Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][N:21]([CH2:20][C:4]1[CH:3]=[C:2]([C:32]2[CH:33]=[CH:34][S:30][CH:31]=2)[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=1)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2ccsc2)n(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c1)C(=O)OC(C)(C)C
Yield: 69.4 %

Procedure:
Using tert-butyl [(5-bromo-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (437 mg), 3-thiopheneboronic acid (223 mg), sodium carbonate (275 mg) and tetrakis(triphenylphosphine)palladium (50.8 mg), a procedure as in Reference Example 267 was performed to give the title compound as a white solid (yield 305 mg, 69%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:15]=[C:16]([C:30]([O:33][Si](C(C)C)(C(C)C)C(C)C)([CH3:32])[CH3:31])[CH:17]=[C:18]([F:29])[C:19]=1B1OC(C)(C)C(C)(C)O1>>[F:13][C:14]1[CH:15]=[C:16]([C:30]([OH:33])([CH3:32])[CH3:31])[CH:17]=[C:18]([F:29])[C:19]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: CC(C)[Si](OC(C)(C)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1)(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(F)c(Br)n1
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)(C)O)cc2F)n1
Yield: 90 %

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) and (2-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yloxy)triisopropylsilane (1.6 equiv.) at 100° C. for 30 min in the microwave to give methyl 6-(2,6-difluoro-4-(2-hydroxypropan-2-yl)phenyl)-5-fluoropicolinate in 90% yield. LC/MS=325.9 (MH+), Rt=0.81 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.59 (s, 6H), 4.00 (s, 3H), 7.15 (d, J=9.00 Hz, 2H), 7.62-7.68 (m, 1H), 8.23-8.29 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]#[N:10].Cl.Cl[CH2:21][CH2:22][N:23]([CH:31]([CH3:33])[CH3:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:21][CH2:22][N:23]([CH:31]([CH3:32])[CH3:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]#[N:10]
Reactant: N#CC(CCN1CCCCC1)c1ccccc1Cl
Reactant: CC(C)N(CCCl)Cc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Product: CC(C)N(CCC(C#N)(CCN1CCCCC1)c1ccccc1Cl)Cc1ccccc1

Procedure:
alkylating α-(2-chlorophenyl)-1-piperidinebutanenitrile with N-(2-chloroethyl)-N-(1-methylethyl)benzenemethanamine, monohydrochloride in the presence of base and dimethyl sulfoxide to give α-(2-chlorophenyl)-α-[2-[(1-methylethyl) (phenylmethyl)amino]ethyl]-1-piperidine butanenitrile;
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[N:15]4[N:16]=[C:17]([CH3:25])[CH:18]=[C:19]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:14]4=[N:13][C:12]=3[CH3:26])[NH:8]2)=[CH:4][CH:3]=1.[CH3:27]N(C=O)C.[H-].[Na+].CI>CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[N:15]4[N:16]=[C:17]([CH3:25])[CH:18]=[C:19]([CH:20]([CH2:21][CH3:22])[CH2:23][CH3:24])[C:14]4=[N:13][C:12]=3[CH3:26])[N:8]2[CH3:27])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1cc(C)nn2c(-c3cc4ccc(Cl)cc4[nH]3)c(C)nc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CCC(CC)c1cc(C)nn2c(-c3cc4ccc(Cl)cc4n3C)c(C)nc12
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 3-(6-chloro-1H-indol-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.050 g, 0.14 mmol) and DMF (2 mL) is added 60% NaH (0.013 g, 0.33 mmol). The solution is stirred for 30 minutes and MeI (0.010 mL, 0.16 mmol) is added. The solution is stirred for 1 hour, diluted with EtOAc (20 mL), washed with water (2×10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated. The residue is purified by silica gel chromatography (30%-50% EtOAc gradient) to furnish the title compound (0.021 g, 0.055 mmol, 40%). 1H NMR (CDCl3), δ 0.90 (t, J=7.4 Hz, 6H), 1.75-1.95 (m, 4H), 2.49 (s, 3H), 2.51 (s, 3H), 3.31-3.40 (m, 1H), 3.57 (s, 3H), 6.65 (d, J=0.9 Hz, 1H), 6.72 (s, 1H), 7.12 (dd, J=8.4, 1.8 Hz, 1H), 7.40-7.42 (m, 1H), 7.58 (8.4 Hz, 1H) ppm. LC/MS (m/z): calcd. for C22H25ClN4 (M+H)+: 380.2. found: 381.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][C:23]=4[O:29][CH3:30])[N:9]=[C:10]([C@H:11]3[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.C(O)C[CH2:33][OH:34].C[OH:37]>>[NH2:21][C:22]([CH2:23][OH:29])([CH2:27][OH:37])[CH2:33][OH:34].[NH2:1][C:2]1[C:7]2=[C:8]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][C:23]=4[O:29][CH3:30])[N:9]=[C:10]([C@H:11]3[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: OCCCO
Reactant: CO
Agent: COc1cccc2cc(-c3nc([C@H]4CC[C@H](C(=O)O)CC4)n4ncnc(N)c34)[nH]c12
Agent: COc1cccc2cc(-c3nc([C@H]4CC[C@H](C(=O)O)CC4)n4ncnc(N)c34)[nH]c12
Product: NC(CO)(CO)CO
Temperature: 25 °C

Procedure:
The compound trans-4-[4-Amino-5-(7-methoxy-1H-indol-2-yl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylic acid can be prepared as known in the art, e.g., according to US 2007/0112005 (Example 258 thereof). This product (5.01 g, 12.3 mmol) was suspended in MeOH (75.0 mL) and heated to reflux. 1,3-Propanediol, 2-amino-2-(hydroxymethyl) (1.79 g, 14.8 mmol) was added and the reaction was heated at reflux for 1 h. The suspension was allowed to cool to RT and then filtered. The solid was washed with MeOH and then dried in vacuo overnight at 50° C. to provide the title compound as a tan solid (4.57 g, 70.2% yield). 1H NMR (400 MHz, CD3OD): δ 1.67 (dddd, J=12.8, 12.8, 12.8, 2.8 Hz, 2H), 1.87 (dddd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 2.14-2.17 (m, 4H), 234 (tt, J=12.4, 2.8 Hz, 1H), 3.40 (tt, J=12.4, 3.2 Hz, 1H), 3.65 (s, 6H), 4.01 (s, 3H), 6.75 (d, J=7.2 Hz, 1H), 6.75 (s, 1H), 7.04 (dd, J=7.6, 7.6 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.88 (s, 1H). 13C NMR (100 MHz, DMSO): δ 29.1, 29.6, 34.3, 43.9, 55.3, 59.0, 61.3, 102.3, 102.5, 110.9, 113.1, 120.1, 126.8, 127.2, 130.0, 132.1, 146.3, 146.7, 178.6. LCMS (ESI+): m/z 407 (MH+). Anal. Calcd. for C25H33N7O6: C, 56.92%; H, 6.30%; N, 18.58%; O, 18.20%. Found: C, 56.23%; H, 6.31%; N, 18.33%; O, 18.63%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:9](=[O:16])[O:8][C:6]=2[CH:7]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:12]2[CH2:13][CH2:14][C:15]3[C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=4[O:8][C:9](=[O:16])[C:10]=3[CH2:11]2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1ccc2c3c(c(=O)oc2c1)CNCC3
Product: Cc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccc(Cl)cc1)CC3
Yield: 65 %

Procedure:
Prepared by the procedure of Example 3 from 8-methyl-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one* and 4-chlorobenzaldehyde. Yield 65%; mp 147°-149° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>>[O:1]([C:8]1[CH:9]=[C:10]([O:14][C:17](=[O:18])[N:16]([CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1cccc(Oc2ccccc2)c1
Product: CN(C(=O)Oc1cccc(Oc2ccccc2)c1)c1ccccc1

Procedure:
The title product was prepared from 3-phenoxyphenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (79%, colourless oil).
Reaction SMILES: [C:1](Br)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:11]=[C:12]([CH2:14][N:15]([C:17](=[NH:19])[NH2:18])[CH3:16])[OH:13].N1C=CC=CC=1.C(=O)=O>ClCCl.CC(C)=O>[CH3:16][N:15]([CH2:14][C:12]([OH:13])=[O:11])[C:17]([NH:19][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[NH:18]
Reactant: CCCCCCCC(=O)Br
Reactant: CN(CC(=O)O)C(=N)N
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCC(=O)NC(=N)N(C)CC(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the octanoyl bromide solution, 7.08 g (54 mmol) of creatine is suspended, with stirring, in 50 ml of dry dichloromethane. To this suspension a catalytic amount (0.1 mmol) of pyridine is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of between to about −10° C. and 0° C. When the target temperature is reached the drop wise addition of octanoyl bromide is commenced. Addition of octanoyl bromide continues, with cooling and stirring, until all of the octanoyl bromide is added, after which the reaction is allowed to warm to room temperature with constant stirring. The solution is then filtered to remove any remaining creatine and the volatile dichloromethane and pyridine are removed under reduced pressure yielding 2-(1-methyl-3-octanoylguanidino)acetic acid.
Reaction SMILES: Cl[C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[NH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:17]([O:26][CH3:27])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:20]>CCOCC>[CH3:27][O:26][C:17]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[NH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:25]
Reactant: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Cl
Reactant: COC(=O)c1ccccc1N
Solvent: CCOCC
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccccc1C(=O)OC
Reaction time: 5 h
Yield: 58 %

Procedure:
trans-1-Chloro-2-ethoxycarbonylaminoindane (20 g, 0.084 moles) was treated with methyl anthranilate (60 ml) and stirred under nitrogen at 60° for 5 hr. The resulting viscous mixture was diluted with ether (500 ml), washed exhaustively with 2.5N HCl (8×250 ml), and then with saturated sodium bicarbonate followed by brine. After drying (Na2SO4) and concentration in vacuo a brown solid (25.7 g) was obtained. Crystallisation from pentane/ether afforded the title compound (14 g; 58%) m.p. 108°-110°. Concentration of mother liquors gave a less pure second crop (2.6 g).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH2:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH:11]([C:13]1[C:21]2[C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=[CH:17][C:16]=2[NH:15][N:14]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCOCC1>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][CH2:11][C:13]3[C:21]4[C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=[CH:17][C:16]=4[NH:15][N:14]=3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: COC(=O)c1cccc2[nH]nc(C=O)c12
Reactant: NCC12CCN(CC1)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1cccc2[nH]nc(CNCC34CCN(CC3)CC4)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 106.6 %

Procedure:
To a stirred solution of quinuclidin-4-ylmethanamine (1.0 g, 7.14 mmol) in 1,4-dioxane (30 mL) was added methyl 3-formyl-1H-indazole-4-carboxylate (1.2 g, 6.0 mmol) in 1,4-dioxane (10 mL). Then glacial acetic acid (1% of total solvent used) was added and the reaction mixture was stirred at 60° C. for 2 h. It was cooled to room temperature and sodium triacetoxyborohydride (3.8 g, 17.9 mmol) was added. The reaction mixture was stirred at room temperature for 4 h). The solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel, 70:27:3 dichloromethane/methanol/concentrated ammonium hydroxide) to give methyl 3-((quinuclidin-4-ylmethylamino)methyl)-1H-indazole-4-carboxylate as a brown oil (2.1 g, quantitative yield): 1H NMR (500 MHz, CD3OD) δ 7.87 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 4.38 (s, 2H), 3.99 (s, 3H), 3.27 (t, J=8.0 Hz, 6H), 2.68 (s, 2H), 1.78 (t, J=8.0 Hz, 6H); MS (ESI+) m/z 329 (M+H).
Reaction SMILES: C(OC([N:8](C)[C@@H:9](CC(C)(C)C)[C:10](O)=[O:11])=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[CH:23][CH:22]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[F:37][C:20]([F:19])([F:36])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH:35][C:10](=[O:11])[CH2:9][NH2:8])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[CH:25][CH:26]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: NCC(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-L-glycine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-[4-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-amine from Example 607 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.27 (d, J=6.9, 1H), 7.58 (d, J=8.7, 2H), 6.61 (d, J=8.7, 2H), 4.39-4.29 (m, 1H), 3.57 (s, 2H), 3.51 (dd, J=10.2, 3.4, 1H), 3.30 (dd, J=10.0, 7.9, 1H), 3.20 (dd, J=9.6, 8.4, 1H), 3.00 (dd, J=9.9, 4.2, 1H), 2.69 (ddd, J=16.0, 8.3, 4.3, 1H), 2.66-2.59 (m, 1H), 2.51-2.17 (bs, 2H), 2.11-2.01 (m, 1H), 1.91 (dtd, J=13.0, 7.9, 5.0, 1H), 1.61 (dq, J=12.6, 8.0, 1H), 1.41-1.29 (m, 1H); MS (ESI+) m/z 328 (M+H)+.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@H:18]2[C:29]([O:31][CH3:32])=[O:30])[C:13]1=[O:33])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@H:18]2[C:29]([O:31][CH3:32])=[O:30])[C:13]1=[O:33]
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Yield: 94.5 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butyl(methyl)amino)cyclohexanecarboxylate (330 mg, 0.65 mmol) in methanol was treated with 100 mg of 10% Pd/C and hydrogenated at 55 psi of H2 in a Parr shaker overnight. The catalyst was filtered and the filtrate concentrated in vacuo to give 200 mg of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butyl(methyl)amino)-cyclohexanecarboxylate as a white solid. This was used without further purification. MS found: (M+H)+=326.50
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=[O:9])[C:7]=1[Cl:8])=O.[F:10][CH:11]([F:20])[O:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>O1CCOCC1>[Cl:8][C:7]1[C:6]([N:15]([C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[O:12][CH:11]([F:10])[F:20])[C:3](=[O:5])[C:2]=1[Cl:1])=[O:9]
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: Nc1ccccc1OC(F)F
Solvent: C1COCCO1
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccccc1OC(F)F
Yield: 89.9 %

Procedure:
16.7 g (0.1 mole) of 2,3-dichloromaleic anhydride is dissolved in 100 ml of dioxane, and a solution of 15.9 g (0.1 mole) of o-difluoromethoxyaniline in 30 ml of dioxane is added dropwise to it at room temperature over 20 minutes with stirring. Thereafter, the resulting solution is stirred at 70°-80° C. for 2 hours and the dioxane is then distilled off under a reduced pressure. Water is added to the residue to precipitate crystals. The precipitated crystals are filtered off and recrystallized from ethanol to give 27.7 g (yield: 90%) of 2,3-dichloro-N-(o-difluoromethoxyphenyl)maleimide melting at 103.5°-104° C. in the form of light yellow crystals.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@:11]([OH:36])([CH3:35])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH:23]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[O:20])[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].C(OCC)(=O)C.O>CN(C=O)C>[CH3:35][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH:23]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[O:20])[CH2:15][CH2:14]2)[O:36][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@]1(CN2CCN(C(=O)OCC=Cc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
3-(4-Trifluoromethylphenyl)-2-propenyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methyl-propyl]piperazine-1-carboxylate prepared in Example 391 (13.2 g, 24.81 mmol) was dissolved in DMF (40 ml). To the solution, sodium hydride (1.19 g, 29.78 mmol) was added followed by stirring for 1.5 hours with cooling on ice-bath. To the reaction mixture, ethyl acetate (13 ml) and water (92 ml) were added in this order followed by stirring for 30 minutes. The precipitates were filtered off, washed with water and purified by silica gel column chromatography (ethyl acetate) to afford 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (10.17 g, yield 83%) as a light yellow powder.
Reaction SMILES: Cl[C:2]1C=C(C)C2C(=CC=C(C#CC3C=CC(C4C=CC(Cl)=CC=4)=CN=3)C=2)[N:3]=1.Br[C:29]1[CH:38]=[C:37]([CH3:39])[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:40]#[C:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]4[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=4)=[CH:44][N:43]=3)[CH:35]=2)[N:30]=1>CN1C(=O)CCC1.CN(C=O)C>[Cl:54][C:51]1[CH:52]=[CH:53][C:48]([C:45]2[CH:46]=[CH:47][C:42]([C:41]#[C:40][C:34]3[CH:35]=[C:36]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([CH2:2][NH2:3])[CH:38]=[C:37]4[CH3:39])=[N:43][CH:44]=2)=[CH:49][CH:50]=1
Reactant: Cc1cc(Br)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Reactant: Cc1cc(Cl)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: Cc1cc(CN)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12

Procedure:
Analogously to Example 1k, the following Examples may be prepared starting from 2-chloro-6-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-4-methylquinoline (Example 1h) or 2-bromo-6-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-4-methylquinoline (Example 1i) and the corresponding amines: Examples 1.8-1.9, 1.11, 1.15-1.21, 1.23 and 1.28 were prepared by heating in NMP in the microwave (300 W, 190° C.; 30-60 min); Example 1.13 was prepared by heating in DMF in the microwave (150 W, 170° C.; 10 min); and Example 1.51 was obtained as a by-product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]3[O:11]C(=O)[C:13]([CH3:19])([C:15]([O:17]C)=O)[N:14]=3)[CH:8]=[CH:9][C:2]1=2.[CH:21]1[S:25][CH:24]=[CH:23][C:22]=1C(Cl)=O.C(N(CC)CC)C.[C:36]([O:39][CH2:40]C)(=[O:38])C>>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]([NH:14][CH:13]([C:15]([C:23]3[CH:22]=[CH:21][S:25][CH:24]=3)=[O:17])[CH2:19][C:36]([O:39][CH3:40])=[O:38])=[O:11])[CH:8]=[CH:9][C:2]1=2
Reactant: COC(=O)C1(C)N=C(c2ccc3occc3c2)OC1=O
Reactant: CCOC(C)=O
Reactant: O=C(Cl)c1ccsc1
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)c1ccc2occc2c1)C(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(5-benzo[b]furyl)-4-methoxycarbonyl-methyl-5-oxo-2-oxazoline (410 mg) and 3-thenoyl chloride (242 mg) in ethyl acetate (8 ml) was added triethyl amine (0.23 ml) under ice-cooling, and the mixture was stirred at room temperature for 0.5 hour. Ethyl acetate was added to the mixture, the mixture was filtered and the resulting filtrate was concentrated under reduced pressure. A mixture of the resulting residue and pyridine (3.6 ml) was stirred at room temperature for 10 minutes followed by stirring at 60° C. for 2 hours. Then, acetic acid (1.35 ml) was added to the mixture and the resulting mixture was stirred at 80° C. for 1.5 hours. After cooling, to the reaction mixture were added water and ethyl acetate, the organic layer was collected, washed successively with a 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane:ethyl acetate=5:1) to obtain methyl 3-(5-benzo[b]furoylamino)-4-(3-thienyl)-4-oxobutyrate (253 mg) as colorless powder.
Reaction SMILES: CN(C[N:5]1[C:9]2=[N:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]3)=[CH:12][CH:13]=[C:8]2[N:7]=[CH:6]1)C.C(NC(C)C)(C)C.[Li].C[O:32][C:33](=O)[C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[C:36]([C:42]2[C:46]([CH3:47])=[N:45][N:44]3[CH2:48][CH2:49][CH2:50][C:43]=23)[CH:35]=1.CCOC(C)=O>C1COCC1>[CH3:22][N:20]([CH3:21])[CH:17]1[CH2:16][CH2:15][N:14]([C:11]2[N:10]=[C:9]3[NH:5][C:6]([C:33]([C:34]4[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[C:36]([C:42]5[C:46]([CH3:47])=[N:45][N:44]6[CH2:48][CH2:49][CH2:50][C:43]=56)[CH:35]=4)=[O:32])=[N:7][C:8]3=[CH:13][CH:12]=2)[CH2:19][CH2:18]1
Reactant: CN(C)Cn1cnc2ccc(N3CCC(N(C)C)CC3)nc21
Reactant: COC(=O)c1ccc(C#N)c(-c2c(C)nn3c2CCC3)c1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: Cc1nn2c(c1-c1cc(C(=O)c3nc4ccc(N5CCC(N(C)C)CC5)nc4[nH]3)ccc1C#N)CCC2
Temperature: -78 °C
Yield: 10 %

Procedure:
To a solution of [1-(3-dimethylaminomethyl-3H-imidazo[4,5-b]pyridin-5-yl)-piperidin-4-yl]-dimethyl-amine (0.36 g, 1.2 mmol) in THF (5 mL) at −78° C. under N2 was added dropwise a freshly prepared solution of lithium diisopropylamine (1M, 1.5 mL, 1.5 mmol) in THF. After 10 m at −78° C. a solution of 4-cyano-3-(2-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-benzoic acid methyl ester (0.28 g, 1.0 mmol) in THF (5 mL) was added. The reaction mixture was stirred at −78° C. under N2 for 15 m before quenching with a 1:1 solution of acetic acid and water (2 mL). After warming to room temperature the quenched reaction was diluted several fold EtOAc and washed with dilute NH4OH followed by brine. The organic layer was dried over Na2SO4, filtered and concentrated. After purifying the crude product by reverse phase HPLC, the product was neutralized with aqueous Na2CO3 yielding the desired product as a orange-colored solid (50 mg, 0.10 mmol). 1H NMR (400 MHz, DMSO-d6) □ ppm 1.32-1.44 (m, J=12.00, 11.81, 11.81, 3.79 Hz, 2H) 1.85 (d, J=10.61 Hz, 2H) 2.20 (s, 6H) 2.25 (s, 3H) 2.33-2.46 (m, 1H) 2.53-2.63 (m, 2H) 2.89-3.02 (m, 4H) 4.43 (d, J=13.14 Hz, 2H) 7.04 (d, J=9.09 Hz, 1H) 7.95 (d, J=9.09 Hz, 1H) 8.10 (d, J=8.08 Hz, 1H) 8.36 (d, J=7.58 Hz, 1H) 8.52 (s, 1H); MS m/z 495.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Li])=[CH:19][CH:18]=1.IC1C=CC(OC)=CC=1>>[NH2:1][C:2]1[C:3]([C:4]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: [Li]c1ccc(OC)cc1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Agent: COc1ccc(I)cc1
Product: COc1ccc(C(=O)c2ccc(Cl)nc2N)cc1

Procedure:
The title compound was prepared from 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (Example 3) and 4-methoxyphenyllithium freshly prepared from 4-iodoanisole (Aldrich) using the procedure described in Example 7. HRMS, observed: 262.0512, Calcd for M+: 262.0509.