Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:14]1[CH2:19][CH:18]=[C:17]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.O>CS(C)=O>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][N:14]3[CH2:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[N:24][CH:25]=[CH:26][CH:27]=5)[NH:22][CH:21]=4)[CH2:18][CH2:19]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1=C(c2c[nH]c3ncccc23)CCNC1
Reactant: ClCCOc1cccc2[nH]ccc12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: C1=C(c2c[nH]c3ncccc23)CCN(CCOc2cccc3[nH]ccc23)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 10.2 %

Procedure:
A solution of 2-(1H-indol-4-yloxy)ethylchloride (0.5 g, 26 mmol), 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (0.61 g, 31 mmol) and triethylamine (0.71 ml, 52 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 4 hours at 80° C. The mixture was poured into water and extracted with ethyl acetate (3×100 ml). The organic layer was washed with water (3×100 ml), sodium bicarbonate and dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride) afforded 0.95 g (97%) of product as a green oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=1[CH3:31]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([F:21])=[C:23]([CH3:31])[CH:24]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: Cc1cc(C(=O)O)ccc1F
Agent: Cl
Product: Cc1cc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)ccc1F

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-fluoro-3-methylbenzoic acid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C@@H:10]1[C@@H:14]2[O:15]C(C)(C)[O:17][C@H:18]([CH:19]=[CH2:20])[C@@H:13]2[O:12][C:11]1=[O:23].O>C1COCC1>[OH:15][C@@H:14]1[C@H:13]([C@H:18]([OH:17])[CH:19]=[CH2:20])[O:12][C:11](=[O:23])[C@@H:10]1[O:9][CH3:8]
Reactant: C=C[C@H]1OC(C)(C)O[C@@H]2[C@H]1OC(=O)[C@@H]2OC
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C=C[C@@H](O)[C@@H]1OC(=O)[C@H](OC)[C@@H]1O
Reaction time: 8 h

Procedure:
10 mL of TFA are added dropwise at 0° C. to a 100 mL round-bottomed flask containing 1.0 g of 30 (4.38 mmol), 10 mL of water and 14 mL of THF. The medium is allowed to return to RT and stirred overnight. The medium is then concentrated at reduced pressure at RT and 50 mL of water are added, and the mixture is frozen and freeze-dried. The freeze-dried product is impasted in heptane in the presence of a minimum amount of methanol, and after evaporation of the solvents, 778 mg of expected product 31 (white solid) are obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:16]=[C:6]2[NH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:10](=[O:11])[N:5]2[N:4]=1.N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl>[C:23]([O:1][CH2:2][C:3]1[N:16]=[C:6]2[NH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:10](=[O:11])[N:5]2[N:4]=1)(=[O:25])[CH3:24]
Reactant: COC(=O)c1cc(=O)n2nc(CO)nc2[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(=O)n2nc(COC(C)=O)nc2[nH]1
Temperature: 55 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
Methyl 4,7-dihydro-2-(hydroxymethyl)-7-oxo-s-triazolo[1,5-a]pyrimidine-5-carboxylate (2.5 g) (11.1 mmol) are suspended in 20 ml of dichloromethane. After the addition of 1.76 g (22.3 mmol) of pyridine and 2.27 g (22.2 mmol) of acetic anhydride the mixture is stirred at 55° C. for 8 hours. The mixture is concentrated in a vacuum and the product is precipitated with diethyl ether. After recrystallization from methanol there are obtained 1.2 g of methyl 2-(acetoxymethyl)-4,7-dihydro-7-oxo-s-triazolo[1,5-a]pyrimidine-5-carboxylate as white crystals of melting point 260° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[N:10]([O-])=O.[Na+].N(O)=O.[F:17][B-:18]([F:21])([F:20])[F:19].[H+]>O>[F:17][B-:18]([F:21])([F:20])[F:19].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]#[N:10])=[CH:5][CH:4]=1
Reactant: O=N[O-]
Reactant: COc1ccc(N)cc1
Agent: F[B-](F)(F)F
Agent: O=NO
Agent: [H+]
Solvent: O
Product: COc1ccc([N+]#N)cc1
Reaction time: 0.75 h

Procedure:
p-Anisidine (30.75 g, 0.25 mole) was dissolved in aqueous tetrafluoroboric acid (48%, 110 ml) in a 500 ml 3 necked flask fitted with mechanical stirring, and cooled to 0°-10° C. Sodium nitrite (17.5 g, 0.25 mole) was separately dissolved in water (34 ml) and the solution cooled to 5°-10° C., and was then added dropwise to the reaction mixture over 60 minutes. The reaction mixture was stirred for about 45 minutes at 0°-10° C., and then tested with starch-iodide paper for excess nitrous acid. Any excess nitrous acid was destroyed by adding a small amount (approx. 0.1 g.) of sulfamic acid. The precipitate was filtered, washed once with ice-cold water (about 30 ml), and then twice with methanol (20 ml each time). The product diazonium tetrafluoroborate was dried under vacuum at ambient temperature. Yield 45.4 g (about 82%). This could be purified by dissolving in minimum amount of acetone, and precipitating with ether, repeating this process three times. The final product was filtered, washed with ether (30 ml), and dried.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05: tR=0.86 min; [M+H]+=420.88.
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:44])[C@@H:18]([NH:27][C:28]([N:30]3[CH2:34][CH2:33][C@H:32]([N:35](C)[C:36](=O)OC(C)(C)C)[CH2:31]3)=[O:29])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)[C:3]1=[O:45]>ClCCl.FC(F)(F)C(O)=O>[CH3:1][C:2]1([CH3:46])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:44])[C@@H:18]([NH:27][C:28]([N:30]3[CH2:34][CH2:33][C@H:32]([NH:35][CH3:36])[CH2:31]3)=[O:29])[CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:13][CH2:12]2)[C:3]1=[O:45]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)N[C@@H](CCc2ccccc2)C(=O)N2CCC(N3C(=O)C(C)(C)c4ccccc43)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H]1CCN(C(=O)N[C@@H](CCc2ccccc2)C(=O)N2CCC(N3C(=O)C(C)(C)c4ccccc43)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A mixture of tert-butyl (S)-1-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-ylcarbamoyl)pyrrolidin-3-yl(methyl)carbamate (267 mg, 0.42 mmol, EXAMPLE 47: Alternative Method, Step 1) in dichloromethane-trifluoroacetic acid (1:1, 6 mL) was stirred at room temperature for 1 h. The mixture was concentrated, diluted with dichloromethane, and washed with saturated sodium hydrogen carbonate aqueous solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residual oil was purified by preparative HPLC (32-96% methanol in 0.01% ammonia aqueous solution) and by amino gel column chromatography to give the title compound (209 mg, 93%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[C:18]([NH:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:45]2[CH2:46][CH2:47][CH:42]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:43][CH2:44]2)=[O:14])=[CH:11][C:10]=1[C:18]([NH:20][C:21]1[CH:22]=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:24]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:26]=1)=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(=O)N2CCC(Cc3ccccc3)CC2)ccc1OCc1ccccc1
Yield: 76.7 %

Procedure:
Using 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid (compound of Example 84(2)) and 4-benzylpiperidine as the raw materials, the same operation as the Example 84(3) gave the title compound.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4](=[N:6]/[N:7]=[C:8](/[C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=1)\[CH3:9])[NH2:5].CCO.Cl>[Fe].O>[ClH:1].[ClH:1].[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10](/[C:8](=[N:7]/[N:6]=[C:4]([NH2:5])[NH2:3])/[CH3:9])[CH:11]=2)=[O:27])=[CH:23][CH:22]=1
Reactant: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc(N)cc2)c1
Yield: 212.2 %

Procedure:
To a refluxing suspension of amide F4 (2.02 g, 5.36 mmol) in 2:1 EtOH:H2O (100 mL) were sequentially added Fe dust (1.20 g, 21.44 mmol) and c.HCl (2 mL), and the resulting suspension was refluxed for 14 h. After this time, the hot reaction mixture was filtered through a pad of Celite, and the solvent was removed under reduced pressure. The residue was re-dissolved in hot H2O, and the resulting suspension filtered through a pad of Celite. Solvent was removed under reduced pressure, and the residue dried via three MeOH-azeotrope cycles. The resulting residue was reprecipitated from acidified MeOH to afford triamine F5 (2.18 g, quantitative) as an amorphous cream solid; 1H NMR (400 MHz, DMSO): δ 11.30 (s, 1H, hydrazonyl-N+—H), 10.05 (s, 1H, ArC(O)NHAr), 8.21 (s, 1H, ArH), 8.20-7.55 (m, 8H, ArH & ═C(NH2)2), 7.36 (t, J=7.90 Hz, 1H, ArH), 6.91 (d, J=7.96 Hz, 1H, ArH), 5.30 (v br s, 3H, ArNH3+), 2.35 (s, 3H, Ar(CH3)═N—); LCMS (APCI+): 311 (100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]4[CH2:19][CH:18]4[C:20](O)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]4[CH2:19][CH:18]4[C:20]([NH:23][C:24]4[S:25][CH:26]=[CH:27][N:28]=4)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1nccs1
Reactant: O=C(O)C1CC1c1ccc2c(cnn2-c2ccc(F)cc2)c1
Product: O=C(Nc1nccs1)C1CC1c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 7 %

Procedure:
Example 103 was prepared from 2-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclopropanecarboxylic acid (34 mg, 0.115 mmol) and 2-aminothiazole using General Coupling Method B to give 3 mg (7% yield). MS found: (M+H)+=379.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([CH2:20][C:21]([F:24])([F:23])[F:22])=[N:18][N:19]=[C:14]2[C@H:13]([NH:25]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>O1CCOCC1>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([CH2:20][C:21]([F:24])([F:22])[F:23])=[N:18][N:19]=[C:14]2[C@H:13]([NH2:25])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Reaction time: 1 h

Procedure:
Hydrochloric acid (4.0 M in dioxane; 10 mL, 40.1 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]carbamate (618 mg, 1.384 mmol) in 1,4-dioxane (5 mL). After 1 h, the reaction was concentrated to give the title compound as a bis hydrochloride salt (584 mg). MS 347.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].[OH-].[Na+]>CO.Cl>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[NH2:8]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(N)ccc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2-Chloro-5-nitro anisole (6.0 g, 0.032 mol) in MeOH (45 ml) was added slowly to stannous chloride (15.1 g, 0.08 mol) in conc. HCl (110 ml) at 40° C. and the temperature was slowly raised to 50° C. Stirring was continued for 2 h. After cooling to RT, the reaction mixture was basified with 50% NaOH solution, extracted by ethyl acetate, washed with water, then brine and dried over Na2SO4. 3-Methoxy-4-chloroaniline was obtained upon concentration and was purified further by column chromatography. Yield: 4.0 g, 79.36%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.[CH:18]#[C:19][CH3:20]>CS(C)=O.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:18]([C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1)#[C:19][CH3:20]
Reactant: C#CC
Reactant: CCOC(=O)c1cc(Br)cnc1C(=O)OCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC#Cc1cnc(C(=O)OCC)c(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 3 g of 5-bromo-pyridine-2,3-dicarboxylic acid, diethyl ester, 0.1 g cuprous iodide and 0.7 g bis(triphenylphosphine)palladium(II)chloride in 40 mL dimethyl sulfoxide and 12 mL triethylamine is cooled to 10°, and 10 mL of liquid propyne is added. The reaction is stirred at room temperature thereafter for 16 hours, then is poured onto water and extracted with methylene chloride. The organic phase is washed with dilute hydrochloric acid, then water, then brine, and dried. Concentration in vacuo, and chromatography of the residue on silica gel using ether-hexane mixture affords the desired product as an oil.
Reaction SMILES: CO.[F:3][S:4]([CH2:7][CH2:8]Cl)(=[O:6])=[O:5].C1COCC1.[OH:15][CH2:16][CH2:17][O:18][Na]>ClCCl.O>[F:3][S:4]([CH2:7][CH2:8][O:15][CH2:16][CH2:17][OH:18])(=[O:6])=[O:5]
Reactant: OCCO[Na]
Reactant: O=S(=O)(F)CCCl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(F)CCOCCO
Reaction time: 2.5 h

Procedure:
Into a round flask, HO(CH2)2OH (140.9 g) and a methanol solution of sodium methylate (28 wt %, 96.4 g) were charged and stirred, and heated under reduced pressure to distill off methanol thereby to obtain a solution of HOCH2CH2ONa. It was confirmed by GC that no methanol remained in the reaction solution. Into a four necked flask, FSO2CH2CH2Cl (50 g) and THF (100 mL) were charged and stirred under cooling with ice bath, and the previously obtained solution of HOCH2CH2ONa was dropwise added thereto over a period of 2.5 hours, while maintaining the internal temperature to be at most 10° C. After completion of the dropwise addition, it was stirred at room temperature for 2 hours and then added to water (400 mL), and dichloromethane (183 g) was added. The obtained crude liquid was subjected to liquid separation, and the obtained aqueous layer was extracted with dichloromethane (124 g). The separated aqueous layer was further extracted with dichloromethane (126 g), and the organic layers were put together. It was dried over magnesium sulfate, and after filtration, the solvent was distilled off to obtain a crude product (47.1 g). The obtained crude liquid was used for the next step without carrying out purification.
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].Br[CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=1.CC[O-].[Na+]>CCO>[CH3:17][O:16][C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([CH3:15])[CH:12]=1)[CH:8]=[O:2]
Reactant: CC(C)[N+](=O)[O-]
Reactant: COc1cc(C)cc(CBr)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C)cc(C=O)c1
Yield: 77.2 %

Procedure:
2-Nitropropane (6.77 ml, 71.3 mmol) and subsequently 1-bromomethyl-3-methoxy-5-methyl-benzene (14.6 g, 67.9 mmol) were added to a solution of NaOEt (4.72 g, 67.9 mmol) in EtOH (60 ml). The mixture was heated for 1.5 h. to 65° C. After cooling the colorless precipitate of filtered off and the filtrate was concentrated. The product was purified by chromatography (SiO2, CH2Cl2/hexane 1:2). There were obtained 7.87 g (77%) of 3-methoxy-5-methyl-benzaldehyde as a colorless liquid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18](I)[C:17]([O:21][CH3:22])=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.CO[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([B:30]3[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]3)[C:17]([O:21][CH3:22])=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1nn([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)cc1I
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1nn([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-4-iodo-3-methoxy-1H-pyrazole (0.0500 g, 0.114 mmol) in anhydrous degassed THF (2.0 mL) was cooled to −10° C. and dropwise charged with 1.30 M of isopropylmagnesium chloride in THF (0.352 mL, 0.458 mmol) over a 5 min period under an atmosphere of Argon. The reaction was maintained at −10° C. for 40 min then charged with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.0939 mL, 0.573 mmol) and stirred for an additional 1 h at 0° C. The reaction mixture was quenched with sat NH4Cl (2.0 mL) and partitioned between EtOAc and H2O. The aqueous was re-extracted with EtOAc (3×) and the combined organic fractions were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo resulting in a crude yellow oil. The crude was purified by chromatography on silica gel [ISCO Combiflash, 4 g gold cartridge, eluting with 100% heptane→30% EtOAc in heptane] resulting in the title compound as a white waxy solid. 1H NMR (400 MHz, CD3OD): δ=−0.02-0.02 (m, 6H), 0.79-0.84 (m, 9H), 1.19 (s, 12H), 1.32-1.44 (m, 2H), 1.66-1.78 (m, 2H), 1.85-1.92 (m, 2H), 1.94-2.02 (m, 2H), 3.60-3.69 (m, 1H), 3.76-3.79 (m, 3H), 3.86 (tt, J=3.8, 12 Hz, 1H), 7.50 (s, 1H). MS (ES+): m/z 436.27, 437.26, 438.29 [MH+]. HPLC: tR=4.05 min (vvnonpolar—5 min, ZQ3).
Reaction SMILES: [C:1](CC(N)=O)(=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:17]([NH:19][C:20]1([C:30]#[N:31])[CH2:24][CH2:23][N:22]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:21]1)=[O:18]>>[C:17]([N:19]=[C:1]([NH:15][CH:16]([CH2:32][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)[C:17]([NH:19][C:20]1([C:30]#[N:31])[CH2:24][CH2:23][N:22]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:21]1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:18])[CH3:16]
Reactant: NC(=O)CC(=S)c1ccccc1
Reactant: CCC(CC)N1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)C1
Agent: Cl
Product: CCC(CC)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC(=NC(C)=O)c2ccccc2)C1

Procedure:
The title compound was prepared starting from thiobenzoyl acetamide and 2-amino-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 1, step b, except that the compound was purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 20% acetonitrile in water to 90% acetonitrile in water. MS, m/z 480=M+1.
Reaction SMILES: BrC1C(N2CCN(CC3C=NC=CC=3)CC2)=C2N=C(C3C=CC(CN)=CC=3)NC2=NC=1.[Br:32][C:33]1[C:34]([N:57]2[CH2:62][CH2:61][N:60]([CH2:63][C:64]3[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=3)[CH2:59][CH2:58]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:43]=[C:44]([CH:54]=[CH:55][CH:56]=3)[CH2:45][NH:46]C(=O)OC(C)(C)C)[NH:39][C:36]2=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:32][C:33]1[C:34]([N:57]2[CH2:58][CH2:59][N:60]([CH2:63][C:64]3[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=3)[CH2:61][CH2:62]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:43]=[C:44]([CH2:45][NH2:46])[CH:54]=[CH:55][CH:56]=3)[NH:39][C:36]2=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)c1
Agent: NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)c1
Yield: 85.4 %

Procedure:
This was prepared using the same procedure as for (4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)methanamine, but here using tert-butyl 3-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzylcarbamate (70 mg, 0.12 mmol), TFA (0.6 mL) and CH2Cl2 (2 mL). The same purification procedure gave the desired product (49 mg, 84%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.63 (s, br, 4H, piperazine N(CH2)2), 3.63 (s, 2H, NCH2Ar), 3.68 (t, J=4.3 Hz, 4H, piperazine N(CH2)2), 3.84 (s, 2H, CH2NH2), 7.40 (dd, J=7.7, 4.8 Hz, 1H, pyridine H-5), 7.48-7.50 (m, 2H, phenyl H-4 & H-6), 7.80 (dt, J=7.7, 1.7 Hz, 1H, pyridine H-4), 8.02-8.05 (m, 1H, phenyl H-5), 8.18 (s, br, 1H, phenyl H-2), 8.25 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.50 (dd, J=4.8, 1.5 Hz, 1H, pyridine H-6), 8.58 (d, J=1.6 Hz, 1H, pyridine H-2);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[O:11]=[C:8]1[CH2:7][C:6]2[C:10](=[C:2]([NH:1][S:17]([C:13]3[S:12][CH:16]=[CH:15][CH:14]=3)(=[O:19])=[O:18])[CH:3]=[CH:4][CH:5]=2)[NH:9]1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Nc1cccc2c1NC(=O)C2
Solvent: c1ccncc1
Product: O=C1Cc2cccc(NS(=O)(=O)c3cccs3)c2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a mixture of 7-amino-2-oxo-2,3-dihydro-1H-indole (1.53 g) and pyridine (20 mL) was added thiophene-2-sulfonyl chloride (2.26 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography, and eluted with ethyl acetate. The eluate was treated with activated carbon and concentrated to give the title compound (2.93 g, yield 97%) as colorless crystals. The crystals were recrystallized from tetrahydrofuran-hexane. melting point>230° C. (decomposition)
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[H-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>C1COCC1>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=[O:21])[O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: O=C=Nc1ccccc1Br
Reactant: OC1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1Br)OC1CN2CCC1CC2
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of quinuclidin-3-ol (382 mg, 3.00 mmol) in THF (15 mL) was added NaH [60% dispersion in mineral oil](156 mg, 3.90 mmol) at room temperature. The mixture was stirred for 15 min and 2-bromophenyl isocyanate (594 mg, 3.00 mmol) was added under stirring. The resulting mixture was stirred at room temperature for 18 h, quenched with brine and extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting crude product was purified by silica gel column chromatography (EtOAc/methanol 3:1) to give the product quinuclidin-3-yl 2-bromophenylcarbamate as viscous oil (0.80 g, 82%).