Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.Cl.[NH2:40][C@@H:41]([CH3:46])[C:42]([NH:44][CH3:45])=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:40][C@@H:41]([CH3:46])[C:42]([NH:44][CH3:45])=[O:43])=[O:4]
Reactant: CNC(=O)[C@H](C)N
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)[C@H](C)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 41.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), (S)-2-amino-N-methylpropanamide-HCl (6.43 mg, 0.046 mmol), and HATU (31.7 mg, 0.083 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N-methyl(S)propanamide (9.6 mg, 0.019 mmol, 40.2% yield): LCMS=516.1 [M+H]+; 1H NMR (Mixture of Diastereomers, 400 MHz, methanol-d4) δ ppm 8.11-8.25 (4 H, m), 7.50-7.78 (14 H, m), 5.16 (2 H, d, J=3.08 Hz), 4.37 (2 H, qd, J=7.08, 1.43 Hz), 2.75 (3 H, s), 2.72 (3 H, s), 1.39 (3 H, d, J=7.26 Hz), 1.35 (3 H, d, J=7.04 Hz); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.3 min+2.4 min (mixture of diastereomers).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1B(O)O)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH3:13])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Product: COc1cc(OC)c(-c2cc3ccccc3n2C(=O)OC(C)(C)C)cc1C=O
Yield: 79 %

Procedure:
Ex-32A: 2-(5-Formyl-2,4-dimethoxyphenyl)indole-l-carboxylic acid tert-butyl ester was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and N-Boc-indole-2-boronic acid in a similar manner as Ex-1A, 79% yield, yellow oil. 1H-NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 8.15 (d, J=8 Hz, 1H), 7.88 (s, 1H), 7.45 (d, J=8 Hz, 3H), 7.27–7.35 (m, 1H), 7.19–7.27 (m, 1H), 6.52 (s, 1H), 6.47 (s, 1H), 4.00 (s, 3H), 3.86 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:14]C(=O)C)(=[O:13])[CH3:12]>>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:12][C:11]([OH:14])=[O:13]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(=O)OC(C)=O
Product: O=C(O)C=Cc1ccc(F)cc1F
Yield: 77 %

Procedure:
A disadvantage here is the high reaction temperature needed, the unsatisfactory yield and the difficult accessibility of the compounds of the formula (I). Monatshefte der Chemie 90, 680 (1959) describes the reaction of 2,4-difluorobenzaldehyde with acetic anhydride at 180° C., 2,4-difluorocinnamic acid being obtained in a 77% yield.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[C:11]([C:12]3[CH:35]=[CH:34][C:15]([O:16][CH2:17][C:18]4[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=4)[C:21]([N:23]4[CH2:30][CH2:29][CH2:28][C@H:24]4[C:25]([OH:27])=[O:26])=[O:22])=[CH:14][CH:13]=3)=[CH:10][C:9]([F:36])=[C:8]([F:37])[C:6]=2[CH:7]=1)#[N:2].C([O-])(=[O:40])C.[Na+].Cl.NO.C(OC(=O)C)(=O)C>C(O)(=O)C>[F:37][C:8]1[C:6]2[CH:7]=[C:3]([CH:1]=[N:2][OH:40])[O:4][C:5]=2[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=3)[C:21]([N:23]3[CH2:30][CH2:29][CH2:28][C@H:24]3[C:25]([OH:27])=[O:26])=[O:22])=[CH:34][CH:35]=2)=[CH:10][C:9]=1[F:36]
Reactant: N#Cc1cc2c(F)c(F)cc(-c3ccc(OCc4cccc(C(=O)N5CCC[C@H]5C(=O)O)c4)cc3)c2o1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)[C@@H]1CCCN1C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)c4cc(C=NO)oc34)cc2)c1
Reaction time: 2 h
Yield: 15 %

Procedure:
The compound (20 mg, 0.04 mmol) of Example 54 was dissolved in acetic acid (5 mL), and sodium acetate (45 mg, 0.56 mmol) and hydroxylamine hydrochloride (14 mg, 0.21 mmol) were added thereto, and at 60° C. for 2 hours and stirred. After that, acetic anhydride (0.026 mL, 0.28 mmol) were added to, at 100° C. for 2 hours and stirred. After cooling, the solvent was distilled away, and the resulting residue was purified by reversed-phase HPLC in the same manner as in Step 2 of Example 1 to thus obtain the title compound.
Reaction SMILES: [CH3:1][S:2]([OH:4])=[O:3].[Na].[Cl:6][C:7]1[N:12]=[C:11]([CH2:13]I)[CH:10]=[C:9]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[N:8]=1>C(#N)C>[Cl:6][C:7]1[N:8]=[C:9]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[CH:10]=[C:11]([CH2:13][S:2]([CH3:1])(=[O:4])=[O:3])[N:12]=1
Reactant: C[C@H]1COCCN1c1cc(CI)nc(Cl)n1
Reactant: CS(=O)O
Agent: [Na]
Solvent: CC#N
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(Cl)n1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
Methanesulfinic acid, sodium salt (11.75 g, 115.11 mmol) was added in one portion to 2-chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (37 g, 104.64 mmol), in acetonitrile (900 mL) and the resulting solution stirred at 85° C. for 24 hours. The organic layers were combined and washed with water (3×100 mL), dried over MgSO4, filtered, and the solvent was removed by evaporation to give the crude product as a dark brown oil, which solidifed (36 g). The crude solid was purified by flash silicachromatography, elution gradient 0 to 30% ethyl acetate in DCM, to give the desired material (22 g) as a cream solid which was identical to previous samples.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][CH2:18][OH:19]>O1CCCC1.C(OCC)(=O)C>[F:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1Cl
Reactant: NCCCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1NCCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To a stirred solution of 2-chloro-5-fluoro-1,3-dinitrobenzene (3.24 g, 14.7 mmol) in tetrahydrofuran (50 mL) was added 3-amino-1-propanol (2.80 mL, 36.8 mmol) at 0° C. After being stirred for 3 h at room temperature, the mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo to give the title compound as a yellow solid (3.59 g, 13.8 mmol, 94%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:16][NH2:17])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[O:18]([CH2:25]CO)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([CH2:25][CH2:14][O:13][C:11](=[O:12])[C:10]([NH:16][NH2:17])([CH3:15])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCOc1ccccc1
Reactant: COC(=O)C(C)(Cc1ccc(O)c(O)c1)NN
Product: CC(Cc1ccc(O)c(O)c1)(NN)C(=O)OCCOc1ccccc1

Procedure:
Following the procedure described in Example 4 Step A for preparation of compound 107, and substituting methanol with 2-phenoxy-ethanol, provided the title compound. 1H NMR (CD3OD, 400 MHz): 1.65 (s, 3H), 3.10 (dd, 2H), 4.40 (t, 2H), 4.70 (t, 2H), 6.60–6.52 (m, 8H). MS (ESI) m/z 347.27 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:14][C:15]4[CH2:20][CH2:19][NH:18][CH2:17][C:16]=4[N:21]=3)[S:12][C:8]=2[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[C:37](Cl)(=[O:39])[CH3:38]>O1CCCC1>[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:14][C:15]4[CH2:20][CH2:19][N:18]([C:37](=[O:39])[CH3:38])[CH2:17][C:16]=4[N:21]=3)[S:12][C:8]=2[C:7]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNC4)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(C)=O)C4)nc12
Yield: 89 %

Procedure:
To a suspension of 0.01 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine hydrochloride in 0.8 ml tetrahydrofurane were added at 0–4° C. 0.02 ml N-ethyldiisopropylamine and 0.002 ml acetyl chloride in 0.25 ml tetrahydrofurane. The mixture was refluxed over night, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with ethylacetate/methanol 95:5 to yield 0.009 g (89%) 1-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl]-ethanone as yellow solid; M.p.: 155–157° C.; MS (ISP): m/e=414 (M+H+).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH2:11]([CH2:13][NH2:14])[OH:12].C([O-])(O)=O.[Na+]>ClCCl>[OH:12][CH2:11][CH2:13][NH:14][S:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: NCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(NCCO)c1ccc(Br)s1
Yield: 65.2 %

Procedure:
A mixture of 5-bromo-thiophene-2-sulfonyl chloride (1.5 g, 4. mmol) and ethanolamine (0.72 mL, 12 mmol) in dichloromethane (8mL)/sat. NaHCO3 solution (8 mL) was stirred at 20° C. for 28 h. The mixture was partitioned between AcOEt (50 mL) and H2O (150 mL). The organic layer was dried (Na2SO4) and evaporated to give the title compound (1.07 g, 93%) as a pale-yellow oil. MS (ISP) 284.0 [(M−H)−].
Reaction SMILES: CC([O-])(C)C.[K+].[CH:7]([O:9][CH3:10])=[O:8].[N:11]1[CH:16]=[C:15]([CH2:17][CH2:18][C:19](OC)=[O:20])[CH:14]=[N:13][CH:12]=1>C1COCC1>[CH:19]([CH:18]([CH2:17][C:15]1[CH:16]=[N:11][CH:12]=[N:13][CH:14]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:20]
Reactant: COC=O
Reactant: COC(=O)CCc1cncnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C=O)Cc1cncnc1
Temperature: 0 °C
Yield: 60.6 %

Procedure:
To an ice-cooled solution of KOtBu (43.0 g, 384 mmol) in anhydrous THF (300 ml) stirred under nitrogen was added methyl formate (18.43 g, 307 mmol) and methyl 3-(pyrimidin-5-yl)propanoate (25.5 g, 153 mmol) in anhydrous THF (10 mL) dropwise for 1 h. The mixture was stirred for 3 hr. The solvent was removed, and the residue was dissolved in water (150 mL). The aqueous phase was washed with ether (200 mL×3), and then to the aqueous solution was added AcOH to adjust the pH=5. The solid was collected and dried to give the target compound. The filtrate was extracted with DCM (200 mL×2), and the combined organic phase was dried over sodium sulfate, filtered and concentrated. The two crops were combined to give the title product as a yellow solid (18 g, 57.4% yield). LCMS: rt=0.96 min, [M+H+]=195
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=S)[N:19]([CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:18]2=[O:29])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:18]2=[O:29])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(=O)OCCN1C(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)SC1=S
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)OCCN1CSC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reaction time: 8 h
Yield: 59.7 %

Procedure:
Under a nitrogen atmosphere, 82.2 g of 5-[[3,5bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-3-[2-(acetyloxy)ethyl]-2-thioxo-4-thiazolidinone in 950 ml of toluene was heated to 65° C. Tri-n-butyl tin hydride (219.7 g) and AIBN (4.65 g) were added and the solution heated at reflux temperature for an additional 10 minutes. After cooling, the mixture was washed with 1.25 1 of 1N hydrochloric acid followed by 500 ml of a saturated sodium chloride solution. The organic layer was stripped and allowed to stand overnight, during which time a precipitate separated. The liquid portion was decanted off, and the resulting residue was purified by chromatography over silica gel, eluting with a gradient of 25-50% of ethyl acetate in hexane. The appropriate fractions were combined and concentrated in vacuo to provide 45.7 g of the desired titled compound, m.p.=152-155° C.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:16]([O-])([OH:18])=[O:17]>>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc(Cl)cc1)C1CCCCC1
Reactant: O=[N+]([O-])O
Product: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)C1CCCCC1
Temperature: -25 °C
Reaction time: 0.17 h

Procedure:
To 50 ml fuming nitric acid are added batchwise at -25° C. 6.4 g (28.8 mmol) of 4-(cyclohexylcarbonyl)-chlorobenzene. The solution is stirred for 10 minutes at -25° C. and then poured onto ice water. The precipitated product is suction filtered, washed with water and dried.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:8]([CH3:11])=[N:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:17](=[CH2:28])[C:18]([O:20]CC1C=CC=CC=1)=[O:19])CCC>C1COCC1.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]Cl>[CH3:11][C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH:17]([CH3:28])[C:18]([OH:20])=[O:19])[C:3]2=[N:10][N:9]=1
Reactant: Cc1nnc2c(Br)cccn12
Reactant: C=C(C(=O)OCc1ccccc1)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nnc2c(C(C)C(=O)O)cccn12
Temperature: 60 °C
Yield: 103.9 %

Procedure:
To a solution of 0.13 g (0.61 mmol) of 8-bromo-3-methyl[1,2,4]triazolo[4,3-a]pyridine from Step B above in 4 mL of anhydrous THF was added a solution of 0.36 g (0.80 mmol) of benzyl 2-(tributylstannyl)acrylate (see Intermediate 62, Step B) in 1 mL of anhydrous THF, 0.11 g (0.09 mmol) of tetrakis(triphenylphosphine)palladium(0) and 0.067 g (0.67 mmol) of copper (I) chloride. The reaction mixture was heated to 60° C. for 6 h, cooled and filtered through a pad of Celite®. The pad was washed with 15 mL of a dichloromethane and the combined filtrates were evaporated to dryness. The crude residue was purified by silica gel chromatography eluting with a 0-6% methanol in ethyl acetate gradient to afford the title compound (0.13 g, 73%). LC-MS: m/z (ES) 294 (MH)+.
Reaction SMILES: C(N([CH2:10][C:11]1[C:19]2[C:18](=[O:20])[N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16](=[O:27])[N:15]([CH2:28][C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[C:14]=2[S:13][C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][O:47][CH3:48])=[O:45])=[CH:39][CH:38]=1)C)C1C=CC=CC=1.[Cl:49]C(OC(Cl)C)=O>C1COCC1.C(=O)(O)[O-].[Na+]>[Cl:49][CH2:10][C:11]1[C:19]2[C:18](=[O:20])[N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16](=[O:27])[N:15]([CH2:28][C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[C:14]=2[S:13][C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][O:47][CH3:48])=[O:45])=[CH:39][CH:38]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CCl)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1
Reaction time: 2.5 h

Procedure:
Into a solution of N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea (7.7 g, 11.53 mmol) in THF (200 ml) which was cooled with a dry ice-acetone bath was added α-chloroethyl chloroformate (1.7 ml, 11.64 mmol). The temperature of the mixture was elevated up to room temperature, and the mixture was stirred for 2.5 hours. The reaction mixture was diluted with saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:15][Si:16]([CH3:19])([CH3:18])Cl>C1(C)C=CC=CC=1>[CH3:15][Si:16]([CH3:19])([CH3:18])[N:5]1[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7]
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCC(=O)N1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
To 400 g (4 moles) of succinimide and 900 ml of triethylamine in 2700 ml of toluene 780 ml of trimethylchlorosilane were added in two hours with vigorous stirring. After refluxing and stirring for an additional hour the mixture was allowed to cool to room temperature. The precipitate was filtered off, washed with 1 l of toluene and 1 l of light petrol (40°-60° C.) and the combined filtrate and washings concentrated to about 700 ml. N-trimethylsilylsuccinimide was isolated by distillation at diminished pressure. The yield was 573 g (3.35 moles) or 83.5%; boiling point 62° C./0.3 mm Hg.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14](F)=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][S-:23].[Na+].Cl>CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:23][CH3:22])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 105 °C
Yield: 81.8 %

Procedure:
A solution of 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (1.52 g, 5.0 mmol) in N,N-dimethylformamide (10 mL) was treated with sodium methanethiolate (0.59 g, 7.5 mmol). The reaction mixture was then heated to 100-110° C. for 14 h. At this time, the reaction was poured onto a mixture of ice and a 2N aqueous hydrochloric acid solution (25 mL). This mixture was extracted into ethyl acetate (3×35 mL) and diethyl ether (1×25 mL). The organics were then washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (3×75 mL). The organics were dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate w/acetic acid) afforded 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid (1.36 g, 83.4%) as a pale yellow oil: EI-HRMS m/e calcd for C16H19F3O2S (M+) 332.1058, found 332.1057.
Reaction SMILES: C(Cl)(=O)C.[N:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(NC1[CH:47]=[CH:46][C:45]([C:48](=[O:53])NCCC)=CC=1)=O)C2>>[CH:45]1([C:48]([N:8]2[CH2:9][CH2:10][N:5]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]4[CH2:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21]4)=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:7]2)=[O:53])[CH2:46][CH2:47]1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: O=C(Nc1ccc(N2CCN(C(=O)C3CC3)CC2)cc1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting cyclopropanecarbonyl chloride for acetyl chloride and N-(4-(piperazin-1-yl)phenyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.15 (s, 1H), 7.38-7.45 (m, 2H), 7.28-7.39 (m, 4H), 6.87-6.93 (m, 2H), 4.74 (s, 4H), 3.73-3.90 (m, 2H), 3.50-3.70 (m, 2H), 3.02-3.18 (m, 4H), 1.98-2.07 (m, 1H), 0.68-0.77 (m, 4H); MS (ESI(−)) m/e 389 (M−H)−.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]2[CH:17]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH:15]=[CH:14][N:13]=2)[N:2]=1.Cl.CCOC(C)=O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]2[CH:17]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:15]=[CH:14][N:13]=2)[N:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccnc(Nc3cc4ccccc4cn3)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc2cc(Nc3cc(CN4CCNCC4)ccn3)ncc2c1

Procedure:
2-(Isoquinolin-3-ylamino)-4-(4-tert-butoxycarbonylpiperazin-1-ylmethyl)-pyridine was treated with 8 M HCl/EtOAc to afford the title compound as a salt in near quantitative yield (50 mg). 1H NMR (CDCl3, 300 MHz) δ: 3.44 (s, 4H, PyridylCH2NCH2CH2), 3.45 (s, 4H, NHCH2), 4.25 (s, 2H, pyridylCH2), 7.01-8.87 (m, 9H, isoquinolyl+pyridyl).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1)[CH3:2].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH:20]=[C:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:10]1=[O:13])[CH3:19]
Reactant: CCc1ccc2c(c1)C(=O)CCC2
Reactant: CCOC(OCC)N(C)C
Product: CCc1ccc2c(c1)C(=O)C(=CN(C)C)CC2

Procedure:
3,4-Dihydro-2-dimethylaminomethylene-7-ethyl-1(2H) naphthalenone was prepared from 7-ethyl-1-tetralone (5 g, 30.0 mmol) and N,N-dimethylformamide diethylacetal (15 ml) to give the compound as a yellow solid (4.6 g) m.p. 132-139°. δH (CDCl3) 7.87 (1H, d, J 1.7 Hz), 7.71 (1H, s), 7.21 (1H, dd, J 2.0, 7.7 Hz), 7.08 (1H, d, J 7.7 Hz), 3.11 (6H, s), 2.85 (4H, m), 2.66 (2H, q, J 7.6 Hz) and 1.24 (3H, m).
Reaction SMILES: [C:1]([C:3]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1)#[N:2].Cl.[CH3:23][NH2:24]>>[C:1]([C:3]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]1[CH2:7][CH2:8][CH:9]([C:12]([NH:24][CH3:23])=[O:14])[CH2:10][CH2:11]1)#[N:2]
Reactant: N#Cc1c(OC2CCC(C(=O)O)CC2)cccc1[N+](=O)[O-]
Reactant: CN
Agent: Cl
Product: CNC(=O)C1CCC(Oc2cccc([N+](=O)[O-])c2C#N)CC1

Procedure:
Prepared as in Example Da from 4-(2-cyano-3-nitrophenoxy)cyclohexanecarboxylic acid (Example 22d) and methylamine hydrochloride as an orange solid (80%). MS 304 (MH+).