Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[N:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:3]=1.[BH4-].[Na+].CCOC(C)=O.O>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[N:26]=[CH:25][C:24]([CH:27]([OH:29])[CH3:28])=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:3]=1
Reactant: CC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.7 %

Procedure:
1-[6-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridin-3-yl]ethan-1-one (Intermediate 141, 0.934 g, 2.40 mmol) was suspended in THF (60 mL), sodium borohydride (0.227 g, 6.01 mmol) was added and the mixture stirred at room temperature for 2 h. EtOAc (50 mL) and water (100 mL) were added and the organic layer separated. The aqueous layer was neutralised using 1M aq. hydrochloric acid and extracted with EtOAc (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford the title compound as a pale yellow solid (1.0 g), which was used in the next step without further purification. Method C HPLC-MS: MH+ requires m/z=391 Found: m/z=391, Rt=1.18 min (84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH2:32][C@H:33]1[CH2:37][CH2:36][C@@H:35]([C:38]([OH:40])=[O:39])[CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][NH:32][C@@H:33]4[CH2:37][CH2:36][C@H:35]([C:38]([OH:40])=[O:39])[CH2:34]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: N[C@H]1CC[C@@H](C(=O)O)C1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: O=C(O)[C@H]1CC[C@@H](NCc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)C1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and (1R,3S)-3-aminocyclopentanecarboxylic acid (125 mg; 0.97 mmol), to give Example 169 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.71 (2H, m), 7.98 (2H, d, J=8.0 Hz), 7.93-7.85 (1H, m), 7.76-7.68 (1H, m), 7.64-7.58 (4H, m), 7.53-7.46 (2H, m), 3.97 (1H, d, J=13.8 Hz), 3.89 (1H, d, J=13.8 Hz), 3.27 (1H, t, J=4.8 Hz), 2.76-2.67 (1H, m), 1.94-1.73 (6H, m). LC/MS (Method C): 524 (M+H)+. HPLC (Method F) Rt 2.86 min (Purity: 96.2%).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11]>CC(O)=O.O=[Pt]=O>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[CH:23]1[CH:14]([CH2:15][C:16]2[C:21]([NH:22]1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CC2Cc3ccccc3NC12
Reaction time: 8.5 h

Procedure:
Camptothecin (32.0 g, 0.092 mol.) obtained from Tainjain-SK&F Ltd., Tainjain, China, was combined with Pt0 [prepared by pre reduction of 8.0 g. amorphous PtO2 in 800 mL HOAc for 1.5 hour (h) under 1 atmosphere (atm.) H2 ] and HOAc (1.6 L). Reduction was carried out at 1 atm. H2 for 8.5 h. while vigorously stirring the mixture. At the end of this time, the theoretical amount of H2 had been absorbed (slightly more than 4.1 L) and the uptake of H2 had slowed considerably. The reaction was degassed with a stream of Ar for approximately 10 minutes (min.), and then filtered through a celite pad which was washed with HOAc (200 mL).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6](Br)[CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:45][N:46]([CH3:78])[C:47]1[CH:48]=[C:49]2[C:54](=[CH:55][CH:56]=1)[C:53](=[O:57])[N:52]([C:58]1[CH:68]=[CH:67][CH:66]=[C:65](B3OC(C)(C)C(C)(C)O3)[C:59]=1[CH2:60][O:61][C:62](=[O:64])[CH3:63])[CH2:51][CH2:50]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OC(=O)C)C.O.C(O)CCC>[NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([C:65]2[CH:66]=[CH:67][CH:68]=[C:58]([N:52]3[CH2:51][CH2:50][C:49]4[C:54](=[CH:55][CH:56]=[C:47]([N:46]([CH3:78])[CH3:45])[CH:48]=4)[C:53]3=[O:57])[C:59]=2[CH2:60][O:61][C:62](=[O:64])[CH3:63])[CH:7]=1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Reactant: Cn1cc(Br)cc(N)c1=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: O
Product: CC(=O)OCc1c(-c2cc(N)c(=O)n(C)c2)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Temperature: 105 °C
Yield: 50.6 %

Procedure:
3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (392 mg, 1.93 mmol) was placed into 13 ml n-butanol. To this mixture under argon was added: Pddba2 (55.2 mg, 0.096 mmol), XPhos (91.2 mg, 0.191 mmol), acetic acid 2-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (900 mg, 1.93 mmol), potassium phosphate (814 mg, 3.84 mmol) and 4 ml water. The mixture was heated under argon in a sealed flask for 45 minutes at 100-110° C. After cooling, the mixture was diluted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromathography using 5% methanol in dichloromethylene to afford 450 mg of Acetic acid 2-(5-amino-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl ester (49% yield).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][C:13]=2[C:21](=[O:23])[CH3:22])=O)[S:7][CH:8]=1)([CH3:3])[CH3:2].OC1C2C(=C(C)C(OC)=CC=2)N=C(C2SC=C(C(C)C)N=2)C=1>>[Cl:18][C:17]1[C:16]([O:19][CH3:20])=[CH:15][CH:14]=[C:13]2[C:12]=1[N:11]=[C:9]([C:6]1[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1)[CH:22]=[C:21]2[OH:23]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1Cl
Agent: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C
Product: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1Cl

Procedure:
The title product 52 was prepared (58%) from 2′-[[(4-isopropylthiazole-2-yl)(oxo)-methyl]amino]-3′-chloro-4′-methoxyacetophenone (51) following the procedure reported for 4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinoline (36): m/z=335 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([OH:22])[CH2:18][CH2:19][C:20]#[CH:21]>N1CCCCC1.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:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:21]#[C:20][CH2:19][CH2:18][CH2:17][OH:22])=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCCO
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(C#CCCCO)cc1
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 115.8 %

Procedure:
The synthesis was performed following a procedure of Stara, Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman, David; Fiedler, Pavel. Coupling reactions of halobenzenes with alkynes. The synthesis of phenylacetylenes and symmetrical or unsymmetrical 1,2-diphenylacetylenes. Collect. Czech. Chem. Commun. (1999), 64(4), 649-672. A solution of 4.45 g (12.5 mmol) of (4-Iodo-phenyl)-methyl-carbamic acid tert-butyl ester in 25 ml piperidine was degassed (argon) and treated with 722 mg (0.625 mmol) Pd(PPh3)4 and 119 mg (0.625 mmol) Cul. The reaction mixture was stirred at 45° C. for 10 min and then slowly (45 min) heated to 80° C. while adding 0.9 ml (9.4 mmol) of 4-pentin-1-ol. At 80° C. a second portion of 0.9 ml (9.4 mmol) 4-pentin-1-ol was added during 45 min. The reaction mixture was stirred at this temperature for 2 h and then extracted with chilled water acidified with KHSO4/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash-chromatography on silica gel (CH2Cl2/EtOAc 95:5) yielded 3.15 g (87%) of [4-(5-Hydroxy-pent-1-ynyl)-phenyl]-methyl-carbamic acid tert-butyl ester, mp: 103-105° C.; MS: 289 (M).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1>>[Cl:20][C:18]1[CH:17]=[C:16]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:23])[CH:15]=[C:14]([Cl:13])[CH:19]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(Cl)cc(Cl)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3,5-dichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (42.2 mg) with purity >90%. LCMS (pos) m/z 395.0, 397.0.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].S(=O)(=O)(O)O.[F:14][C:15](I)([F:17])[F:16].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:14][C:15]([F:17])([F:16])[C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
1.1 g (10 mmol) of uracil was weighed and placed in a 100 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 0.055 ml of concentrated sulfuric acid, 9 ml of dimethyl sulfoxide, 24.5 mmol of trifluoromethyl iodide, 2.0 ml of a 30% hydrogen peroxide aqueous solution and 1.5 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate. The mixture was stirred at 60 to 70° C. for 10 minutes and then the resulting solution was cooled to room temperature. Formation of 5-trifluoromethyluracil (19F-NMR yield: 97%) was confirmed in the same manner as in Example 1.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[C:13]1(=[O:19])[O:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CCCCCC.CCOCC>[OH:19][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:18]
Reactant: O=C1CCCCO1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(CCCCO)c1cccnc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution prepared by adding 497 ml (1 mole) of 2.01 molar solution of n-butyllithium in hexane into 2 l of ether at -60° C., is added dropwise with stirring under argon at -78° C. a solution of 172 g (1.09 mole) of 3-bromopyridine in 50 ml of ether over a period of 15 min. The mixture is stirred at -78° C. for an additional 30 min and a solution of 100 g(1 mole) of δ-valerolactone in 100 ml of ether is added dropwise over a period of 15 min. The mixture is stirred at -78° C. for 3 h, quenched with 500 ml of concentrated aqueous ammonium chloride, washed with water, dried (MgSO4) and evaporated to give 5-hydroxy-1-(3-pyridyl)pentan-1-one as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[C:29]([F:53])=[CH:30][C:31]([Cl:52])=[C:32]([CH:51]=1)[O:33][C:34]1[CH:48]=[CH:47][C:37]2[N:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[S:40][C:36]=2[C:35]=1[C:49]#[N:50]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:28]1[CH:51]=[C:32]([O:33][C:34]2[CH:48]=[CH:47][C:37]3[N:38]=[C:39]([NH:41][C:42]([CH:44]4[CH2:46][CH2:45]4)=[O:43])[S:40][C:36]=3[C:35]=2[C:49]#[N:50])[C:31]([Cl:52])=[CH:30][C:29]=1[F:53])=[O:6]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Reactant: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c(Cl)cc2F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (74 mg, 0.330 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (35 μL, 0.408 mmol) and N,N-dimethylformamide (5 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(5-Amino-2-chloro-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (90 mg, 0.223 mmol) produced in Example 23(vi) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (7 mL) and saturated brine (7 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=20/80→80/20), and the obtained solution was concentrated under reduced pressure to give the title compound (120 mg, 88%) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[C:25]([NH:27][C:28](=[N:31][CH3:32])SC)#[N:26]>C(#N)C>[C:25]([NH:27][C:28]([NH:31][CH3:32])=[N:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)#[N:26]
Reactant: CN=C(NC#N)SC
Reactant: NCCCCc1nccs1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC#N
Product: CNC(=NCCCCc1nccs1)NC#N

Procedure:
A solution of 2-(4-aminobutyl)thiazole (from the dihydrochloride 13.8 g.) and N-cyano-N', S-dimethylisothiourea (7.75 g) in acetonitrile was heated under reflux for 24 hours. Following concentration, the residue was chromatographed on a column of silica gel with acetonitrile as eluant and the product obtained was recrystallised from isopropyl alcohol-isopropyl acetate to yield N-cyano-N'-methyl-N"-[4-(2-thiazolyl)butyl]guanidine m.p. 87°-89.5°.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:28])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([Cl:28])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[O:14]1)=[N+:30]=[N-:31]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4ccccc4)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cc(Cl)cc(-c3ccccc3)c2O1
Yield: 92.1 %

Procedure:
Treatment of (±)-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.55 g, 1.33 mmol) with sodium azide (0.345 g, 5.31 mmol) generally according to the procedure described for Intermediate 98 provided 0.35 g of (±)-2-(azidomethyl)-5-chloro-7-phenyl-2,3-dihydro-1-benzofuran as a colorless oil. Treatment of the azide with sulfided platinum on carbon (90 mg, 5 wt. %) generally according to the procedure described for Example 1 provided 0.14 g (40%) of (±)-1-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 258° C. (dec); Anal. calcd. for C15H14ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found: C, 60.13; H, 4.95; N, 4.6.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[C:29]([O:33][C:34]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([C:36]1[CH:37]=[CH:38][C:39]([NH:40]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:41][CH:42]=1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(C(=O)OC(C)(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-tert.butyloxycarbonyl-aniline Rf value: 0.4 (aluminium oxide, methylene chloride/ethanol=40:1) C29H28N2O5
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:21][OH:22])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[CH3:30][S:31](O)(=[O:33])=[O:32].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH2:21][OH:22])[C:3]([CH2:2][NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: CS(=O)(=O)O
Reactant: NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
A round bottom flask was charged with (R)-2-(3-(aminomethyl)-6-(5-cyclopropyl-1H-pyrazol -3-ylamino)-5-fluoropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Example 8; 0.20 g, 0.50 mmol), methanesulfonic acid loaded TFP resin (0.9 mmol/g loading, 0.50 mmol), DIEA (0.13 g, 1.00 mmol), DMAP (0.067 g, 0.067 mmol), and THF (10 ml). The resulting solution was shaken vigorously at 60° C. for 8 hrs. The reaction was filtered and the resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.075 g, 31%). 1H NMR (400 MHz, CD3OD) δ 7.50-7.41 (m, 2H), 7.15 (d, J=9.1 Hz, 1H), 7.04-7.00 (m, 2H), 6.09 (br s, 1H), 5.22-5.03 (m, 1H), 4.20-4.07 (m, 2H), 3.86-3.74 (m, 2H), 2.98 (s, 3H), 1.89-1.85 (m, 1H), 1.04-0.92 (m, 2H), 0.78-0.66 (m, 2H). MS: Calcd.: 478; Found: [M+H]+ 479.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37].C(N(CC)CC)C>CN(C=O)C.O>[O:37]=[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:35][NH:34][C:12]([C:10]1[S:11][C:7]2[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:14]
Reactant: NCC(=O)c1ccccc1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3ccccc3)nc12
Reaction time: 48 h
Yield: 64.4 %

Procedure:
0.20 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 0.125 g 1,1′-carbonyl-diimidazole in 1 ml DMF were stirred at room temperature for 1 hour. 0.13 g 2-aminoacetophenone hydrochloride and 0.08 g triethylamine were added and stirring was continued for two days at room temperature. 200 ml water was added and the mixture was extracted with ethylacetate. Chromatography on silicagel with ethylacetate/hexane 4:6 yielded 0.18 g (64%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-oxo-2-phenyl-ethyl)-amide as a yellow solid; M.p.: 197–200° C.; MS (ISP): m/e=412 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][C:8]([N:17]1[CH2:21][CH2:20][C@H:19]([O:22][NH:23][C:24]([C@@H:26]2[CH2:32][CH2:31][C@@H:30]3[CH2:33][N:27]2[C:28](=[O:42])[N:29]3[O:34]CC2C=CC=CC=2)=[O:25])[CH2:18]1)=[N:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:12]([O:11][C:10](=[O:16])[NH:9][C:8]([N:17]1[CH2:21][CH2:20][C@H:19]([O:22][NH:23][C:24]([C@@H:26]2[CH2:32][CH2:31][C@@H:30]3[CH2:33][N:27]2[C:28](=[O:42])[N:29]3[OH:34])=[O:25])[CH2:18]1)=[N:7][C:6](=[O:43])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A mixture of di-tert-butyl[{(3S)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidin-1-yl}methylylidene]biscarbamate 279 (0.34 g, 0.56 mmol) and Pd/C (0.15 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 280 (0.28 g, 97%) as white solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:20][CH:19]([CH3:21])[CH2:18][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=[C:4]1[CH2:3][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C1COCCN1
Reactant: CC(C)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Agent: Cl
Product: CC(C)Cn1c(CN2CCOCC2)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Yield: 68 %

Procedure:
2-Chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (Example 10, prepared from 2.0 g of the corresponding alcohol) was added to morpholine (5 mL). The mixture was refluxed for 4 hr. The resulting solution was cooled to room temperature. A solid precipitated. The solid was filtered from the mixture and slurried in aqueous sodium bicarbonate solution. The product was filtered from the mixture, washed with water, and dried to yield 1.7 g (68.0%) of solid, which was recrystallized from ethanol to give a pure product m.p. 228-234° C. Analysis: Calculated: C, 67.2; H, 7.4; N, 20.6. Found: C, 67.3; H, 7.9; N, 20.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18]([OH:20])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18]([NH:38][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[O:20])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenylbenzoic acid (33 mg, 0.0841 mmol) was dissolved in methylene chloride (3 ml), then p-anisidine (21 mg, 0.1707 mmol), triethylamine (34 mg, 0.3366 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (57 mg, 0.3372 mmol) were added thereto and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:1) to give the title compound (28 mg, 0.0563 mmol, 67%).