Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=N[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1>CN(C=O)C>[N:38]1([C:12]([C:9]2[CH:8]=[C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[S:11][CH:10]=2)=[O:14])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1csc(C2CCOCC2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C(c1csc(C2CCOCC2)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
5-(Tetrahydro-pyran-4-yl)-thiophene-3-carboxylic acid (0.107 g, 0.5 mmol) was dissolved in DMF (2 mL). DIPEA (1.0 mmol), HATU (0.5 mmol) and piperidine (0.5 mmol) were added and the reaction stirred at room temperature for 1 hour. The reaction was then partitioned between ethyl acetate and water and the organic solution separated and dried over magnesium sulphate, filtered and the solvent evaporated. The product was purified by HPLC, eluting with 40%-90% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (74 mg). LCMS m/z 280.22 [M+H]+ RT=8.77 min (Analytical Method 1). 1H NMR δ (ppm)(CHCl3-d): 7.25 (s, 1H), 6.9 (t, 1H), 4.1-4.0 (m, 2H), 3.6 (m, 4H), 3.5 (m, 2H), 3.1-3.0 (m, 1H), 1.95-1.6 (m, 10H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]=[C:11]3[N:12]([CH2:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:20])[CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1c(-c2ccc(Br)cc2)[nH]c2ncccc12
Product: Cc1c2cccn(CC(=O)c3ccccc3)c-2nc1-c1ccc(Br)cc1

Procedure:
The title compound was prepared from 2-(p-bromophenyl)-3-methyl-pyrrolo-[2,3-b]pyridine and phenacylbromide on a 1.7 mmol scale according to the procedure described in example 8 yielding 620 mg (74%).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13]C)=[N:6][C:5]=1[O:15][CH2:16][CH:17]([F:19])[F:18].C1COCC1.[OH-].[Na+]>O>[F:19][CH:17]([F:18])[CH2:16][O:15][C:5]1[N:6]=[C:7]([NH2:13])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:3]([OH:20])=[O:2]
Reactant: CNc1nc(OCC(F)F)c(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(OCC(F)F)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl-2-(2,2-difluoro-ethoxy)-6-methylamino-5-nitro-nicotinate (9.1 g, 32 mmol, prepared according to WO2010/34799), THF (100 mL), water (60 mL) and 1N aq. NaOH-solution (60 mL) is stirred for 3 h at rt, then the mixture is concentrated i.vac. The water phase is washed with Et2O, 60 mL 1N HCl solution is added and the resulting precipitate is collected and dried.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([N:11]=[C:12]=[O:13])([CH3:10])[CH3:9].[CH3:14][C:15]1[NH:19][N:18]=[C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH:16]=1.Cl>C(OCC)(=O)C>[CH:8]([NH:11][C:12]([N:19]1[C:15]([CH3:14])=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[N:18]1)=[O:13])([CH3:10])[CH3:9]
Reactant: Cc1cc(Oc2cccc(C(F)(F)F)c2)n[nH]1
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)nn1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.6 %

Procedure:
Triethylamine (0.17 g, 1.7 mmol) and isopropyl isocyanate (0.14 g, 1.7 mmol) were added to a solution of 5-methyl-3-(3-trifluoromethylphenyloxy)pyrazole (0.36 g, 1.5 mmol) in ethyl acetate (5 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a colorless viscous substance of N-isopropyl-5-methyl-3-(3-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.15 g, yield: 30.6%). 1H-NMR (CDCl3, TMS, ppm): δ 1.25 (d, J=6.6 Hz, 6H), 2.60 (d, J=0.6 Hz, 3H), 4.05 (sep, J=6.6 and 6.6 Hz, 1H), 5.71 (q, J=0.6 Hz, 1H), 6.81 (br d, J=6.6 Hz, 1H), 7.30-7.35 (m, 1H), 7.40-7.52 (m, 3H).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:41][CH3:42])[CH:40]=1)[C:35](O)=[O:36]>>[CH3:42][O:41][C:39]1[CH:38]=[C:34]([CH:33]=[C:32]([O:31][CH3:30])[CH:40]=1)[C:35]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:36]
Reactant: COc1cc(OC)cc(C(=O)O)c1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: COc1cc(OC)cc(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3,5-dimethoxybenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3,5-dimethoxybenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 530 (M+H)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:33]([CH3:34])=[CH:32][N:31]([CH3:35])[C:28]5=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:33]([CH3:34])=[CH:32][N:31]([CH3:35])[C:28]5=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(c4)c(C)cn5C)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccnc(-c4cnc5c(c4)c(C)cn5C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(1,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate: (28 mg, 0.044 mmol) in THF/CH3OH (1.0 mL/1.0 mL) was added 2N NaOH (0.22 mL, 0.44 mmol). The reaction mixture was heated at 50° C. for 2 h and the crude was purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C34H31ClN4O3S: 611.2 (M+H+); Found: 611.2 (M+H+); 1H NMR (400 MHz, CD3OD) δ 9.11 (s, 1H), 8.79 (d, J=5.6 Hz, 1H), 8.18-7.64 (m, 8H), 7.32 (s, 1H), 5.29 (s, 1H), 3.96 (s, 3H), 2.66 (s, 3H), 2.34 (s, 3H), 0.99 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([NH:10][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)[CH:9]=1)=[O:4]
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)c1cc(N)nn1C
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(NCc2cccc(Cl)c2)nn1C

Procedure:
5-Amino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (644, 1.3 g, 8.0 mmol) was combined with 3-chlorobenzaldehyde (645, 0.95 mL, 8.4 mmol) and acetonitrile (40 mL). Trifluoroacetic acid (3.2 mL, 42.0 mmol) was added followed by triethylsilane (6.7 mL, 42.0 mmol). The reaction was heated to reflux overnight and then concentrated. Ethyl acetate was added and the solution was washed with 1N potassium carbonate. The organic portion was dried over anhydrous sodium sulfate, filtered and concentrated. The compound (646, 0.944 g, 42%) was crystallized from a mixture of ethyl acetate:hexane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[N:6][CH:7]=1.[CH3:20][C:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[CH:23][N:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[N:6][CH:7]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CC(C)(C)OC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Cc1cc(B(O)O)ccn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(-c2cnc(OCC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)ccn1
Temperature: 100 °C
Yield: 45 %

Procedure:
To a flask with tert-butyl 2-(5-bromo-3-nitropyridin-2-yloxy)acetate (78.F) (700 mg from last step, about 406 mg of estimated pure 78.F by NMR) was added tris(dibenzylideneacetone)dipalladium (o) (67 mg, 0.073 mmol), 2-methylpyridin-4-ylboronic acid (250 mg, 1.8 mmol), X-phos (139 mg, 0.29 mmol), potassium phosphate (1.04 g, 4.9 mmol). The solids were purged with nitrogen. Degassed t-amyl alcohol was added as a solvent. The reaction was heated at 100° C. for 2 hr. 40 min.s. The solids were filtered off. Silica gel purification afforded 280 mg (67%) 78.G.
Reaction SMILES: C([SiH](CC)CC)C.[C:8]1([C:14]2[CH:28]=[CH:27][C:17]([C:18]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=O)=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>FC(F)(F)C(O)=O.O>[C:8]1([C:14]2[CH:28]=[CH:27][C:17]([CH2:18][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(-c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
Triethylsilane (32.62 ml) was added in one portion to a stirred solution of ethyl 3-(4-phenylbenzoyl)propanoate [(2), 25.06 g] in trifluoroacetic acid (71.5 ml) and the resulting mixture was stirred at room temperature for about 20 hours. The resulting clear dark orange solution was diluted with water and extracted with ether. The extracts were washed with aqueous sodium bicarbonate (x2) and then water (x2), dried and concentrated to give a mobile brown liquid. Triethylsilane remaining in this liquid was removed by Kugelrohr evaporative distillation at 110° C. and a pressure of ca. 1 mmHg to leave crude ethyl 4-(4-phenylphenyl)butanoate (21.20 g) as a brown oil. (Compare method of C. T. West, S. J. Donnelly, D. A. Kooistra and M. P. Doyle, J. Org. Chem., 1973, 38, 2675).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32]([OH:34])=O)[CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[NH:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)[C:32]([N:39]3[CH2:44][CH2:43][CH:42]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:47][CH2:46]4)[CH2:41][CH2:40]3)=[O:34])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)O)cc(C)c2[nH]1
Reactant: CCOC(=O)CN1CCN(C2CCNCC2)CC1
Product: CCOC(=O)CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c4[nH]c(OC)nc4c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 7i from 150 mg (0.27 mmol) (R)-1-carboxy-2-(2-methoxy-7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 85 mg (0.33 mmol) ethyl (4-piperidin-4-yl-piperazin-1-yl)-acetate.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:35]=[CH:34][CH:33]=[CH:32][C:8]=2[C:9]=1[CH2:10][CH2:11][C:12]1[CH:31]=[CH:30][C:15]([O:16][S:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([OH:29])[CH:21]=2)(=[O:19])=[O:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[C:36](OC(=O)C)(=[O:38])[CH3:37].O>CCOC(C)=O.CN(C)C1C=CN=CC=1>[C:36]([O:29][C:22]1[CH:21]=[C:20]([S:17]([O:16][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C:9]3[C:8]4[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=4[O:6][C:5]=3[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:31][CH:30]=2)(=[O:18])=[O:19])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1oc2ccccc2c1CCc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1oc2ccccc2c1CCc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(OC(C)=O)c2)cc1
Reaction time: 24 h
Yield: 76 %

Procedure:
At ambient temperature, to a stirred solution containing 4-{4-[2-(2-butyl-benzofuran-3-yl)-ethyl]-phenoxysulfonyl}-2-hydroxy-benzoic acid (0.298 g, 0.602 mmol) and acetic anhydride (1 mL) In EtOAc (2 mL) was added 4-(dimethylamino)pyridine (3.7 mg, 0.0301 mmol). The reaction was refluxed for 72 h. The reaction was cooled to ambient temperature, hydrolyzed with H2O (5 mL) and stirred for 24 h. The reaction was diluted with EtOAc and the organic phase washed sequentially with H2O (2×), brine (2×), dried (MgSO4) and concentrated. Purification on 2% H3PO4 /MeOH treated silica gel, eluting with a 10 & 20% EtOAc/pet ether step gradient gave 0.122 g (76%) of the title compound as a yellow solid, mp 54-57° C. 1H NMR consistent. IR (KBr) 3400, 2900, 1700, 1380 and 1190 cm-1. mass spectrum (-ESI) m/z 535 (M-H).
Reaction SMILES: C([NH:4][C:5]1[CH:27]=[CH:26][C:8]([O:9][CH2:10][CH2:11][N:12]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:15]=3[CH2:14][CH2:13]2)=[CH:7][C:6]=1[CH3:28])(=O)C.[ClH:29]>>[ClH:29].[ClH:29].[NH2:4][C:5]1[CH:27]=[CH:26][C:8]([O:9][CH2:10][CH2:11][N:12]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:15]=3[CH2:14][CH2:13]2)=[CH:7][C:6]=1[CH3:28]
Reactant: CC(=O)Nc1ccc(OCCN2CCc3ccc([N+](=O)[O-])cc3CC2)cc1C
Agent: Cl
Product: Cc1cc(OCCN2CCc3ccc([N+](=O)[O-])cc3CC2)ccc1N

Procedure:
3-[2-(4-Acetylamino-3-methylphenoxy)ethyl]-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (1 g) was stirred in 6M hydrochloric acid (20 ml) at 90° for 18 hours. After cooling, the precipitate was collected by filtration and recrystallised from ethanol to give the title compound, yield 0.65 g, m.p. 253°-256°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]2[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([CH3:25])([CH3:24])[C:17]=2[CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:31]=[C:32]=O)(=O)=O>>[C:1]([O:5][C:6]([N:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]3[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([CH3:25])([CH3:24])[C:17]=3[CH:26]=2)=[CH:10][CH:11]=[C:12]1[C:32]#[N:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(C)OCC(=O)N2
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OCC(=O)N2

Procedure:
Prepared from tert-butyl-2-(5,5-dimethyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate and chlorosulfonyl isocyanate generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.03 (s, 1H), 7.35 (d, J=1.79 Hz, 1H), 7.31 (d, J=3.8 Hz, 1H), 7.23 (dd, J=1.79, 8.31 Hz, 1H), 7.12 (d, J=8.36 Hz, 1H), 6.44 (d, J=3.81 Hz, 1H), 4.25 (s, 2H), 1.55 (s, 6H), 1.39 (s, 9H).
Reaction SMILES: C(Cl)CCl.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[CH3:26][NH:27][O:28][CH3:29].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl.C1C=CC2N(O)N=NC=2C=1.O>[CH3:29][O:28][N:27]([CH3:26])[C:22]([C@@H:19]1[CH2:18][CH2:17][C@H:16]([NH:15][C:13](=[O:14])[O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:21][CH2:20]1)=[O:24]
Reactant: O=C(N[C@H]1CC[C@@H](C(=O)O)CC1)OCc1ccccc1
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)[C@H]1CC[C@@H](NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (6.9 g, 36 mmol) was added in several portions to a stirring solution of cis-4-benzyloxycarbonylamino-cyclohexanecarboxylic acid (5.0 g, 18 mmol), DMAP (10 mg), HOBt (10 mg) and N,O-dimethylhydroxylamine hydrochloride (3.5 g, 36 mmol) in dichloromethane (100 mL). To this solution was added dropwise triethylamine (10 mL, 72.0 mmol), and the reaction mixture was allowed to stir at room temperature overnight. After completion of stirring, the reaction mixture was poured into water and the aqueous layer was extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give benzyl cis-4-(methoxy(methyl)carbamoyl)cyclohexylcarbamate as a colorless oil (5.48 g, 17.1 mmol, 95%). 1H NMR (CDCl3, 300 MHz) δ 7.38-7.28 (m, 5H), 5.09 (bs, 2H), 5.02 (m, 1H), 3.92-3.82 (m, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 2.81-2.68 (m, 1H), 1.91-1.78 (m, 2H), 1.74-1.6 (m, 6H).
Reaction SMILES: [C:1]1([CH:7]2O[C:8]2([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][NH2:20]>C(O)C>[CH3:10][C:9]1[C:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:20][N:19]=1
Reactant: NN
Reactant: CC(=O)C1(c2ccncc2)OC1c1ccccc1
Solvent: CCO
Product: Cc1n[nH]c(-c2ccccc2)c1-c1ccncc1
Yield: 34.4 %

Procedure:
Using the procedure of Example A-1, step 3, a solution of 4-phenyl-3-(4-pyridyl)-3,4-epoxy-2-butanone (step 3) (250 mg, 1 mmol) in ethanol (15 ml) was treated with anhydrous hydrazine (50 mg, 1.5 mmol) and heated to reflux for 4 hours. The crude product was purified by chromatography (silica gel, 1:1 acetone/hexane). The product was recrystallized from ethyl acetate and hexane to give 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine (81 mg, 35%) as a crystalline solid; m. p. 212-214° C. Anal. Calc'd for C15H13N3 (235.29): C, 76.57; H, 5.57; N, 17.86. Found: C, 76.49; H, 5.42; N, 17.39.
Reaction SMILES: [CH2:1]([C:4]1[CH:44]=[CH:43][CH:42]=[CH:41][C:5]=1[CH2:6][O:7][CH2:8][C:9]1[CH:40]=[C:12]2[N:13]=[C:14]([CH3:39])[C:15]([C@H:28]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:16]([N:17]3[CH2:22][CH2:21][C:20]([O:24][CH2:25][CH:26]=C)([CH3:23])[CH2:19][CH2:18]3)[N:11]2[N:10]=1)[CH:2]=C>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.[Cu]I>[C:35]([O:34][C@@H:28]([C:15]1[C:14]([CH3:39])=[N:13][C:12]2=[CH:40][C:9]3=[N:10][N:11]2[C:16]=1[N:17]1[CH2:22][CH2:21][C:20]([CH3:23])([O:24][CH2:25][CH:26]=[CH:2][CH2:1][C:4]2[CH:44]=[CH:43][CH:42]=[CH:41][C:5]=2[CH2:6][O:7][CH2:8]3)[CH2:19][CH2:18]1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:36])([CH3:38])[CH3:37]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccccc4CC=C)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [Cu]I
Solvent: ClCCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=CCc1ccccc1COC3
Temperature: 70 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
A solution of (S)-ethyl 2-(2-(((2-allylbenzyl)oxy)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.059 g, 0.098 mmol) and Copper(I) iodide (0.019 g, 0.098 mmol) in DCE (70.0 ml) was heated to 70° C. Added to this was Hoveyda-Grubbs Catalyst 2nd generation (0.012 g, 19.6 μmol) and the mixture was stirred at 70° C. for two hours then cooled to room temperature overnight. The mixture was concentrated and purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane; 20 CV) to give the title compound (0.0429 g, 0.074 mmol, 76% yield) as a mixture of cis/trans isomers. LCMS (M+H) calcd for C33H45N4O5: 577.33. found: 577.2.
Reaction SMILES: [C:1]([C:5]1[CH:32]=[C:8]2[N:9]=[C:10]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:11]=[C:12]([N:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)C(=O)OC(C)(C)C)[N:7]2[N:6]=1)(=[O:4])[CH2:2][CH3:3].N([O-])=[O:34].[Na+].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[N:27]1([C:10]2[CH:11]=[C:12]([NH:13][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:7]3[N:6]=[C:5]([C:1](=[O:4])[C:2](=[O:34])[CH3:3])[CH:32]=[C:8]3[N:9]=2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=N[O-]
Reactant: CCC(=O)c1cc2nc(N3CCCC3)cc(N(C(=O)OC(C)(C)C)C3CCOCC3)n2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C(=O)c1cc2nc(N3CCCC3)cc(NC3CCOCC3)n2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of tert-butyl (2-propionyl-5-pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidin-7-yl)tetrahydro-2H-pyran-4-ylcarbamate (500 mg, 1.13 mmol) and sodium nitrite (233 mg, 3.38 mmol) in tetrahydrofuran (10 mL) was added conc. hydrochloric acid solution (36%, 5.0 mL) at 0° C. After being stirred for 20 h at room temperature, the reaction mixture was poured into saturated sodium bicarbonate. The mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (chloroform:ethyl acetate=1:1 to 1:9) to give 1-[5-pyrrolidin-1-yl-7-(tetrahydro-2H-pyran-4-ylamino)-pyrazolo[1,5-a]pyrimidin-2-yl]propane-1,2-dione. MS (APCI): m/z 358 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[O:20][CH3:21])=O)[CH:6]=[CH:7][CH:8]=1.Cl.[F:23][C:24]1[CH:25]=[C:26]([CH:31]([NH2:33])[CH3:32])[CH:27]=[CH:28][C:29]=1[F:30].C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:23][C:24]1[CH:25]=[C:26]([CH:31]([NH:33][CH:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[O:20][CH3:21])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:32])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: COc1cccc(C(=O)c2cc([N+](=O)[O-])ccc2OC)c1
Reactant: CC(N)c1ccc(F)c(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1cccc(C(NC(C)c2ccc(F)c(F)c2)c2cc([N+](=O)[O-])ccc2OC)c1
Yield: 92.8 %

Procedure:
Following a similar procedure to that described in Example (1a), 600 mg of 2-methoxy-5-nitrophenyl 3-methoxyphenyl ketone, 809 mg of 1-(3,4-difluorophenyl)ethylamine hydrochloride, 1.75 ml of triethylamine, 0.28 ml of titanium tetrachloride, 583 mg of sodium cyanoborohydride and 0.18 ml of acetic acid were reacted, to obtain 830 mg of the title compound as a yellow foamy solid.