Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:93]=[CH:94][CH:95]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[CH:67][C:66]=4[O:81][CH3:82])[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:93]=[CH:94][CH:95]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[CH:67][C:66]=4[O:81][CH3:82])[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: COc1cc(N2CCN(C[C@H](C)O)CC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(N2CCN(C[C@H](C)O)CC2)ccc1-c1cnc2[nH]cc(-c3cnn(Cc4cccc(F)c4)c3)c2c1
Yield: 29 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxyphenyl)piperazin-1-yl)propan-2-ol (120 mg, 0.172 mmol) was hydrolyzed with lithium hydroxide (22 mg, 0.518 mmol) in THF/methanol/water (2/2/1 mL) to yield 27 mg (29.0% yield). 1H NMR (CD3OD, 400 MHz): δ 8.55-8.54 (d, 1H), 8.438-8.434 (d, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 7.42-7.38 (m, 2H), 7.14-7.12 (d, 1H), 7.05-7.03 (qd, 2H), 6.80-6.76 (m, 2H), 5.44 (s, 2H), 4.29-4.24 (m, 1H), 3.99-3.96 (m, 2H), 3.86 (s, 3H), 3.75-3.38 (m, 2H), 3.29-3.12 (m, 6H), 1.29-1.28 (d, 3H). MS: m/z=541.4 (M+1), HPLC: 92.28% in method A.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][C:11]([OH:13])=O)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Cl.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][C:20]=1[O:31][CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:11](=[O:13])[CH2:10][N:6]3[C:5]4[CH:14]=[CH:15][C:2]([OH:1])=[CH:3][C:4]=4[O:8][C:7]3=[O:9])[CH2:29][CH2:30]2)=[CH:21][C:20]=1[O:31][CH3:32]
Reactant: COc1cc(N2CCNCC2)ccc1Cl
Reactant: O=C(O)Cn1c(=O)oc2cc(O)ccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(O)ccc43)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (6-hydroxy-2-oxo-benzooxazol-3-yl)-acetic acid (53) (800 mg, 1 equiv), 1-(4-chloro-3-methoxy-phenyl)-piperazine dihydrochloride (1.16 g, 1 equiv), BOP (1.7 g, 1 equiv), triethylamine (5 mL, 5 equiv) in 10 ml of DMF was stirred at room temperature for overnight. The resultant solution was then diluted with EtOAc (50 mL) and washed with water. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide a crude residue which was purified by flash chromatography to provide 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-hydroxy-3H-benzooxazol-2-one (54).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:11]([NH2:17])[C:12]1[O:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH2:1]([NH:8][C:9]([NH:17][CH2:11][C:12]1[O:16][CH:15]=[CH:14][CH:13]=1)=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NCc1ccco1
Reactant: CCCCCCCN=C=S
Solvent: c1ccccc1
Product: CCCCCCCNC(=S)NCc1ccco1

Procedure:
To a mixture of 3.1 grams (0.02 mole) of n-heptyl isothiocyanate and 25 milliliters of benzene was added 1.77 milliliters (0.02 mole) of furfuryl amine. The mixture was refluxed for 30 minutes on a steam bath and then evaporated under vaccum to yield 1-n-heptyl-3-furfuryl thiourea. The product was cooled and 4.1 grams (0.02 mole) of bromoethylamine hydrobromide and 25 milliliters of ethanol 2B was added. The resulting mixture was refluxed on a steam bath overnight. The solid product was removed by filtration and air dried. A yield of 5.2 grams of solid, melting point 140°-145° C., was obtained. Structure of the product was confirmed by NMR.
Reaction SMILES: [CH2:1]([S:6][C:7]1[S:11][C:10]([CH2:12][NH:13][OH:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C[Si]([N:19]=[C:20]=[S:21])(C)C>O1CCOCC1>[OH:14][N:13]([CH2:12][C:10]1[S:11][C:7]([S:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:8][CH:9]=1)[C:20]([NH2:19])=[S:21]
Reactant: CCCCCSc1ccc(CNO)s1
Reactant: C[Si](C)(C)N=C=S
Solvent: C1COCCO1
Product: CCCCCSc1ccc(CN(O)C(N)=S)s1

Procedure:
To a solution of N-[5-n-pentylthiothien-2-ylmethyl]-hydroxylamine (4.36 g) in dioxan (60 ml) at room temperature under nitrogen, was added trimethylsilylisothiocyanate (3.11 g) and the solution heated at reflux for 1 hour. The cooled solution was quenched with saturated aqueous ammonium chloride, dried over MgSO4 and evaporated under reduced pressure to give a brown oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using ether to give a pale yellow solid, recrystallized from n-hexane to give a cream crystalline solid m.p. 112°-114° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=O)C.O>O1CCCC1>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:10][OH:9])[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CCOC(=O)C1CCN(S(C)(=O)=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(CO)CC1
Temperature: 7.5 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
A solution of 1.0 M lithium aluminum hydride (200 ml, 0.2 mole) in tetrahydrofuran was added dropwise to a solution of 1-methanesulfonylpiperidine-4-carboxylic acid ethyl ester (68 grams, 0.29 mole) in tetrahydrofuran (500 ml) at about +5° C. The reaction mixture was stirred at 5-10° C. for 15 minutes. Water (10 ml) was added dropwise and the mixture was filtered. The filtrate was concentrated under reduced pressure and triturated with 50% ethyl ether-hexane (100 ml). The resulting white solid was collected and dried to give 1-methanesulfonylpiperidine-4-methanol (46 grams, 82%), m.p. 96-97° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[NH:30][CH2:29][C@@H:28]3[CH3:34])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)[CH3:2].[CH:37](=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[N:30]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:29][C@@H:28]3[CH3:34])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Product: CCOC(=O)CN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)c2)CC1
Yield: 34.4 %

Procedure:
The title compound was made by a procedure identical to that of Example 66 with 1.50 g of (4-{3-[(R)-((2S,5R)-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperazin-1-yl)-acetic acid ethyl ester (3.03 mmol) and 0.64 g of benzaldehyde (6.07 mmol) to give 0.61 g (34%) of the desired compound as a light yellow solid. 1H NMR (300 MHz, d6-DMSO): □ 1.00-1.02 (d, J=4.7 Hz, 6H); 1.15-1.19 (t, 3H), 1.87-2.00 (m, 2H); 2.48-2.65 (m, 8H); 3.25 (s, 2H); 3.36-3.57 (m, 5H); 3.73-3.77 (dd, 1H); 4.03-4.10 (q, 2H); 4.96 (s, 1H); 6.62-6.69 (m, 3H); 7.08-7.42 (m, 10H); 9.35 (s, 1H). Calculated for C35H44N4O4.0.16 CH2Cl2: C, 70.58; H, 7.47; N, 9.36. Found: C, 70.57; H, 7.52; N, 9.39.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[OH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].N1C=CN=C1.C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C>[OH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:2]([CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:9])[CH3:11])[CH3:1])=[O:17]
Reactant: O=C(Cl)c1ccccc1O
Reactant: CNCCNC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CN(CCNC(=O)OC(C)(C)C)C(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
To a mixture of tert-butyl 2-(methylamino)ethylcarbamate (0.348 g, 2 mmol), 2-hydroxybenzoyl chloride (0.276 g, 2 mmol) and imidazole (0.136 g, 2 mmol) in ethyl acetate (8 mL) at 0° C. was slowly added a solution of DCC (0.412 g, 2 mmol) in ethyl acetate (2 mL). The mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel, eluting with ethyl acetate/petroleum ether (20-50%) to afford tert-butyl 2-(2-hydroxy-N-methylbenzamido)ethylcarbamate (0.2 g, 34%) as a colorless oil. 1HNMR (CDCl3): δ7.5 (m, 2H, CH), 7.0 (d, 1H, CH), 6.8 (d, 1H, CH), 3.7 (m, 2H, CH2), 3.48 (m, 2H, CH2), 3.2 (m, 3H, CH3), 1.5 (s, 9H, CH3).
Reaction SMILES: [N:1]([C:4]1([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[O:24][CH3:25])[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[NH2:1][C:4]1([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[O:24][CH3:25])[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14]
Reactant: COc1cc(C(C)C)ccc1C1(N=[N+]=[N-])C(=O)c2ccccc2C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COc1cc(C(C)C)ccc1C1(N)C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 53874.8 %

Procedure:
To a solution of 2-azido-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (50 mg, 0.15 mmol) in methanol (10 ml) were added with triphenylphosphine (47 mg, 0.18 mmol), followed by stirring at 60° C. for 4 hrs. The concentrated reaction mixture was purified using silica column chromatography (25% ethylacetate in hexane) to afford the title compound (25 g, 54%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])[C:7]2=[O:12].CN(C)C=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([CH3:34])[C:31](O)=[O:32])=[CH:26][C:25]=1[C:35]([F:38])([F:37])[F:36].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CCOC(C)=O>[NH2:16][C:14](=[O:15])[C@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:31](=[O:32])[CH:30]([C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[C:25]([C:35]([F:36])([F:37])[F:38])[CH:26]=2)[CH3:34])[C:7]1=[O:12])[CH3:17]
Reactant: CC(C(=O)O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C[C@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C(=O)Nc1cccc2c(=O)n([C@H](C)C(N)=O)ccc12)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)propanamide (183.1 mg, 0.0007522 mol) in N,N-dimethylformamide (6 mL, 0.08 mol) was added 2-(4-chloro-3-(trifluoromethyl)phenyl)propanoic acid (110.0 mg, 0.0004137 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (360 mg, 0.00095 mol) and N,N-diisopropylethylamine (305 μL, 0.00175 mol). The reaction mixture was stirred at 50° C. overnight. LC/MS was checked, and the reaction was complete. In the work up, EtOAc (100 mL) was added to the reaction solution, and the solution was washed with water (2×100 mL), Sat. NaHCO3, H2O, and brine. The mixture was dried with MgSO4 and was rotovaped. The residue was purified by HPLC. The product was recovered as a solid. MS m/z=466.1 (M+1). 1H NMR (400 MHz; DMSO-d6) δ 10.08(s, 1 H), 8.07(d, J=7.9 Hz, 1 H), 7.92(s, 1 H), 7.80-70(m, 3 H), 7.63(s, 1 H), 7.50-7.40(m, 2 H), 7.23 (s, 1 H), 6.51(dd, J=7.6, 4.8 Hz, 1 H), 5.47(q, J=7.2 Hz, 1 H), 4.16(q, J=7.0 Hz, 1 H), 1.58-1.45(m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14]CC)=O)=[N:10][N:11]=2)[CH:8]=1.Cl.Cl.[F:19][C:20]([F:38])([F:37])[C:21]1[CH:22]=[C:23]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[F:38][C:20]([F:19])([F:37])[C:21]1[CH:22]=[C:23]([CH:31]2[CH2:36][CH2:35][N:34]([C:12]([C:9]3[N:7]4[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]4=[N:11][N:10]=3)=[O:14])[CH2:33][CH2:32]2)[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1
Reactant: CCOC(=O)c1nnc2ccc(OC)cn12
Reactant: FC(F)(F)c1cc(C2CCNCC2)cc(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc2nnc(C(=O)N3CCC(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)n2c1
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
To a solution of ethyl 6-methoxy-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (66 mg, 0.30 mmol) in THF (2.5 mL) was added a solution of LiOH monohydrate (25 mg, 0.60 mmol) in H2O (1.6 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (3.3 mL) under an atmosphere of N2. To this mixture was added 4-(3,5-bis(trifluoromethyl)phenyl)piperidine hydrochloride (20, 100 mg, 0.30 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (266 mg, 0.60 mmol), and diisopropylethylamine (0.16 mL, 0.90 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4×30 mL). The combined organic extracts were washed with a saturated brine solution (3×30 ml) and concentrated under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 24 g Redisep column, 0% to 2% MeOH in CH2Cl2 with 0.1% NH4OH in CH2Cl2). The obtained residue was dissolved in CH2Cl2 (10 mL) and hexanes (100 mL). The solution was partially concentrated and the resulting solids were collected by filtration to provide (4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl) methanone as an off-white solid (80 mg, 56%): mp 146-149° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.55 (d, J=2.0 Hz, 1H), 8.03 (s, 2H), 7.95-7.89 (m, 2H), 7.38 (dd, J=10, 2.5 Hz, 1H), 5.40-5.33 (m, 1H), 4.81-4.73 (m, 1H), 3.85 (s, 3H), 3.39-3.31 (m, 1H, overlaps with H2O), 3.26-3.16 (m, 1H), 3.02-2.93 (m, 1H), 2.03-1.77 (m, 4H); ESI MS m/z 473 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25].C(N(CC)CC)C>C(#N)C>[C:19]([NH:18][C:10]([NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[N:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[Cl:21])#[N:20]
Reactant: N#CN=C(Nc1cc(Cl)cc(Cl)c1)Oc1ccccc1
Reactant: NCc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#CNC(=NCc1ccccc1Cl)Nc1cc(Cl)cc(Cl)c1
Temperature: 82 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a solution of N-(3,5-dichlorophenyl)-N'-cyano-O-phenylisourea (0.8 mmol, 250 mg) in dry acetonitrile (2 ml), 2-chlorobenzylamine (0.9 mmol, 0.108 ml) and triethylamine (0.125 ml) were added. The mixture was stirred for 21/2 h at 82° C. under nitrogen. After concentration the residue was recrystallized from ethyl acetate to give the title compound (208 mg, 72%). Mp 186-187.5° C.; 1H-NMR (CDCl3): δ 4.54 (d, 2H), 5.53 (br, 1H), 7.15 (m, 2H), 7.3 (m, 3H), 7.4 (m, 2H), 7.75 ppm (br, 1H); EI SP/MS: 394 (M+). MA calc for C15H11C13N4 : C, 50.95%; H, 3.14%; N, 15.84%. Found: C, 50.68%; H, 3.10%; N, 15.49%.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]#[C:12]/[CH:13]=[CH:14]/[CH2:15][OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:21]O)(C)(C)C>C1C=CC=CC=1.C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V]>[C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]#[C:12][C@@H:13]2[O:21][C@H:14]2[CH2:15][OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC/C=C/C#CC#CC#Cc1ccccc1
Reactant: CC(C)(C)OO
Agent: O=[V]
Agent: CC(=O)/C=C(\C)O
Solvent: c1ccccc1
Product: OC[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Reaction time: 18 h

Procedure:
To a stirred solution of 103 mg (0.50 mmole) of (E)-9-phenyl-2-nonen-4,6,8-triyn-1-ol in 20 ml of dry benzene was added 5 mg of vanadyl acetylacetonate and 0.095 ml (0.50 mmole) of a 5.24M solution of t-butylhydroperoxide in benzene. Further 0.095 ml portions of t-butyl hydroperoxide solution were added after 2 hours and 31/2 hours. After stirring for 18 hours, the benzene solution was concentrated and purified via preparative thin layer chromatography (Analtech, 2 mm, silica gel; ether-hexane 1:1) to afford 59 mg of the title compound, melting point 68°-70° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9](Cl)=[N:10][CH:11]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH2:5][C:6]1[C:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:8][C:9]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:10][CH:11]=1
Reactant: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccccc1OC
Reactant: Nc1ccccc1
Product: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccccc1OC
Temperature: 120 °C

Procedure:
A mixture of 3-(2,4-dichloro-pyrimidin-5-yl)-2-(2-methoxy-phenyl)-propionic acid methyl ester (0.34 g, 1.0 mmol) (from Example 7a supra) and aniline (2.0 mL) (Aldrich) was heated at 120° C. for 1 hour. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with ethyl acetate-hexanes. The resulting solid was collected by filtration and washed with diethyl ether to give 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(2-methoxy-phenyl) propionic acid methyl ester as a yellow solid which was used in the next step without further purification. (Yield 340.0 mg, 74.9%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22](Br)[N:23]=3)[N:18]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:17]=2)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]1[CH:43]=[C:42]2[C:38]([C:39]([Sn](CCCC)(CCCC)CCCC)=[N:40][N:41]2[CH3:44])=[CH:37][CH:36]=1>CN(C=O)C.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>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:39]4[C:38]5[C:42](=[CH:43][C:35]([F:34])=[CH:36][CH:37]=5)[N:41]([CH3:44])[N:40]=4)[N:23]=3)[N:18]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:17]=2)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(F)ccc12
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H]2CCN(Cc3ccccc3)C2)c2nc(Br)cnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H]2CCN(Cc4ccccc4)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
In a 40 ml vial containing 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide (1.32 g, 2.49 mmol) was added a solution of 6-fluoro-1-methyl-3-tributylstannyl-1H-indazole (1.20 g, 2.73 mmol) in DMF (25 ml). The vial was backfilled with nitrogen and tetrakis(triphenylphosphine)palladium (0) (159 mg, 0.14 mmol) and copper (I) iodide (107 mg, 0.56 mmol) were added. Again the vial was backfilled with nitrogen, then sealed and the reaction mixture was stirred in a heating block at 80° C. for 4 h. The reaction mixture was cooled to room temperature diluted with EtOAc/hexanes (100/30 ml) and washed with water (100 ml). The aqueous layer was extracted with EtOAc/hexanes (100/30 ml). The combined organic layers were washed with brine then dried over MgSO4, filtered, and concentrated. The crude was purified by flash chromatography (120 g Analogix) with 20% to 100% EtOAc in hexanes. The approriate fractions were combined and concentrated to yield 1.02 g (62%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide as a light yellow solid. LC-MS (M+H)+=600.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[CH2:13][CH2:14][N:15]([CH:27]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:28](=[O:31])[NH:29][OH:30])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>C(O)C.O>[OH2:3].[CH:32]1([CH:27]([N:15]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:14][CH2:13][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:38])[C:28](=[O:31])[NH:29][OH:30])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CCOC(=O)C1CCN(C(=O)CCN(C(C(=O)NO)C2CCCCC2)S(=O)(=O)c2ccc(OC)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCC(C(=O)O)CC2)C(C(=O)NO)C2CCCCC2)cc1
Reaction time: 0.25 h
Yield: 164.9 %

Procedure:
To a solution of 1-{3-[(cyclohexylhydroxycarbamoylmethyl)(4-methoxybenzenesulfonyl) amino]propionyl}piperidine-4-carboxylic acid ethyl ester (0.62 grams, 1.16 mmol) (Example 17) in ethanol (45 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.24 grams, 5.72 mmol). After stirring for 3 hours at room temperature ethanol-washed Amberlite IR-120 plus ion exchange resin (6 grams) was added. Stirring was continued for 15 minutes and then the mixture was filtered. The filtrate was concentrated in vacuo to give 1-{3-[(cyclohexylhydroxycarbamoylmethyl)-(4-methoxy-benzenesulfonyl)amino]propionyl}-piperidine-4-carboxylic acid monohydrate as a white solid (0.52 grams, 88%). MS: 526 (M+1). Analysis calculated for C24H35N3O8S·H2O: C, 53.05; H, 6.86; N, 7.73. Found: C, 53.53; H, 7.15; N, 7.70.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[N+:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([O-:28])=[O:27].N>CN(C=O)C>[N+:26]([C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: COC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: N
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
Prepared analogously to Example 77 from 1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-nitroaniline in DMF and subsequent treatment with methanolic ammonia.