Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[C:18]([Cl:28])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>C(O)C.O1CCCC1>[Cl:28][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:29])([CH3:30])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Cl)cc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(Cl)cc(N2CCOCC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 30.6 %

Procedure:
A mixture of 2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.7 g, 1.63 mmol), lithium hydroxide hydrate (0.69 g, 16.3 mmol), water (5 mL) in ethanol (20 mL) and tetrahydrofuran (20 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 31%) as a white solid: LC/MS m/e calcd for C22H25ClN2O3 M+: 400.9, observed: 401.2.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[C:21]([CH3:24])[CH:20]=[C:19]([OH:25])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:26](=[O:28])[NH2:27])[CH:7]=[CH:8][CH:9]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[C:21]([CH3:24])[CH:20]=[C:19]([O:25][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:26](=[O:28])[NH2:27])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc(O)c2c3c(C(N)=O)cccc3n(Cc3cccc(F)c3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(C)cc2c1c1c(C(N)=O)cccc1n2Cc1cccc(F)c1
Reaction time: 0.17 h
Yield: 78 %

Procedure:
60% Sodium hydride in mineral oil (25.9 mg, 0.65 mM) was added to a solution of 9-[(3-fluorophenyl)methyl]-2-methyl-4-hydroxy-5-carbamoyl carbazole (181 mg, 0.52 mM) in 18 mL DMF and 3.9 ml THF. After 10 minutes, methyl bromoacetate (66 μl, 0.70 mM) was added and the resultant mixture stirred at room temperature for 1.25 hours. The mixture was diluted with ethyl acetate and washed with H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layers were extracted with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with methylene chloride/acetone gradient) to afford 170 mg (78%) of the {9-[(3-fluorophenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester. 1H NMR (DMSO-d6) δ 7.55 (d, 1H, J=8 Hz), 7.5 (bs, 1H), 7.4-7.25 (m, 2H), 7.2 (bs, 1H), 7.05 (m, 3H), 6.95 (d, J=8 Hz, 1H), 6.9 (d, J=8 Hz), 6.45 (s, 1H), 5.65 (s, 2H), 4.9 (s, 2H), 3.75 (s, 3H), 2.4 (s, 3H). MS (FD) m/e 404, 421.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][CH2:32][C:33]([F:36])([F:35])[F:34].CC(=O)OCC>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][CH2:32][C:33]([F:34])([F:36])[F:35]
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Reactant: C=C(c1cc(Cl)c(OCC(F)(F)F)c(Cl)c1)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(OCC(F)(F)F)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.3 %

Procedure:
To a solution of (Z)-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (253 mg, 1.06 mmol) and 1,3-dichloro-2-(2,2,2-trifluoroethoxy)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (360 mg, 1.06 mmol) in DMF (10 mL) at rt was added TEA (107 mg, 1.06 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (6:1) to give the final title compound (105 mg; yield 18.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.76-7.69 (m, 5H), 4.80 (q, J=8.8 Hz, 2H), 4.37 (q, J=18.4 Hz, 2H), 1.48 (s, 6H) ppm; HPLC purity: 96.2% at 220 nm and 98.3% at 254 nm; MS: m/z=542.2 (M+, ESI+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[H-].[Na+].[N+:20]([C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:39])([F:38])[F:37])[CH:26]=[CH:27][C:28]=1[NH2:29])([O-:22])=[O:21]>C(Cl)Cl.CN(C=O)C.C1COCC1>[N+:20]([C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:37])([F:38])[F:39])[CH:26]=[CH:27][C:28]=1[NH:29][C:9](=[O:11])/[CH:8]=[CH:7]/[CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)([O-:22])=[O:21]
Reactant: O=C(O)/C=C/C1CCOCC1
Reactant: Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(/C=C/C1CCOCC1)Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (E)-3-(tetrahydro-pyran-4-yl)-acrylic acid (prepared as described in PCT Publication WO 2005/101989 (A2,A3), 0.200 g, 1.28 mmol) in dry CH2Cl2 (5 mL) was treated with oxalyl chloride (0.110 mL, 0.00128 mol) and DMF (1 drop) at room temperature for 1 h. The volatiles were evaporated in vacuo (water bath temperature <30° C.). At the same time, a suspension of NaH (78.8 mg, 1.97 mmol, 60% dispersion in oil) in dry THF (3 mL) was treated portionwise with 3-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (278 mg, 0.985 mmol, prepared as in STEP A above) and stirred at room temperature for 30 min. The residue was taken up in dry THF (2 mL) and slowly added to the NaH mixture. The resulting mixture was stirred at room temperature overnight, quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g Sepra Si 50 SPE column (Isco system: flow rate=20 mL/min; eluting with EtOAc/hexane, 5:95, v/v over 5 min and 5:95 to 40:60, v/v over 25 min) to yield (E)-N-(3-nitro-2′-trifluoromethyl-biphenyl-4-yl)-3-(tetrahydro-pyran-4-yl)-acrylamide as a yellow solid.
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[C:12]1([C:18]2[N:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH2:27][C:28]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>C(Cl)Cl.C(N(CC)CC)C>[C:41]1([C:39]2[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])=[C:28]([NH:27][C:24]([C:21]3[CH:22]=[N:23][C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:19][CH:20]=3)=[O:26])[CH:40]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccccc2)nc1
Reaction time: 1 h

Procedure:
N,N-Dimethylformamide (0.9 μl) and oxalyl chloride (0.023 mL) were added to a methylene chloride (0.5 mL) suspension of 6-phenylpyridine-3-carboxylic acid (44 mg) at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was added to a solution mixture of tert-butyl 2-amino-4-phenylbenzoate (40 mg) in methylene chloride (1 mL) and triethylamine (0.17 mL) at room temperature, followed by stirring at same temperature for 1 hour. The solvent was evaporated under reduced pressure, and ethyl acetate and a 10% aqueous solution of citric acid were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Trikonex AB, FlashTube 2008, eluent: hexane/ethyl acetate=2:1] to obtain tert-butyl 4-phenyl-2-(6-phenylpyridine-3-carboxamido)benzoate.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[CH3:20][NH:21][C:22]([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:22]([N:21]([CH3:20])[C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[N:8]=1)=[O:19])([CH3:25])([CH3:24])[CH3:23]
Reactant: CNC(C)(C)C
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CS(=O)(=O)c1nc(C(=O)N(C)C(C)(C)C)ccc1C1CC1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU and DIEA to give the title compound as white solid; MS (EI): m/e=353.5 [MH+].
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:17])=[C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:6]=[C:7]([F:10])[C:8]=1[F:9].[Cl:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[CH:27][C:22]2=[CH:21][N:20]=1>>[Cl:18][C:19]1[N:24]=[C:23]2[N:25]([CH2:2][C:3]3[C:4]([F:17])=[C:5]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[CH:6]=[C:7]([F:10])[C:8]=3[F:9])[N:26]=[CH:27][C:22]2=[CH:21][N:20]=1
Reactant: Fc1cc(N2CCOCC2)c(F)c(CBr)c1F
Reactant: Clc1ncc2cn[nH]c2n1
Product: Fc1cc(N2CCOCC2)c(F)c(Cn2ncc3cnc(Cl)nc32)c1F

Procedure:
4-(3-(bromomethyl)-2,4,5-trifluorophenyl)morpholine and 6-chloro-1H-pyrazolo[3,4-d]pyrimidine were coupled as in Procedure D (Step ii) to afford 4-(3-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2,4,5-trifluorophenyl)morpholine followed by Procedure D (Step i) using tert-butyl 4-amino-1H-pyrazole-1-carboxylate to afford the title product. 1H NMR (d6-DMSO) δ 12.55 (s, 1H), 9.87 (br s, 1H), 8.89 (s, 1H), 8.15 (br s, 1H), 8.00 (s, 1H), 7.70 (s, 1H), 7.21-7.14 (m, 1H), 5.58 (s, 2H), 3.68 (t, 4H), 2.93 (t, 4H); LC-MS method B, (ES+) 431.1, RT=7.59 min.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:21][N:22]=[C:23]=[O:24].C(=O)([O-])[O-].[K+].[K+].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>O1CCCC1.C(O)C.C(OC(C)C)(C)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[CH3:21][NH:22][C:23](=[O:24])[O:20][C:17]1[CH:16]=[CH:15][C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:9]2[CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:19][CH:18]=1
Reactant: CN=C=O
Reactant: Oc1ccc(C2CCCN2CCN2CCOCC2)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CNC(=O)Oc1ccc(C2CCCN2CCN2CCOCC2)cc1
Yield: 57.7 %

Procedure:
To a solution of 4-{1-[2-(4-morpholinyl)ethyl]-2-pyrrolidinyl}phenol (0.92 g) in dry tetrahydrofuran (50 ml) was added methyl isocyanate (0.22 ml) at ambient temperature, with stirring, over ten mins. Milled potassium carbonate (0.55 g) was added and the reaction mixture was stirred for 2 days and filtered through a pad of celite. The filter cake was washed with ethyl acetate and the combined filtrates concentrated. The residue was purified by flash column chromatography (silica gel, 10% methanol/ether). The appropriate fractions were collected and concentrated. The residue was dissolved in dichloromethane and washed with water (5-6 times). The combined aqueous layers were back-extracted with ether, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. Fumaric acid (2.02 equivalents) in absolute ethanol and diisopropyl ether was added to the residue to yield (0.55 g, 57.7%) of product, mp 119°-121° C.
Reaction SMILES: S(=O)(=O)(O)O.CO.[CH3:8][C:9](=[CH2:18])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH3:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[CH3:26]>O>[CH3:19][C:20]1[CH:21]=[C:22]([C:9]([CH3:18])([CH3:8])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:23]=[CH:24][C:25]=1[CH3:26]
Reactant: C=C(C)CCCCC(=O)OC
Reactant: Cc1ccccc1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)CCCCC(C)(C)c1ccc(C)c(C)c1

Procedure:
300 parts of 98% sulfuric acid, 64 parts of methanol, 71 parts of methyl 5-methylhex-5-enecarboxylate and 53 parts of o-xylene are stirred at room temperature for 3 days and then poured into 2000 parts of water. This is followed by extraction with ether, washing of the extract with water and evaporation of the ether. The residue is dissolved in 500 parts of methanol, one part of p-toluenesulfonic acid, and the mixture is heated under reflux for 6 hours. The methanol is then distilled off, and the residue is taken up in ether and washed first with aqueous sodium bicarbonate and then with water. The ether is evaporated off and the residue is distilled to give methyl 5-(3,4-dimethylphenyl)-5-methylhexanecarboxylate having a boiling point of 176°-182° C./16 mbar.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38]>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 80.8 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (3.5 g, 16 mmol), K2CO3 (2.2 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (3.8 g, 16 mmol) acetonitrile (90 ml) was refluxed for 16 hours. The reaction was poured into water and the resulting white solid, which precipitated from solution, was collected to afford 5.5 g of the desired product. The compound was recrystallized from dimethylformamide (twice) to afford 3.0 g (44%) of 1-[4[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]propoxy]-methoxyphenyl]ethanone as a white solid, m.p.=202°-204° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Br[CH2:39][CH:40]([CH3:42])[CH3:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:39][CH:40]([CH3:42])[CH3:41])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: CC(C)CBr
Product: COc1ccc(CC2c3cc(OCC(C)C)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 1-bromo-2-methyl-propane
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][NH2:8])=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([CH3:12])=[N:3]1.[CH3:13][O:14][C:15]1[C:16]([O:28][CH3:29])=[CH:17][C:18]2[NH:24][C:23](=[O:25])[CH2:22][CH2:21][C:20](=O)[C:19]=2[CH:27]=1.O>C(O)(=O)C>[CH3:1][N:2]1[C:6]([NH:7][N:8]=[C:20]2[CH2:21][CH2:22][C:23](=[O:25])[NH:24][C:18]3[CH:17]=[C:16]([O:28][CH3:29])[C:15]([O:14][CH3:13])=[CH:27][C:19]2=3)=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([CH3:12])=[N:3]1
Reactant: Cc1nn(C)c(NN)c1[N+](=O)[O-]
Reactant: COc1cc2c(cc1OC)C(=O)CCC(=O)N2
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(cc1OC)C(=NNc1c([N+](=O)[O-])c(C)nn1C)CCC(=O)N2
Temperature: 70 °C
Yield: 12.2 %

Procedure:
1,3-Dimethyl-4-nitro-1H-pyrazol-5-yl-hydrazine (0.073 g, 0.4 mmol) was added to a suspension of 7,8-dimethoxy-1H-[1]benzazepin-2,5(3H, 4H)-dione (0.100 g, 0.4 mmol) in acetic acid (5 ml) with stirring under argon. The mixture was heated at 70° C. for 2 days, cooled and water (5 ml) added. The precipitate was then filtered off to give the title compound as a yellow solid (0.019 g, yield 11.5%); 1H-NMR (DMSO-d6, 300 MHz): δ (ppm)=12.8 (v br s; 1 H), 9.59 (s; 1H), 7.2 (s; 1H), 6.63 (s; 1H), 3.96 (s; 3H), 3.75-3.77 (s, 6H), 3.05 (br t, 2H), 2.57 (br t, 2H), 2.35 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.CCN(CC)CC.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)Cl>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH:1][C@H:2]1[C@H:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:3]1)=[O:33]
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1N
Reactant: O=C(Cl)CCCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1NC(=O)CCCCBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
To a solution of trans-1-tert-butyl 4-ethyl 3-aminopiperidine-1,4-dicarboxylate 7 (2.5 g, 9.2 mmol, 1.0 equiv) in CH2Cl2 (50 mL), Et3N (2.5 mL, 18.4 mmol, 2.0 equiv) was added at rt. After the reaction solution was stirred at rt for 10 min, 5-bromovaleryl chloride (1.9 g, 9.6 mmol, 1.05 eq) was added. The reaction solution was stirred at rt for 2 h. The mixture was quenched with H2O (20 mL) and extracted with CH2Cl2 (50 mL×3). The organic layer was collected, concentrated in vacuo, and the residue was purified by column chromatography (silica, petroleum ether/EtOAc=1:1) to give (trans)-1-tert-butyl 4-ethyl 3-(5-bromopentanamido)piperidine-1,4-dicarboxylate 8 as yellow oil (3.2 g, yield: 80%). ESI-MS (M+H-56)+: 379.0. 1H NMR (400 MHz, CDCl3) δ: 5.99 (d, 1H), 4.39-4.38 (m, 1H), 4.15 (q, 2H), 3.79-3.74 (m, 1H), 3.66-3.60 (m, 1H), 3.41 (t, 2H), 3.30-3.26 (m, 1H), 3.21-3.14 (m, 1H), 2.78-2.74 (m, 1H), 2.19 (t, 2H), 1.99-1.85 (m, 3H), 1.80-1.72 (m, 3H), 1.45 (s, 9H), 1.27 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][N:30]3[CH2:31][CH2:32][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)[CH2:28][CH2:29]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCCCC1C(=O)Nc2cc(F)ccc21
Reactant: c1ccc(N2CCNCC2)nc1
Product: O=C1Nc2cc(F)ccc2C1CCCCN1CCN(c2ccccn2)CC1

Procedure:
The title compound is prepared according to process B by applying processing method 1 starting from 6-fluoro-3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(pyridin-2-yl)-piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]1([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[O:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[CH2:14]1.C([O-])(O)=O.[Na+].C(Cl)[Cl:32]>>[Cl:32][C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH2:11][CH2:12][C:13]2([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[O:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[CH2:14]2)[CH:5]=1
Reactant: ClCCl
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
A solution of 6-[2-(2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (from example A(39); 4.50 g, 13 mmol) in CH2Cl2 (20 mL) was cooled to −5° C. and treated with a solution of SO2Cl2 (1.94 g, 14.3 mmol) in CH2Cl2 (10 mL) dropwise under nitrogen. The reaction mixture was stirred for an additional 15 minutes at −5° C., then allowed to warm gradually to room temperature. After a total reaction time of 2 h, an aqueous solution of NaHCO3 (5 wt %) was added to achieve a pH of 8 in the aqueous phase. The volatiles were removed in vacuo. The residue was treated with water and extracted with ethyl acetate (3×25 mL). The combined ethyl acetate extract was acidified to a pH 2 using 2 N HCl, then washed with water. The organic phase was dried over Na2SO4, filtered, and concentrated to a yellowish solid. Recrystallization from ether afforded the title product as a white solid (2.18 g, 44%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:9](=[O:18])[N:10]([C@H:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]3[CH3:17])[C:4]=2[C:3]=1[NH2:19].[CH2:20](OC(OCC)OCC)C>Cl>[CH3:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:11]1[N:10]1[C:4]2=[C:3]3[N:19]=[CH:20][NH:1][C:2]3=[N:7][CH:6]=[C:5]2[NH:8][C:9]1=[O:18]
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc(N)c(N)c21
Reactant: CCOC(OCC)OCC
Agent: Cl
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]cnc3c21
Temperature: 25 °C

Procedure:
A mixture of 6,7-diamino-1-[(1S,2R)-2-methylcyclohexyl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (40 mg), orthoformic acid triethyl ester (1 mL) and HCl (20 uL) was stirred at ambient temperature for an hour. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH2 silica gel, chloroform:methanol=95:5) to give 8-[(1S,2R)-2-methylcyclohexyl]-6,8-dihydrodiimidazo[4,5-b:4′,5′-d]pyridin-7(3H)-one (21 mg) as a white powder.
Reaction SMILES: [CH2:1](N=C=S)C=C.[CH2:7]([N:10]1[C:14]([SH:15])=[N:13][N:12]=[C:11]1[OH:16])[CH:8]=[CH2:9].Br[C:18]1[S:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21]N=1>>[CH2:7]([N:10]1[C:14]([S:15][C:18]2[S:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:1]=2)=[N:13][N:12]=[C:11]1[OH:16])[CH:8]=[CH2:9]
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: C=CCN=C=S
Reactant: C=CCn1c(O)nnc1S
Product: C=CCn1c(O)nnc1Sc1ccc([N+](=O)[O-])s1

Procedure:
The title compound was prepared in a similar manner described in Example 5 starting with allyl isothiocyanate. 4-Allyl-3-hydroxy-5-mercapto-1,2,4-triazole was reacted with 2-bromo-5-nitrothiazole as in Example 5. Crystallization from ethanol and water gave 4-allyl-3-hydroxy-5-[(5-nitrothien-2-yl)mercapto]-1,2,4-triazole as a yellow solid.