Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:20])[CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>CCO.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:20])[CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Nc1cnc2ccccc2c1NCC1(O)CCC1
Reaction time: 8 h
Yield: 100.7 %

Procedure:
A mixture of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclobutanol (6.32 g, 23.1 mmol) and 20% palladium hydroxide on carbon (0.60 g) in EtOH (100 mL) was hydrogenated overnight on a Parr apparatus at 40 psi (2.8×105 Pa). The mixture was filtered through CELITE filter agent, which was rinsed several times with EtOH, and the filtrate was concentrated to provide 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclobutanol as a pale yellow solid (5.66 g). The solid was concentrated from toluene and chloroform to remove ethanol before using directly in the next reaction.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9]1
Reactant: Cc1ccc2c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CC[C@H](N)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 0.92 h

Procedure:
To (S)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (690 mg, 1.64 mmol) was added at room temperature 3 mL of 1:1 TFA:CH2Cl2. The reaction mixture was stirred for 55 min, diluted with 20 mL of CH2Cl2 and washed with 15 mL of satd. NaHCO3 solution. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give (S)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol as an oil which was used without further purification.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([O:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=2)[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:27]([Si:24]([CH3:26])([CH3:25])[O:23][CH2:22][CH:21]([CH:10]1[CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][NH:8][CH2:9]1)[O:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCC(Oc1ccc(Cl)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCC(Oc1ccc(Cl)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 51.4 %

Procedure:
To a solution of 2-[(RS)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-pyridine (7A-1) 108 mg (0.182 mmol) dissolved in toluene (2 mL) was added 0.059 mL (0.547 mmol) of 1-chloroethyl chloroformate and 0.093 mL (0.547 mmol) of Hunig base subsequently, and the mixture was heated at 100° C. for 40 minutes, then concentrated in vaccuo. The residue was dissolved in methanol (5 mL) and heated at reflux temperature for 30 minutes. The mixture was concentrated in vacuo and diluted with ethyl acetate, then washed with aq. sodium bicarbonate solution twice. The combined organic layers was dried over sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by silica gel column chromatography (DCM/MeOH 10:1 to 4:1) yielding 0.047 g (51%) of the title compound as a light brown oil. ES-MS m/e: 501.2 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=3[F:28])[CH2:15][CH2:14]2)[O:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>CO>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:15][CH2:14][CH:13]([C:11]3[O:10][C:9](=[O:29])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:12]=3)[CH2:18][CH2:17]2)=[C:20]([F:28])[CH:21]=1
Reactant: O=c1oc(C2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)nn1Cc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Nc1ccc(N2CCC(c3nn(Cc4ccccc4)c(=O)o3)CC2)c(F)c1
Yield: 85.5 %

Procedure:
5-[1-(2-Fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.23 g, 4 mmol) on reacting with C6H5CH2Br (0.82 g, 1 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at room temperature (27° C.) for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-benzyl-5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6f, 1.52 g, 96%). Nitro compound (6f, 1.59 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-3-benzyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7 h, 1.26 g, 86%). To a stirred solution of 5-nitro2-furanoic acid in DMF add. HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethyl aminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7 h, 0.36 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-benzyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperi dino]-3-fluorophenyl-5-nitro-2-furamide (8 h, 430 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][C:10]([OH:14])([C:12]#[CH:13])[CH3:11].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:13]#[C:12][C:10]([CH3:11])([OH:14])[CH3:9])=[CH:6][CH:7]=1
Reactant: C#CC(C)(C)O
Reactant: Clc1ccc(Cl)nn1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1ccc(Cl)nn1
Temperature: 80 °C

Procedure:
To a solution of 3,6-dichloropyridazine (250 mg, 1.68 mmol) and 2-methylbut-3-yn-2-ol (282 mg, 3.36 mmol) in DMF (4 mL) were added CuI (64 mg, 0.33 mmol), triethylamine (0.47 mL, 3.36 mmol), and palladium tetrakis triphenylphosphine (194, 0.168 mmol). The solution was degassed and heated to 80° C. overnight. The residue was worked up with EtOAc and water, dried with MgSO4, filtered, and concentrated. Column chromatography on silica gel 100% Hex to 100% EtOAc provided the title compound.
Reaction SMILES: CN(C)C=O.[F:6][C:7](I)([F:9])[F:8].[CH2:11]([N:15]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH:25]=[O:26])[N:17]=[C:16]1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:12]#[C:13][CH3:14].[Cl-].[NH4+]>[Zn].C(OCC)(=O)C>[CH2:11]([N:15]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH:25]([OH:26])[C:7]([F:9])([F:8])[F:6])[N:17]=[C:16]1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:29][CH2:28]1)[C:12]#[C:13][CH3:14]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C(=O)OCC
Reactant: FC(F)(F)I
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(O)C(F)(F)F)c1C(=O)OCC
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
0.065 g of zinc and a 2 ml N,N-dimethylformamide solution of 0.200 g of trifluoromethyl iodide were added to a 3 ml N,N-dimethylformamide solution of 0.155 g of t-butyl 4-[1-(2-butynyl)-5-ethoxycarbonyl-4-formyl-1H-imidazol-2-yl]piperazine-1-carboxylate under a nitrogen atmosphere, and the mixture was stirred under sonication for 30 minutes. 30 ml of ethyl acetate and 30 ml of a 5% ammonium chloride solution were added to the mixture. The organic layer was washed twice with 20 ml of water and then with 20 ml of a saturated sodium chloride solution, and dried over magnesium sulfate. The organic liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.013 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1:9).
Reaction SMILES: [CH2:1]([O:6][C:7](Cl)=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:10]1([C@H:16]2[NH:19][C:18](=[O:20])[C@@H:17]2[O:21][Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([O:6][C:7]([N:19]1[C@H:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:17]([O:21][Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[C:18]1=[O:20])=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@@H]1c1ccccc1
Reactant: CC(C)(C)COC(=O)Cl
Product: CC[Si](CC)(CC)O[C@H]1C(=O)N(C(=O)OCC(C)(C)C)[C@@H]1c1ccccc1

Procedure:
By following the above procedure and using neopentylchloroformate, (3R,4R)-4-phenyl-3-triethylsilyloxy-azetidin-2-one was converted to the title product: 1H NMR (CDCl3) δ 0.39-0.97 (m, 24H), 3.73 (d, 1H, J=10.2 Hz), 3.90 (d, 1H, J=10.2 Hz), 5.10 (m, 2H), 7.31 (m, 5H).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][CH2:19][C@H:12]2[NH:11][C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1(=[O:38])[N:28]([CH2:29][C:30](Cl)=[O:31])[C:27](=[O:33])[C:26]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:25]12.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCCl>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][CH2:19][C@H:12]2[N:11]([C:30](=[O:31])[CH2:29][N:28]2[C:27](=[O:33])[C:26]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:25]3[C:24]2=[O:38])[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@H]2CCCC[C@H]2Nc2ccccc2N1Cc1ccccc1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCCC[C@H]21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a solution of (4aR*,11aS*)-10-benzyl-1,2,3,4,4a,5,10,11a-octahydro-11H-dibenzo[b,e][1,4]-diazepin-11-one (200 mg, 0.65 mmol) in 1,2-dichloroethane (2 mL) was added phthalimidoacetyl chloride (175 mg, 0.78 mmol), and the mixture was stirred for 15 minutes at room temperature. To this solution was added pyridine (0.08 mL), and the mixture was stirred for 15 minutes at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was separated, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, which was dried over magnesium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was crystallized from ethanol to give 138 mg (yield 43%) of the titled compound, m.p. 241°-242.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][NH:8][C@H:7]1[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=1)=[O:5])[CH3:2].CCN(CC)CC.[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:36](=[O:37])[C:35]2[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=2[CH3:33])[C@H:7]1[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[CH:16][CH:17]=1)=[O:5])[CH3:2]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCOC(=O)[C@H]1CCCN[C@H]1c1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCCN(C(=O)c2ccccc2C)[C@H]1c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a 0° C. solution of the (2R,3S)-2-(4-tert-Butoxycarbonylaminophenyl)-piperidine-3-carboxylic acid ethyl ester prepared above (600 mg, 1.72 mmol) in dry CH2Cl2 (5 mL) containing Et3N (480 μL, 3.44 mmol) was added 2-methylbenzoyl chloride (266 mg, 1.72 mmol) and the mixture was stirred at room temperature for over night. The reaction mixture was then diluted with CH2Cl2 (20 mL), washed with 1 N aqueous HCl, water, and brine. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to give (2R,3S)-2-(4-tert-Butoxycarbonylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester in quantitative yield and the crude product was used as such in the next step.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:18]([O:17][C:15]([C:14]1[CH:13]=[C:12]([CH:22]=[CH:21][CH:20]=1)[O:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)=[O:16])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Yield: 88.2 %

Procedure:
A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 150 mmol) and K2CO3 (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux temp. overnight, cooled to room temp. and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3×150 mL). The combined organic phases were sequentially washed with water (3×100 mL) and a saturated NaCl solution (2×100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: NCCCCSc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCCCSc1cccc2nccn12
Yield: 50.7 %

Procedure:
To a solution of 5-[4-(amino)butylthio]imidazo[1,2-a]pyridine (440 mg, 1.99 mmoles) and triethylamine (0.42 ml, 3.01 mmoles) in methylene chloride (20 ml) was added methanesulfonyl chloride (0.19 ml, 2.45 mmoles) under ice-cooling with stirring and the mixture was stirred under ice-cooling for 1 hour. The reaction mixture was washed in turn with an aqueous saturated sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 302 mg of the desired product (50.8%, light red brown solid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH2:30][CH2:31][OH:32])[N:9]=2)[CH:7]=1.C(OC(N1CCCC[C@H]1C(=O)NC1C=CC(C#CC2C(C3C=C(Cl)C=CC=3O)=NN(CCO)C=2)=CC=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:19][CH:20]=3)=[CH:11][N:10]([CH2:30][CH2:31][OH:32])[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@H]1CCCCN1
Agent: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@@H]1CCCCN1

Procedure:
Using the same procedure for the preparation of 5A, treatment compound 9A with TFA in methylene chloride to give compound 10A in quantitative yield. Its 1H NMR and LCMS data are identical with those of compound 5A.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl.[NH2:23][OH:24]>O.CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[NH:15])[NH:23][OH:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Temperature: 25 °C

Procedure:
To a mixture of 4-cyano-piperidine-1-carboxylic acid tert-butyl ester (6.3 g, 30 mmol), K2CO3 (4.2 g, 30 mmol) in H2O (50 mL) and EtOH (30 mL) was added hydroxylamine hydrogenchloride (4.17 g, 60 mmol). The mixture was heated under reflux overnight, cooled to room temperature and ethanol was removed in vacuo. The residue was extracted with EtOAc (300 mL). The organic layer was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed to afford the desired product.
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:5])[CH3:4].[CH:6]1([N:9]([CH:36]2[CH2:38][CH2:37]2)[C:10]([C:12]2[N:33]([CH2:34][CH3:35])[C:15]3=[N:16][C:17]([NH:24][C:25]4[S:26][C:27]([C:30]([OH:32])=O)=[CH:28][N:29]=4)=[C:18]4[N:22]=[CH:21][N:20]([CH3:23])[C:19]4=[C:14]3[CH:13]=2)=[O:11])[CH2:8][CH2:7]1>>[CH:6]1([N:9]([CH:36]2[CH2:38][CH2:37]2)[C:10]([C:12]2[N:33]([CH2:34][CH3:35])[C:15]3=[N:16][C:17]([NH:24][C:25]4[S:26][C:27]([C:30]([N:2]([CH:3]([CH3:5])[CH3:4])[CH3:1])=[O:32])=[CH:28][N:29]=4)=[C:18]4[N:22]=[CH:21][N:20]([CH3:23])[C:19]4=[C:14]3[CH:13]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)O)s3)nc21
Reactant: CNC(C)C
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)N(C)C(C)C)s3)nc21

Procedure:
This compound was prepared according to Example 20 using N-methylpropan-2-amine and 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxylic acid (example 20A) to provide 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-N-isopropyl-N-methylthiazole-5-carboxamide
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18](=[O:20])[CH3:19])=[CH:15][CH:16]=3)[C:11]([CH3:22])([CH3:21])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[C:23]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)([OH:25])=[O:24].[OH-].[Na+]>CO>[O:20]=[C:18]([C:14]1[CH:15]=[CH:16][C:17]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:9][CH2:10][C:11]([CH3:22])([CH3:21])[C:12]=2[CH:13]=1)[CH:19]=[CH:30][C:29]1[CH:32]=[CH:33][C:26]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC=C2c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C2=CCC(C)(C)c3cc(C(=O)C=Cc4ccc(C(=O)O)cc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 78.7 mg (0.272 mmol) 3,4-dihydro-1-(4-methylphenyl)-4,4-dimethyl-6-acetylnaphthalene (Compound 100G) in 4.0 ml of MeOH was added 53.1 mg (0.354 mmol) of 4-carboxy benzaldehyde, and 80. mg (2.00 mmol; 2.0 ml of 1M aqueous NaOH). The resulting solution was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residual oil dissolved in EtOAc. The solution was treated with 10% HCl, and the organic layer was washed with H2O, and saturated aqueous NaCl, then dried over Na2SO4. Removal of the solvents under reduced pressure gave the title compound as a colorless solid which was purified by recrystallization from CH3CN. 1H NMR (acetone-d6): δ8.00 (7H, m), 7.83 (1H, d, J=15.6 Hz), 7.24 (4H, s), 7.13 (1H, d, J=8.1 Hz), 6.12 (1H, t, J=4.5 Hz), 2.42 (2H, d, J=4.8 Hz), 2.38 (3H, s), 1.41 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17]C(=O)OC(C)(C)C)[CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:25]([NH:27][CH2:28][C:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2)=[O:26].CO.[ClH:41]>O1CCOCC1>[ClH:1].[ClH:41].[NH2:17][CH2:16][CH:13]1[CH2:14][CH2:15][CH:10]([NH:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:4]=2)[C:25]([NH:27][CH2:28][C:29]23[CH2:36][CH:35]4[CH2:34][CH:33]([CH2:32][CH:31]([CH2:37]4)[CH2:30]2)[CH2:38]3)=[O:26])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(NCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCC1CCC(NCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1

Procedure:
Prepared from [[4-[[[4chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]methyl]amino]cyclohexyl]methyl]-carbamic acid, 1,1-dimethylethyl ester (0.26 g, Example 32a) methanol (5 ml) and 4N hydrochloric acid solution in dioxane (2 ml). Solvents were removed under reduced pressure and the residue was triturated with diethyl ether to give the title compound as a white powder (0.191 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3]1.I[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:13][CH2:14][OH:15])[CH:4]=[CH:3]1
Reactant: Cn1ccc2cccc(O)c21
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(OCCO)c21
Reaction time: 20 h
Yield: 63.1 %

Procedure:
To a solution of 1-methyl-1-H-indol-7-ol (Chemstep, CAS: 47577-33-4, 0.98 g, 6.8 mmol) and 2-iodoethanol (Fluka, 1.60 g, 8.6 mmol)) in DMF abs. (10 mL) was added potassium carbonate (1.84 g, 13 mmol). The reaction mixture at rt for 20 h, then at 70° C. for 24 h, quenched with ice/water, extracted with ethyl acetate. The organics were washed, dried and concentrated, the residue chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain the desired compound (0.82 g) as a creamy solid. MS (ISP): m/e 192.3 (M+H)+
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][N:9]([CH2:12][CH2:13][CH3:14])[CH2:8][CH2:7][C:6]=2[C:5]([NH2:15])=[C:4]([N+:16]([O-])=O)[CH:3]=1>CO.[Pd]>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:2][CH:3]=[C:4]([NH2:16])[C:5]=2[NH2:15])[CH2:10]1)[CH2:13][CH3:14]
Reactant: CCCN1CCc2c(N)c([N+](=O)[O-])cc(Br)c2C1
Agent: [Pd]
Solvent: CO
Product: CCCN1CCc2c(ccc(N)c2N)C1
Reaction time: 24 h
Yield: 129.7 %

Procedure:
A solution of the product from Example 12 (1.50 g, 4.77 mmol) and 20% Pd on carbon (0.30 g) in 75 mL of MeOH was hydrogenated at room temperature and pressure for 24 hours. The reaction mixture was concentrated and the residue was suspended in iPr2O and collected by filtration to give the title compound as a yellow solid (1.27 g, 93%).