Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][N:6]1[C@@H:10](/[CH:11]=[C:12](/[Sn](CCCC)(CCCC)CCCC)\[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:36].[CH:43]1([O:48][C:49]2[C:50]([O:56][CH3:57])=[N:51][C:52](I)=[CH:53][CH:54]=2)[CH2:47][CH2:46][CH2:45][CH2:44]1.[F-].[Cs+].O>CN(C)C=O.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.[Cu](I)I.C(OCC)(=O)C>[CH:43]1([O:48][C:49]2[CH:54]=[CH:53][C:52](/[C:12](/[C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:18]=3)=[CH:11]/[C@@H:10]3[N:6]([CH2:5][C:4]4[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:3]=4[O:2][CH3:1])[C:7](=[O:36])[CH2:8][CH2:9]3)=[N:51][C:50]=2[O:56][CH3:57])[CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: COc1nc(I)ccc1OC1CCCC1
Reactant: CCCC[Sn](CCCC)(CCCC)/C(=C/[C@H]1CCC(=O)N1Cc1ccc(OC)cc1OC)c1ccc(C(F)(F)F)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(F)(F)F)cc2)c2ccc(OC3CCCC3)c(OC)n2)c(OC)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (30 mg) was added to a solution of (5R)-1-(2,4-dimethoxybenzyl)-5-{(E)-2-(tributylstannyl)-2-[4-(trifluoromethyl)phenyl]ethenyl}pyrrolidin-2-one obtained in Reference Example 4-29 (184 mg), 3-(cyclopentyloxy)-6-iodo-2-methoxypyridine obtained in Reference Example 4-37 (169 mg), cesium fluoride (80 mg) and copper iodide (60 mg) in N,N-dimethylformamide (2 mL) in a nitrogen atmosphere, and the mixture was stirred at 65° C. for three hours. The reaction solution was left to cool, and then water and ethyl acetate were added, followed by filtration through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→1:1) to give (5R)-5-{(E)-2-[5-(cyclopentyloxy)-6-methoxypyridin-2-yl]-2-[4-(trifluoromethyl)phenyl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a light yellow oil (184 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.I[C:32]1[CH:36]=[CH:35][N:34]([CH3:37])[N:33]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>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.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[CH:36]=[CH:35][N:34]([CH3:37])[N:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cn1ccc(I)n1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-c2ccn(C)n2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Yield: 38 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (120 mg, 0.292 mmol), 3-iodo-1-methyl-1H-pyrazole (121.4 mg, 0.584 mmol), 1,2-dimethoxyethane (3 mL), 1 N Na2CO3 aqueous solution (0.96 mL, 0.96 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (33.7 mg, 0.029 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give white solids, 40.5 mg (yield 38.0%). 1H NMR (300 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.59 (broad s, 1H), 7.56 (d, J=1.1 Hz, 1H), 7.28 (broad s, 1H), 6.72 (d, J=2.2 Hz, 1H), 4.77 (m, 1H), 3.88 (s, 3H), 3.74-3.62 (m, 1H), 3.45-3.35 (m, 1H), 3.24-3.14 (m, 1H), 2.88-2.75 (m, 1H), 2.42-2.21 (m, 2H), 1.32 (d, J=6.0 Hz, 3H), 1.12-1.06 (m, 2H), 1.02 (m, 2H) ppm; MS (ESI+) m/z 366.34 (M+H).
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][C@@H:12]2[O:16][C:15](=[O:17])[CH2:14][CH2:13]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([C:27]([C:46]1[CH:51]=[CH:50][C:49](O)=[C:48]([CH3:53])[CH:47]=1)([C:30]1[CH:35]=[CH:34][C:33]([B:36]2[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]2)=[C:32]([CH3:45])[CH:31]=1)[CH2:28][CH3:29])[CH3:26].C(OCC)(=O)C>CN(C)C=O>[CH2:25]([C:27]([C:46]1[CH:51]=[CH:50][C:49]([O:10][CH2:11][C@@H:12]2[O:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[C:48]([CH3:53])[CH:47]=1)([C:30]1[CH:35]=[CH:34][C:33]([B:36]2[O:40][C:39]([CH3:41])([CH3:42])[C:38]([CH3:43])([CH3:44])[O:37]2)=[C:32]([CH3:45])[CH:31]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC(=O)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
(R)-(−)-Dihydro-5-(p-tolyl-sulfonyloxymethyl)-2(3H)-furanone (293 mg, 1.084 mmol) and potassium carbonate (180 mg, 1.301 mmol) were added to a solution of 4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenol (Example 15-(2); 171 mg, 0.434 mmol) in N,N-dimethylformamide (1.5 mL) at room temperature, and the mixture was stirred at 110° C. for one hour. Ethyl acetate was added to the reaction solution. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=80/20 to ethyl acetate only) to give the title compound (164 mg, 76.8%).
Reaction SMILES: ClC1C=C(CCNCC2C=CC(C(O)(C(F)(F)F)C(F)(F)F)=CC=2)C=CC=1Cl.[Cl:29][C:30]1[CH:31]=[C:32]([CH:48]=[CH:49][C:50]=1[C:51]([F:54])([F:53])[F:52])[C:33]([NH:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=1)=O>C1COCC1>[Cl:29][C:30]1[CH:31]=[C:32]([CH:48]=[CH:49][C:50]=1[C:51]([F:52])([F:53])[F:54])[CH2:33][NH:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:47])[F:46])[CH:39]=1
Reactant: O=C(NCCc1cccc(C(F)(F)F)c1)c1ccc(C(F)(F)F)c(Cl)c1
Agent: OC(c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc(CCNCc2ccc(C(F)(F)F)c(Cl)c2)c1
Yield: 92.5 %

Procedure:
The title compound was synthesized in analogy to [2-(3,4-dichloro-phenyl)-ethyl]-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-benzyl]-amine (described in example S98) using 200 mg of 3-chloro-4-trifluoromethyl-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (0.51 mmol) and 2.02 ml of a 1 molar solution of BH3-THF complex in THF. The isolated residue was purified by flash column chromatography to give 180 mg of (3-chloro-4-trifluoromethyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine (93%) as a colorless oil. MS (ISP) 382.1 (M+H)+.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[S:16])=[CH:10][C:9]=2[O:17][CH3:18])[CH:7]=1>>[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:1])=[S:16])=[CH:10][C:9]=2[O:17][CH3:18])[CH:7]=1
Reactant: N
Reactant: COc1cc(N=C=S)ccc1-n1cnc(Cl)c1
Product: COc1cc(NC(N)=S)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
Step A (4): Methanolic ammonia (1.0 M, 100 mL, 100 mmol) was added to a flask charged with 4-chloro-1-(4-isothiocyanato-2-methoxy-phenyl)-1H-imidazole (4.27 g, 16.1 mmol) in a ice-water bath. After the addition was complete, the resulting slurry was stirred for 10 min and then allowed to warm to rt. After 24 h, the reaction mixture was concentrated to dryness in vacuo. The solid was suspended in ethanol (200 mL) and stirred for 2 hours. The solid was collected by vacuum filtration and dried under high vacuum for 24 h to afford 1-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)thiourea (3.85 g, 83% yield) as a white solid. LC-MS (M+H)+ 283.0.
Reaction SMILES: [N+:1]([C:4]1[N:5]([C:9]([CH2:11][CH2:12][OH:13])=[O:10])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[P:14](Cl)([Cl:17])([Cl:16])=[O:15]>C1COCC1>[P:14]([Cl:17])([Cl:16])(=[O:15])[O:13][CH2:12][CH2:11][C:9]([N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2])=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(CCO)n1ccnc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: O=C(CCOP(=O)(Cl)Cl)n1ccnc1[N+](=O)[O-]

Procedure:
A solution of 3.0 mmol of 2-(2-nitro-1-imidazoyl)ethanol in 17 ml dry THF is added dropwise over 1 hr to 7.0 mmol phosphorus oxychloride in 5 ml THF at -7° to -2° C. with stirring. The suspension is stirred for another 75 min at 0° C., then allowed to reach room temperature and filtered. The residual powder is washed under a nitrogen flow with THF and the solvent and excess POCl3 removed from the filtrate in vacuo over 1 hr to yield 2-(2-nitro-1-imidazoyl)ethyl phosphorodichloridate as an oil.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14][NH:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>C(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14][N:13]2[C:31]([O:32][CH3:33])=[O:34])=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(S(C)(=O)=O)cc2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(S(C)(=O)=O)cc2)C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 107.5 %

Procedure:
Methyl 2-(4-(methylsulfonyl)phenyl)piperidine-4-carboxylate hydrochloride (5.2 g, 15.58 mmol) and DIPEA (6.78 mL, 38.94 mmol) were dissolved in DCM (40 mL) and methyl carbonochloridate (1.472 mL, 18.69 mmol) added. The reaction was stirred at room temperature for 50 min. DCM (160 mL) was added. The organic phase was washed with 0.1 M HCl (2×200 mL), satd NaHCO3 (200 mL), dried with a phase separator and evaporated in vacuo yielding crude dimethyl 2-(4-(methylsulfonyl)phenyl)piperidine-1,4-dicarboxylate (5.95 g, 108%). MS m/z 356 (M+H)+
Reaction SMILES: C[O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1([C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[CH:15]=1)O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>>[Br:16][C:14]1[CH:15]=[C:10]([CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:3]2=[O:2])[CH:11]=[N:12][CH:13]=1
Reactant: COC1CCCCC1(O)c1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1CCCCC1c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3,5-dibromopyridine (30.45 g, 0.13 mol) in anhydrous ether (400 ml) was added dropwise to a stirred solution of n-butyllithium (1.6M in hexane, 88.3 ml) and anhydrous ether (40 ml) over 0.5 hours at -70° C. The pale yellow suspension was stirred at -70° C. for 1 hour, and a solution of 2-methoxycyclohexanone (16.5 g, 0.13 mol) in anhydrous ether (60 ml) was added dropwise. The reaction mixture was stirred at -70° C. for 2 hours and allowed to warm to room temperature. The reaction mixture was poured onto ice/water (11); sodium chloride (50 g) was added and the ether layer separated. The aqueous layer was extracted with ether (2×200ml). The combined ether layers were extracted with 2N hydrochloric acid (2×250 ml). The acid extract was washed with ether (200 ml), basified with 4N aqueous sodium hydroxide solution at room temperature (pH11), sodium chloride (50 g) was added and the precipitated oil was extracted with ether (2×400 ml). The combined extracts were dried over magnesium sulphate and concentrated in vacuo to give 2-methoxy-1-(5-bromopyrid-3-yl)cyclohexanol (30.6 g). The cyclohexanol was added in small portions to stirred sulphuric acid (114 ml). The reaction exothermed to 50° C., but no external cooling was applied. When the addition was completed after 20 minutes the red/brown solution was stirred at room temperature for 4 hours. The reaction mixture was poured onto ice/water (11) and basified to pH8 with sodium carbonate. The product was extracted with ether (2×300 ml). The ether extracts were combined, dried with magnesium sulphate and evaporated to give a pale orange oil. The oil was purified by flash chromatography over silica gel eluting with hexane/ethyl acetate 6.4 to give 2-(5-bromopyrid-3-yl)cyclohexanone (15.1 g) m.p. 67°-9° C. NMR(CDCl3). 1.6-2.1(m,4H); 2.1-2.4(m,2H); 2.4-2.6 (m,2H); 3.6-3.66(dd,1H); 7.6(s,1H); 8.18(s,1H); 8.38(s,1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:15][N:14]([C:16]2[CH:27]=[CH:26][C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=2)[CH2:13]1.C(N(CC)CC)C>>[CH:23]([NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([N:14]2[CH2:13][C:12](=[O:11])[CH2:15]2)=[CH:27][CH:26]=1)([CH3:25])[CH3:24]
Reactant: CC(C)NC(=O)c1ccc(N2CC(O)C2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1ccc(N2CC(=O)C2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride (1.05 mL, 12.4 mmol) in dichloromethylene (20 mL) was added dropwise dimethyl sulfoxide (1.71 mL, 24.1 mmol). The mixture was stirred at −78° C. for 10 min. Then a suspension of 4-(3-hydroxyazetidin-1-yl)-N-isopropylbenzamide (1.72 g, 7.34 mmol) in dichloromethylene (20 mL) was added. The mixture was stirred at −78° C. for 1 h, and then triethylamine (7.04 mL, 50.5 mmol) was added. The mixture was stirred at −78° C. for an additional 1.5 h. The mixture was washed with aq. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The precipitates were washed with ether and collected by filtration to afford the desired product (1.32 g, 77%) which was directly used in the next step without further purification. LCMS cacld. for C13H17N2O2 (M+1)+: m/z=233.1. Found: 233.1.
Reaction SMILES: C(N[C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=O)CC.[C:13](NC1C=C(C=CC=1)N)(=[O:17])CCC>>[NH2:9][C:8]1[CH:7]=[C:6]([O:17][CH3:13])[CH:12]=[CH:11][CH:10]=1
Reactant: CCC(=O)Nc1cccc(N)c1
Reactant: CCCC(=O)Nc1cccc(N)c1
Product: COc1cccc(N)c1

Procedure:
m-propionylaminoaniline, m-butyrylaminoaniline or
Reaction SMILES: C([S:4][CH:5]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:6]([NH:8][CH:9]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20]CC)=[O:19])[C:13]([CH3:24])([CH3:23])[CH2:12][CH2:11][CH2:10]1)=[O:7])(=O)C.[OH-].[Na+].Cl>CO.SCC(C(CS)O)O>[SH:4][CH:5]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:6]([NH:8][CH:9]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([OH:20])=[O:19])[C:13]([CH3:23])([CH3:24])[CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: CCOC(=O)CN1C(=O)C(NC(=O)C(Cc2ccccc2)SC(C)=O)CCCC1(C)C
Agent: Cl
Agent: OC(CS)C(O)CS
Agent: [Na+]
Solvent: CO
Product: CC1(C)CCCC(NC(=O)C(S)Cc2ccccc2)C(=O)N1CC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
[S-(R*,R*)]-Hexahydro-6-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-2,2-dimethyl-7-oxo-1H-azepine-1-acetic acid, ethyl ester (2.0 g, 4.46 mmole) [prepared as described in Example 66 (g) of U.S. Pat. No. 5,552,397] was dissolved in methanol (9 ml) in a 100-ml flask equipped with an addition funnel, internal temperature probe and argon inlet. To the solution was added DL-dithiothreitol (34 mg, 0.22 mmole). The solution was sparged with argon for 15 minutes and then kept under argon. The resulting solution was cooled to 0° C. in an ice-bath. In the addition funnel, 1N sodium hydroxide (26.8 ml, 26.8 mmole) was sparged with argon for 30 minutes. The sparged sodium hydroxide solution was added to the reaction flask over 30 minutes so that the internal temperature did not exceed 5° C. The reaction was allowed to stir at 0° C. for 30 minutes and then the ice-bath was removed to allow the reaction to warm to room temperature over one hour. The reaction was stirred at room temperature for an additional 1.5 hours at which time TLC showed that the reaction was complete. A pH probe was attached to the reaction flask. The reaction was acidified with previously sparged 3N HCl to a pH of 6. A few seed crytals were added and the mixture was stirred for 5 minutes. The mixture was then further acidified to pH 2. The resulting slurry was stirred at room temperature for one hour. The product was collected by filtration and washed with distilled water until the wash-water tested negative for chloride with silver nitrate solution. The product was air-dried for 30 minutes, washed with t-butyl methyl ether (2×4 ml) and hexane (2×4 ml), air-dried, and dried under a high vacuum to give 1.5 g of title product as a white crystalline solid (890% yield),
Reaction SMILES: C(OC([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:36]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:35][N:22]4[N:23]=[C:24]5[C:29]([CH:28]=[CH:27][CH:26]=[C:25]5/[CH:30]=[CH:31]/[C:32]([NH2:34])=[O:33])=[C:21]4[N:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:36]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:35][N:22]4[N:23]=[C:24]5[C:29]([CH:28]=[CH:27][CH:26]=[C:25]5/[CH:30]=[CH:31]/[C:32]([NH2:34])=[O:33])=[C:21]4[N:20]=3)=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cccc(/C=C/C(N)=O)c5nn4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)/C=C/c1cccc2c1nn1cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc21

Procedure:
281 mg of the crude (E)-3-[2-(4-{1-[(tert-Butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenyl-pyrimido[1,2-b]indazol-7-yl]acrylamide were stirred in 15.9 mL 4M hydrogen chloride in dioxane for 18 hours at room temperature as described in example 13 (step 2). After the usual work-up and purification by HPLC 28.5 mg (12.4%) of the title compound were obtained.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][NH:5][CH3:6].CC1(C)CCCC(C)(C)N1.[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Cl>C(#N)C>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:5]([CH2:4][CH2:3][CH:2]([OH:1])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:6]
Reactant: CNCCC(O)c1ccccc1
Reactant: Fc1ccccc1CCl
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CC#N
Product: CN(CCC(O)c1ccccc1)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
A mixture of 3-hydroxy-N-methyl-3-phenylpropylamine (8.3 g, 50 mM), 2,2,6,6-tetramethylpiperidine (8.4 ml, 50 mM), o-fluorobenzyl chloride (7.25 g, 50 mM) and acetonitrile (100 ml) was stirred for 24 hours at ambient temperature. The resulting precipitate was removed by filtration, the precipitate washed with acetonitrile and the combined filtrate and washings evaporated under reduced pressure. The residue was partitioned between 2 N hydrochloric acid (100 ml) and ether (100 ml), the aqueous layer basified and extracted with ether (2×100 ml). The ether extract was dried and the solvent removed under reduced pressure to yield an oil (10.3 g). Distillation gave the title compound b.p. 160°-2° C./0.6 mbar. Found: C, 74.4; H, 7.3; N, 5.4%; C17H20FNO requires: C, 74.7; H, 7.4; N, 5.1%.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Cl[CH2:33][CH2:34][CH2:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH3:46])([CH3:45])[C:37]1=[O:47].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:46][C:38]1([CH3:45])[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:36]([CH2:35][CH2:34][CH2:33][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=4)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)[C:37]1=[O:47]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: CC1(C)C(=O)N(CCCCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)C(C)(C)c5ccccc54)CC3)C2=O)c1
Temperature: 81 °C
Reaction time: 16 h
Yield: 47.5 %

Procedure:
A mixture of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (300 mg, 0.71 mmol, 1 equiv), 1-(3-chloropropyl)-3,3-dimethylindolin-2-one (200.8 mg, 0.71 mmol, 1 equiv), sodium iodide (42.7 mg, 0.285 mmol, 0.4 equiv), and potassium carbonate (295.2 mg, 2.136 mmol, 3 equiv) in 2-butanone was stirred at 81° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using preparatory thin layer chromatography in 5% methanol in dichloromethane to afford the title compound as cream crystals (210 mg, 47.4%); 1H NMR (400 MHz, DMSO-d6): δ 1.27 (s, 6H); 1.52 (s, 9H); 1.63 (d, 2H, J=12.4 Hz); 1.79 (bs, 2H); 2.36 (bs, 2H); 2.52-2.59 (m, 2H); 2.66-2.73 (m, 4H); 3.75 (t, 2H, J=6.8 Hz); 4.59 (s, 2H); 4.61 (s, 2H); 6.77 (t, 1H, J=6.8 and 7.2 Hz); 6.85 (d, 2H, J=8.4 Hz); 7.03 (t, 1H, J=7.6 and 6.8 Hz); 7.13 (d, 1H, J=7.6 Hz); 7.23 (t, 3H, J=8 and 7.6 Hz); 7.35 (d, 1H, J=7.2 Hz); 7.48-7.55 (m, 2H); 7.79 (s, 1H); 7.82-7.84 (m, 1H); MS for C38H46N4O4 m/z 623.18 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([C:17]#[N:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2].Cl.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:24][NH2:25].C(N(C(C)C)CC)(C)C.O>C(O)CC>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:24][C:23]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:21]([Cl:20])[CH:22]=1)=[CH:13][C:12]([C:17]#[N:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: COc1ccc(CN)cc1Cl
Reactant: CCOC(=O)c1cnc2ccc(C#N)cc2c1Cl
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: CCOC(=O)c1cnc2ccc(C#N)cc2c1NCc1ccc(OC)c(Cl)c1
Yield: 97.9 %

Procedure:
To 10.0 g (38.4 mmol) 4-chloro-6-cyanoquinoline-3-carboxylic acid ethyl ester was added 10.4 g (50 mmol, 1.5 eq) 3-chloro-4-methoxybenzyl amine hydrochloride and 35 mL (228 mmol, 6 eq) diisopropylethylamine (Aldrich, 99.5+%). The mixture was dispersed in 200 mL n-propanol and brought to reflux for two hours. The solution was then poured into 500 mL water. The resulting precipitate was filtered, then washed with 500 mL water, then twice washed with 50 mL absolute ethanol to yield 14.87 g (37.6 mmol, 97% yield) of the title compound as a white fiberous solid after codistilling with absolute ethanol: mp: 161-162° C.; LC/MS (M/Z) 396 [M+H] observed, 97% purity.