Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH:31]2[CH2:33][CH2:32]2)[C:5]([C:7]2[N:28]([CH2:29][CH3:30])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:24]=[C:23]([CH:25]=O)[N:22]([CH3:27])[N:21]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO>[CH:1]1([N:4]([CH:31]2[CH2:33][CH2:32]2)[C:5]([C:7]2[N:28]([CH2:29][CH3:30])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:24]=[C:23]([CH2:25][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[N:22]([CH3:27])[N:21]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(C=O)n(C)n3)nc21
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(CN4CCOCC4)n(C)n3)nc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.1 %

Procedure:
To a stirred solution of N,N-dicyclopropyl-6-ethyl-4-(5-formyl-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 112B, 22 mg, 0.049 mmol) and molecular seives 4 Å (30 mg) in MeOH (2 mL) was added morpholine (0.017 mL, 0.197 mmol). After the solution was stirred at room temperature for 12 hrs, sodium borohydride (7.46 mg, 0.197 mmol) was then added and stirred for 3 hrs. The solution was brought to pH=4 with 1N HCl, neutralized with saturated aqueous sodium bicarbonate, and then extracted with CH2Cl2. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica-gel flash chromatography using an Isco 40 g column eluting from 0-10% MeOH/CH2Cl2 to yield N,N-dicyclopropyl-6-ethyl-1-methyl-4-(1-methyl-5-(morpholinomethyl)-1H-pyrazol-3-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (14.3 mg, 0.027 mmol, 54.9% yield) as a white solid.
Reaction SMILES: CO.[C:3]([O-])(=[S:5])[CH3:4].[K+].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([CH:18](Br)[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].CCCCCCC>O>[C:3]([CH:18]([C:15]1[CH:16]=[CH:17][C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:13][CH:14]=1)[C:19]([O:21][CH3:22])=[O:20])(=[S:5])[CH3:4]
Reactant: COC(=O)C(Br)c1ccc(C(C)(C)C)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCCCCCC
Solvent: O
Solvent: CO
Product: COC(=O)C(C(C)=S)c1ccc(C(C)(C)C)cc1
Temperature: 35 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a methanol (203 g) solution of potassium thioacetate (70.4 g, 0.616 mol, 1.3 equivalent amounts based on the starting material), a mixed solution of a 33 mass % methanol solution (408.5 g, 0.473 mol) of methyl 2-(4-t-butylphenyl)-2-bromoacetate and methanol (270 g) was dropwise added over a period of 1 hour and 20 minutes, followed by stirring at from 30 to 40° C. for 1 hour. Then, the reaction solution was mixed with heptane (674 g) and water (675 g) and stirred for 20 minutes, followed by liquid separation. The solvent was distilled off from the obtained organic layer under reduced pressure at 40° C. until the total amount became 382 g. The obtained solution was cooled to 30° C. over a period of 1 hour, and 0.13 g of seed crystals were added. Then, the solution was stirred for 1 hour and further cooled to −10° C. over a period of 3 hours. Then, the solution was stirred for 1 hour and subjected to filtration, and the obtained crystals were dried to give the desired product (110.7 g, yield: 83.3%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1.[B-](F)(F)(F)[CH:23]=[CH2:24].[K+].C(O)(C)C.C(N(CC)CC)C>O1CCCC1>[CH3:21][C:17]1[N:16]=[C:15]([CH2:14][N:4]2[C:5]3[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[C:2]([CH:23]=[CH2:24])=[N:3]2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C=Cc1nn(Cc2cccc(C)n2)c2cccc([N+](=O)[O-])c12
Temperature: 95 °C
Yield: 87.4 %

Procedure:
To a reaction vial was added 3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (216 mg, 0.548 mmol) and potassium trifluoro(vinyl)borate (156 mg, 1.64 mmol). Isopropanol (2 mL) and tetrahydrofuran (0.5 mL) were added. Argon was bubbled through the mixture for 20 minutes. Triethylamine (229 μL, 1.64 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (44.8 mg, 0.0548 mmol) were added. The vial was sealed and the mixture was heated at 90-100° C. for 3 hours. The mixture was allowed to cool and filtered through glass fiber filter paper, washing with ethyl acetate. The solution was concentrated under reduced pressure. The residue was dissolved in chloroform (30 mL) and washed with water (10 mL). The solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 1-((6-methylpyridin-2-yl)methyl)-4-nitro-3-vinyl-1H-indazole as an oil (141 mg).
Reaction SMILES: C(N(CC)CC)C.O1CCCC1.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])(OCC)=O>O>[C:23]([O:22][C:20]([N:17]1[CH2:16][CH2:15][CH:14]([N:13]2[C:36](=[O:37])[C:35]3[C:34](=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:33]2=[O:42])[CH2:19][CH2:18]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
16.7 ml of triethylamine was added to 200 ml of a tetrahydrofuran solution containing 16 g of 4-amino-1-tert-butoxycarbonylpiperidine and 17.5 g of N-carboethoxyphthalimide under ice-cooling, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was suspended in ether-hexane, and crystals were collected by filtration to obtain 25.7 g of 2-(1-tert-butoxycarbonyl-4-piperidyl)isoindoline-1,3-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[NH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[CH2:29][CH2:28][CH2:27]1.[N:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][N:44]=2)[CH:39]=[CH:38][CH:37]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[NH:34]1[C:35]2[C:30](=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:31][CH2:32][CH2:33]1.[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:4]2[C:5]([C:8]([N:44]3[C:45]4[C:40](=[CH:39][CH:38]=[CH:37][N:36]=4)[CH2:41][CH2:42][CH2:43]3)=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:13])=[O:14])=[CH:16][C:17]=1[C:22]([F:25])([F:23])[F:24]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: c1cnc2ncccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)CCCN2
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCCc2cccnc21

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (208 mg, 0.50 mmol), 1,2,3,4-tetrahydro-[1,8]naphthyridine [(135 mg, 1.0 mmol) 1,2,3,4-tetrahydro-[1,8]naphthyridine was prepared freshly from 1,8-napthyridine via hydrogenation over Pt2O], BOP (486 mg, 1.1 mmol), DIEA (185 mg, 1.4 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 4-chloro-N[5-chloro-2-(3,4-dihydro-2H-[1,8]naphthyridine-1-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide: MS m/z: 531.0 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][N:6]([C:12](=[O:28])[C@H:13]([CH:25]([CH3:27])[CH3:26])[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[K+]>C(O)C>[C:15]([NH:14][C@H:13]([C:12]([N:6]([CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:5][C:4]([OH:29])=[O:3])=[O:28])[CH:25]([CH3:26])[CH3:27])([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: CCOC(=O)CN(C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)C1CCCC1
Yield: 58 %

Procedure:
N-CBZ-L-Valyl-N-(cyclopentyl)glycine ethyl ester (4.8 g, 0.0119 mol) was dissolved in ethanol (60 mL) and treated with 1N KOH (12.5 mL) in portions of 3 mL. After the mixture was allowed to stir at room temperature over night the ethanol was removed under vacuum, and the residue was treated with water. The residue was extracted three times with ethyl acetate and afterwards the aqueous layer was acidified with dilute HCl. The product was extracted into ethyl acetate and then washed with saturated aqueous sodium chloride. After drying over MgSO<, filtration and evaporation under reduced pressure afforded the product as a white semisolid (2.6 g).
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[N:5]1[C:14]2[C:9](=[C:10]([CH3:18])[C:11]([F:17])=[C:12]([F:16])[C:13]=2[F:15])[C:8](=[O:19])[C:7]([C:20]([O:22]CC)=[O:21])=[CH:6]1.Cl.C(O)(=O)C>O>[F:1][C@H:2]1[CH2:4][C@H:3]1[N:5]1[C:14]2[C:9](=[C:10]([CH3:18])[C:11]([F:17])=[C:12]([F:16])[C:13]=2[F:15])[C:8](=[O:19])[C:7]([C:20]([OH:22])=[O:21])=[CH:6]1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(F)c(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 104.5 %

Procedure:
A mixture of 1.00 g of ethyl 1-[-(1R,2S)-2-fluorocyclopropyl]-6,7,8-trifluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate, 10 ml of concentrated hydrochloric acid, and 20 ml of acetic acid was heated under reflux for 1 hour and, after allowing to cool, water was added thereto. The precipitated crystals were collected by filtration, washed with water and ethanol, and dried to yield 960 mg of the titled compound as a pale yellow powderous crystal, which was then recrystallized from a mixed solvent of ethanol and chloroform.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:30][C:31]1[CH:32]=[C:33]([NH:37][C:38]2[CH:43]=[C:42]([NH:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:47][CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH:34]=[CH:35][CH:36]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:51]([C:48]1[CH:47]=[CH:46][C:45]([NH:44][C:42]2[N:41]=[CH:40][N:39]=[C:38]([NH:37][C:33]3[CH:32]=[C:31]([NH:30][C:1](=[O:5])[CH2:2][CH3:3])[CH:36]=[CH:35][CH:34]=3)[CH:43]=2)=[CH:50][CH:49]=1)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CCC(=O)O
Reactant: Nc1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of propionic acid (12 mg, 0.1 mmol) in DMF (0.6 mL) was added HATU (92 mg, 0.2 mmol) and the reaction mixture was stirred at room temperature for 30 min. To it was added N4-(3-aminophenyl)-N6-(4-phenoxyphenyl)pyrimidine-4,6-diamine (60 mg, 0.1 mmol) followed by DIPEA (41 mg, 0.3 mmol) and the reaction mixture was stirred at this temperature for 16 h. It was concentrated under reduced pressure. The residue was diluted with CH2Cl2 (5 mL) and was washed with NaHCO3 solution (2 mL), water (2 mL), and brine (2 mL). Drying over Na2SO4 followed by concentration under reduced pressure offered a residue that was purified by column chromatography (SiO2, 230-400, chloroform/methanol:9/1) to give N-(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)phenyl)propionamide (IR-10) as a brown solid. 1H NMR (DMSO-d6) δ ppm: 1.06 (t, J=7.56 Hz, 3H), 2.30 (q, J=7.48 Hz, 2H), 6.13 (s, 1H), 6.94-6.99 (m, 4H), 7.08 (t, J=7.36 Hz, 1H), 7.16-7.24 (m, 3H), 7.36 (t, J=7.44 Hz, 2H), 7.54 (d, J=8.88 Hz, 2H), 7.81 (s, 1H), 8.23 (s, 1H), 9.12 (s, 2H), 9.81 (s, 1H); LCMS: m/e 426.3 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)=[N:3][C:4]=1[CH3:12]
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)nc1C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: Cc1cc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)nc1C
Yield: 37 %

Procedure:
A mixture of 2-chloro-5,6-dimethyl-3-nitropyridine (Godard, A.; Rocca, P.; Pomel, V.; et al. J. Organomet. Chem., 1996, 517, 25.; Rocca, P.; Marsais, F.; Godard, A.; et al. Tetrahedron Lett., 1993, 34, 2937., 3.3 g, 17.5 mmol), 4-aminophenylethyl alcohol (3.6 g, 26.3 mmol) and 2,6-lutidine (3.7 mL) in toluene (80 mL) was stirred under reflux temperature for 19 h. The mixture was diluted with ethyl acetate (100 mL) and washed with 1N aqueous NaOH (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 1.8 g (37%) of the title compound as orange solids: 1H-NMR (CDCl3) δ 8.24 (1H, br.s), 7.68 (2H, d, J=8.6 Hz), 7.24 (2H, d, J=8.6 Hz), 3.88 (2H, dt, J=6.1, 7.6 Hz), 2.88 (2H, t, J=7.6 Hz), 2.49 (3H, s), 2.26 (3H, s), 1.43 (1H, t, J=6.1 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][C:3]=1[CH3:10].[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1.[Cl-].[NH4+]>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:19]=[O:20])=[C:3]([CH3:10])[CH:4]=1
Reactant: Cc1cc(Br)c(C)cc1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C=O)c(C)cc1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
4 g (15 mmol, 1 eq.) of 1,4-dibromo-2,5-dimethylbenzene are solubilized in 50 mL of distilled THF, in a Schlenk tube under argon. The medium is then cooled to −78° C., then 6.6 mL (16.6 mmol, 1.1 eq.) of BuLi (2.5M in hexane) are added dropwise. After stirring at this temperature for 1 hour, 5.3 mL (68 mmol, 4.5 eq.) of freshly distilled DMF are added. The reaction medium is again stirred at this temperature for 1 hour, and then the temperature returns to ambient temperature overnight. Next, the medium is diluted with a solution of ammonium chloride and then extracted three times with ethyl acetate. The organic phases are combined, dried over magnesium sulphate, and concentrated under reduced pressure. The residue is purified by silica column chromatography (eluent: ethyl acetate/petroleum ether: 80/20), so as to give a white solid (m: 1.3 g, yield: 40%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].C1COCC1.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)[CH2:40][CH2:39]1>CCOC(C)=O.CCCCCC>[CH3:37][N:38]1[CH2:39][CH2:40][N:41]([C:44]2[CH:49]=[CH:48][C:47]([NH:50][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH:28]([CH3:29])[CH3:30])[N:25]=[CH:26][CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:46][CH:45]=2)[CH2:42][CH2:43]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)n1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)n1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A small screw cap test tube was charged with 2-Isopropyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 138 mg, 0.3314 mmol) and THF (3.3 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (63.3 mg, 0.331 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (˜10 mL) to afford the title compound in 65% yield (0.127 g, 0.215 mmol).
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[CH:9])([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.Cl[C:18]1[C:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=[CH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:8]([Si:3]([C:6]#[C:7][C:18]1[C:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=[CH:20][N:19]=1)([CH2:4][CH3:5])[CH2:1][CH3:2])[CH3:9]
Reactant: C#C[Si](CC)(CC)CC
Reactant: COC(=O)Cc1cccnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[Si](C#Cc1ncccc1CC(=O)OC)(CC)CC
Temperature: 90 °C

Procedure:
A solution of triethylsilyl acetylene (0.579 mL, 3.23 mmol) in degassed DMF (3 mL) and triethylamine (0.901 mL, 6.47 mmol) were added to a mixture of methyl 2-(2-chloropyridin-3-yl)acetate (I118) (0.200 g, 1.08 mmol), Pd(PPh3)2Cl2 (75.6 mg, 0.108 mmol), Cu(I)I (30.8 mg, 0.162 mmol) and triphenylphosphine (42.4 mg, 0.162 mmol) in degassed DMF (4 mL) and the resulting mixture was heated at 90° C. for 20 hours. The cooled mixture was diluted with EtOAc and passed through a plug of celite, washing with ethyl acetate (100 mL). Water (75 mL) was added to the filtrate and the layers separated. The aqueous layer was extracted with EtOAc (2×75 mL). The combined organic extracts were washed with brine (100 mL) and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a dark brown residue. The residue was purified by column chromatography on silica gel (0-50% EtOAc in cyclohexane) to yield the title compound (I119) (0.353 g) as a brown oil which was used without further purification; 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=4.8, 1.6 Hz, 1H), 7.62 (dd, J=7.8, 1.6 Hz, 1H), 7.22 (dd, J=7.8, 4.8 Hz, 1H), 3.86 (s, 2H), 3.70 (s, 3H), 1.05 (t, J=7.9 Hz, 9H), 0.75-0.67 (m, 6H). LCMS Method C: rt 6.55 min; m/z 290 [M+H]+.
Reaction SMILES: [ClH:1].[C:2]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].C[O:17][C:18]1[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24]Br)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[ClH:1].[C:2]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:6][N:7]([CH2:24][CH2:23][O:22][C:21]2[CH:26]=[CH:27][C:18]([OH:17])=[CH:19][CH:20]=2)[CH2:8][CH2:9]1)#[N:3]
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: COc1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#CC1(c2ccccc2)CCN(CCOc2ccc(O)cc2)CC1

Procedure:
The title compound was prepared from 4-cyano-4-phenylpiperidine hydrochloride (600 mg, 2.69 mmol), 2-(4-methoxyphenoxy)ethyl bromide (653 mg, 2.82 mmol) and K2CO3 (761 mg, 5.51 mmol) in two steps as a colorless solid (28 mg, 60%), mp 199-200° C.; 1H NMR (CD3OD) 2.48-2.64 (m, 4H), 3.48-3.64 (m, 2H), 3.73 (t, J=4.8 Hz, 2H), 3.95 (d, J=12 Hz, 2H), 4.36 (t, J=4.5 Hz, 2H), 6.74 (d, J=8.7 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 7.38-7.64 (m, 5H); HRMS calcd for C20H22N2O2 322.1681, found 322.1678.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:10][CH:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1)N.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]2[NH:1][C:3]3[C:12]([C:22]=2[CH2:21]1)=[C:7]1[C:8]([CH3:11])=[CH:9][S:10][C:6]1=[CH:5][CH:4]=3)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1csc2ccc(NN)cc12
Product: Cc1csc2ccc3[nH]c4c(c3c12)CN(Cc1ccccc1)CC4

Procedure:
The compound is formed analogously to the compound described in Example 5, from 10.1 g of 5-hydrazino-3-methylbenzothiophene and 10 ml of benzyl-4-piperidone. Melting point: 93° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH:24]=[CH:23][C:22]([NH2:25])=[N:21]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH:24]=[CH:23][C:22]([NH:25][CH:10]3[CH2:11][CH2:12][N:7]([C:5]4[S:4][N:3]=[C:2]([CH3:1])[N:6]=4)[CH2:8][CH2:9]3)=[N:21]2)=[CH:17][CH:16]=1
Reactant: Nc1ccn(Cc2ccc(F)cc2)n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3ccn(Cc4ccc(F)cc4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(4-fluoro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a colorless oil.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([NH:3][CH:4]([C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(C(N)C(=O)O[C@H]2CN3CCC2CC3)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(NC(=O)c2ccccc2)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-p-tolylacetate dihydrochloride (I109) (116 mg, 0.33 mmol) in DCM (5 ml), were added triethylamine (139 μl, 1.00 mmol) and benzoyl chloride (46.5 μl, 0.40 mmol). The reaction was stirred at RT for 3 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with Na2CO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-benzamido-2-p-tolylacetate (70.0 mg; 55% yield). The product was used in the next step without any further purification.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][N:8]1[CH:12]=[N:11][N:10]=[CH:9]1.F[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].Cl>CS(C)=O.O>[C:16]([C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[NH:7][N:8]1[CH:12]=[N:11][N:10]=[CH:9]1)#[N:17]
Reactant: Nn1cnnc1
Reactant: N#Cc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccccc1Nn1cnnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
6.67 Grams of potassium tert-butoxide was dissolved in 36 ml of anhydrous dimethylsulfoxide, and 5.00 g of 4-amino-4H-1,2,4-triazole was added thereto and the mixture was stirred for 15 minutes at room temperature. Subsequently, 9 ml of an anhydrous dimethylsulfoxide solution containing 3.23 g of 2-fluorobenzonitrile was added dropwise to the solution over a period of 10 minutes, and the mixture was stirred for further 15 minutes. The reaction mixture was poured into 90 ml of water and 90 g of ice, and the solution was then adjusted to have pH of 5.7 with 1N hydrochloric acid. The crystals precipitated out were collected by filtration and dried to give 2.64 g of 4-[(2-cyanophenyl)amino]-4H-1,2,4-triazole.