

Procedure:
A solution of 0.1 g of ethyl-1-[[4,5-dihydro-7-oxo-8-phenyl-7H -thieno[2,3-a]quinolizin-10-yl]carbonyl]-4-piperidinecarboxylate and 0.016 g of sodium hydroxide in 2 ml of methanol, was heated under reflux for 3 hours. The mixture was then evaporated in vacuo, the residue was taken up in water and extracted with chloroform. The aqueous phase was made acid with 3N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated in vacuo and there was obtained crude 1-[[4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]-quinolizin-10-yl]carbonyl-4-piperidinecarboxylic acid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20](O)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31](=[O:41])[CH2:32][C:33]1[N:34]([CH3:40])[C:35]([CH2:38][OH:39])=[CH:36][CH:37]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([O:39][CH2:38][C:35]3[N:34]([CH3:40])[C:33]([CH2:32][C:31]([O:30][CH3:29])=[O:41])=[CH:37][CH:36]=3)=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:26])([F:27])[F:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)Cc1ccc(CO)n1C
Product: COC(=O)Cc1ccc(COc2ccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)cc2)n1C

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and (5-hydroxymethyl-1-methyl-1H-pyrrol-2-yl)-acetic acid methyl ester according to the procedure of Example 69. MS (ESI) m/z 545.
Reaction SMILES: [CH2:1]1[C@H:6]2[CH2:7][C:8](=[O:10])[CH2:9][C@H:5]2[CH2:4][C:3](=[O:11])[NH:2]1.[CH:12](O)([OH:14])[CH3:13].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]1[C@H:6]2[CH2:7][C:8]3([O:14][CH2:12][CH2:13][O:10]3)[CH2:9][C@H:5]2[CH2:4][C:3](=[O:11])[NH:2]1
Reactant: O=C1C[C@@H]2CNC(=O)C[C@@H]2C1
Reactant: CC(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1C[C@@H]2CC3(C[C@@H]2CN1)OCCO3
Yield: 71.5 %

Procedure:
(cis)-2,4,4a,5,7,7a-hexahydro-1H-cyclopenta[c]pyridine-3,6-dione 14d (1.20 g, 7.80 mmol), ethanediol (1.34 g, 21.50 mmol) and p-toluenesulfonic acid (24 mg, 0.13 mmol) were dissolved in 60 mL of toluene, heated to reflux for 8 hours with stirring, then added dropwise with saturated sodium bicarbonate solution to adjust pH to 7 around and extracted with dichloromethane (50 mL). The aqueous phase was extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (cis)-spiro[1,3-dioxolane-2,6′-2,4,4a,5,7,7a-hexahydro-1H-cyclopenta[c]pyridine]-3′-one 14e (1.10 g, yield: 70.0%) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N+:11]([C:14]1[C:15]([Cl:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18])([O-:13])=[O:12].C(N(CC)CC)C>ClCCl>[N+:11]([C:14]1[C:15]([Cl:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc(CO)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cccc([N+](=O)[O-])c1Cl
Temperature: -65 °C
Reaction time: 0.75 h
Yield: 78.1 %

Procedure:
A solution of oxalyl chloride in dichloromethane (2.0M, 116 mmol) was chilled to −70° C. (internal temperature) under a nitrogen atmosphere. DMSO (15 mL, 211.3 mmol) was added dropwise maintaining −65° C. and then stirring was continued for 45 min. at −70° C. A solution of the 3-nitro-2-chlorobenzyl alcohol (14.4 g, 76.6 mmol) in dichloromethane (250 mL) was then added and the reaction stirred at −70° C. for 2 h. Triethylamine (54 mL, 387 mmol) was added dropwise and the reaction stirred for 2 h at −70° C. and then 12 h at room temperature. The reaction was quenched by the addition of 500 mL of water. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried with MgSO4, filtered, and evaporated to obtain a light brown solid. Column Chromatography (silica gel, 30% dichloromethane/hexanes to 70% dichloromethane/hexanes) produced 11.1 g (78%) of the desired 3-nitro-2-chlorobenzaldehyde as a yellow solid.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]([CH2:25][C:26]2[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH3:37])=[C:31]3[C:27]=2[CH:28]=[N:29][N:30]3S(C2C=CC=CC=2)(=O)=O)[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]1([S:7]([NH:10][CH:11]([CH2:25][C:26]2[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH3:37])=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1c(Cl)cc(CC(NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)c2cnn(S(=O)(=O)c3ccccc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1c(Cl)cc(CC(NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)c2cn[nH]c12
Reaction time: 1 h

Procedure:
2-Benzenesulfonylamino-3-(1-benzenesulfonyl-6-chloro-7-methoxy-1H-indazol-4-yl)-N-(4-phenyl-butyl)-propionamide (0.17 g, 0.25 mmol) is dissolved in MeOH (2 mL) and K2CO3 is added and the reaction is stirred for 1 h. The reaction is quenched by the addition of 2 N HCl (0.1 mL) and then concentrated. The residue is dissolved in EtOAc and washed with water, brine and dried over MgSO4. The solution is concentrated and purified by column chromatography (silica, 60% EtOAc/hexanes) to provide 2-benzenesulfonylamino-3-(6-chloro-7-methoxy-1H-indazol-4-yl)-N-(4-phenyl-butyl)-propionamide.
Reaction SMILES: CO.[OH-].[K+].Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][N:17]3[C:21]4=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]4[N:19]=[C:18]3[CH2:28][CH3:29])[CH:14]=2)[N:9]=[C:8]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N+:36]([O-])=O)[CH:7]=1>[C].[Pd].C(Cl)(Cl)Cl>[CH2:28]([C:18]1[N:17]([CH2:16][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH2:36])[CH:7]=[CH:6]3)[C:21]2=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]2[N:19]=1)[CH3:29]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3[N+](=O)[O-])cc(Cl)c2c1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3N)ccc2c1
Reaction time: 17 h
Yield: 47.1 %

Procedure:
To 240 ml of methanol containing 8.0 g of potassium hydroxide, 8.12 g (17.2 mmol) of 4-chloro-6-[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2-(nitrophenyl)quinoline obtained in Example 4 and 0.80 g of a 5% palladium-carbon catalyst were added and the thus-prepared mixture was stirred under a hydrogen atmosphere for 17 hours. After adding 120 ml of chloroform thereto, the thus-prepared mixture was filtered through celite. To the resulting filtrate, 120 ml of water was added, and the thus-prepared mixture was then separated out. The resulting organic layer was washed with 120 ml of water. Then, 60 ml of water was added to the organic layer, and a 130 ml portion thereof was distilled off by heating under atmospheric pressure. After allowing to stand at 0° C., the crystals precipitated were collected by filtration, and the resulting filtration residue was further recrystallized from a mixture of chloroform with methanol to obtain 3.30 g of 2-{6-[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]quinolin-2-yl}aniline.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][OH:11])[N:7]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1.[CH3:18][N:19](C=O)C>CO.[C-]#N.[C-]#N.[Zn+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:11][CH2:10][C:8]1[N:7]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[CH:17]=[C:2]([C:18]#[N:19])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: CC(C)CCn1c(CO)nc2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CO
Product: CC(C)CCn1c(CO)nc2ccc(C#N)cc21
Temperature: 80 °C
Yield: 66 %

Procedure:
A mixture of [6-bromo-1-(3-methyl-butyl)-1H-benzoimidazol-2-yl]-methanol (30 mg, 0.1 mmol), Zn(CN)2 (7 mg, 0.06 mmol) and tetrakis(triphenylphosphine) palladium(0) (12 mg, 0.01 mmol) in DMF (1 mL) was heated to 80° C. for 4 h. After cooling, the reaction mixture was diluted with MeOH and filtered. The filtrate was purified by prep-HPLC (gradient 10%-100% B) to give 16 mg (66%) of 2-hydroxymethyl-3-(3-methyl-butyl)-3H-benzoimidazole-5-carbonitrile as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:5]=1[C:6]([NH:8][C:9]1[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:13]=1)=[O:7])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:5]=1[C:6]([NH:8][C:9]1[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[N:13]=1)=[O:7]
Reactant: O=C(Nc1nc(-c2cccc(C(F)(F)F)c2)n[nH]1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1nc(-c2cccc(C(F)(F)F)c2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of 2-nitro-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3-yl)benzamide (130 mg, 0.28 mmol, 1.00 equiv) in methanol (3 mL) was added Pd/C (130 mg, 10%) and the suspension stirred under an atmosphere of hydrogen for 2 h at room temperature. The solids were filtered out and the resulting mixture was concentrated under vacuum to yield 50 mg (41%) of product as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH:5]=1)[CH3:2].[H-].[Na+].[CH3:17]C(N(C)C)=O>>[CH3:17][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]1=[O:14]
Reactant: CC(=O)N(C)C
Reactant: CCOc1cc(=O)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Product: CCOc1cc(=O)n(C)c2ccccc12
Reaction time: 2 h

Procedure:
To a suspension of 1.9 g. of 4-ethoxyquinolin-2(1H)-one in 40 ml. of dimethylacetamide is added 0.42 g. of sodium hydride (56% in mineral oil, pentane washed), and the resulting mixture is heated at 60° C. for one hour. The mixture is filtered (while excluding moisture), cooled and there is then added 1.5 g. of methyliodide followed by stirring for 2 hours at ambient temperatures. The resulting mixture is poured into 200 ml. of cold water and the resulting slurry extracted 3 times each with 100 ml. of ethyl acetate. The combined organic extracts are washed with water and saturated sodium chloride solution, dried and evaporated in vacuo. The residue is crystallized from ether to obtain 1-methyl-4-ethoxyquinolin-2(1H)-one, m.p. 80°-82° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:28][N:29]2[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH:20]=[CH:19][CH2:18]1)[N:11]=2.O.CO>[Pd].C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:28][N:29]2[CH2:30][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:32]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]1)[N:11]=2
Reactant: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC=CC5)nc4s3)c(F)c2)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CCCC5)nc4s3)c(F)c2)C1
Reaction time: 4 h

Procedure:
To a mixture of methyl 1-((3-fluoro-4-(5-(1-phenylcyclopent-3-enyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate (0.333 g, 0.667 mmol) and 10% Pd/C, 50% water (0.355 g, 0.333 mmol) under nitrogen was added 5 mL MeOH and 5 mL THF. The resulting mixture was stirred rapidly under an H2 balloon for 4 h. The reaction mixture was flushed with nitrogen, filtered, rinsing with DCM, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography, ISCO 0-100% EA/hexanes, to give methyl 1-((3-fluoro-4-(5-(1-phenylcyclopentyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate as a clear and colorless oil. MS (ESI) m/z: Calculated: 501.2; Observed: 502.1 (M++1).
Reaction SMILES: [N+](C1C=CC=C2C(NC(=O)C=12)=O)([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]#[N:30])=[CH:24][CH:23]=1.[Br:31]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>CN(C=O)C.C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]#[N:30])=[CH:24][CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(CC#N)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])[O-]
Agent: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#CCc1ccc(CBr)cc1

Procedure:
9.79 g (50.93 mmol) of 3-nitrophthalimide are dissolved in 450 ml of DMF, and 10.56 g (76.39 mmol) of potassium carbonate are added. The suspension is treated with ultrasound for 10 min. 10.7 g (50.93 mmol) of 2-[4-(bromomethyl)phenyl]acetonitrile (obtained by reaction of 2-(4-methylphenyl)acetonitrile with N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in carbon tetrachloride, cf. E. Laurent, B. Marquet, R. Tardivel; Tetrahedron; 47; 24; 1991; pp. 3969-3980) are then added, and the reaction mixture is stirred at room temperature for 20 h. The suspension is then poured into a mixture of 300 ml of 2 N hydrochloric acid and 3 l of water. The crystals formed are filtered off with suction, washed with water and dried under reduced pressure. This gives 12 g (73% of theory) of the desired compound. Rf (SiO2, CH2Cl2/EtOH=100/1)=0.55, MS=322.2 (M+H+).