Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:4]([NH:6][CH2:7][C:8]2[NH:9][C:10](=[O:18])[C:11]3[CH2:17][O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH3:5])[CH2:3][CH2:2]1.[F:19][C:20]1[CH:37]=[CH:36][C:23]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1>>[CH:1]1([C@H:4]([N:6]([CH2:7][C:8]2[NH:9][C:10](=[O:18])[C:11]3[CH2:17][O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[C:33](=[O:34])[CH2:32][N:29]2[CH2:30][CH2:31][CH:26]([C:24](=[O:25])[C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:37][CH:36]=3)[CH2:27][CH2:28]2)[CH3:5])[CH2:3][CH2:2]1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: C[C@@H](NCc1nc2c(c(=O)[nH]1)COCC2)C1CC1
Product: C[C@H](C1CC1)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (9 mg) from (R)-2-((1-cyclopropylethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C27H33FN4O4 496.6. found 497.6 (ESI, M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98-8.21 (m, 2H) 7.40 (t, J=8.84 Hz, 2H) 4.25-4.54 (m, 5H) 3.84 (ddd, J=17.31, 5.56, 5.43 Hz, 3H) 3.70 (d, J=6.06 Hz, 1H) 3.56 (br. s., 2H) 3.23 (br. s., 1H) 2.99-3.20 (m, 2H) 1.99 (br. s., 4H) 1.00-1.29 (m, 4H) 0.68-0.94 (m, 1H) 0.46-0.68 (m, 1H) 0.38 (d, J=5.05 Hz, 1H) 0.24-0.34 (m, 1H) 0.15-0.24 (m, 1H).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:25]2[N:26]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][N:10]2[C:25]2[N:26]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:27]=[C:28]([CH3:30])[CH:29]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CN1CCNCC1
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CCN(C)CC4)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 385b) was reacted with 1-methylpiperazine (CAS Reg. No. 109-01-3) to give the title compound as colorless foam. MS (ESI): m/z=586.1 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]([Si:14]([CH3:38])([CH3:37])[O:15][CH2:16][C@@H:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=1)[C:23]([OH:25])=O)[CH3:18])([CH3:13])[CH3:12].[NH2:39][C:40]1[CH:44]=[CH:43][N:42]([CH3:45])[N:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:10][C:11]([Si:14]([CH3:38])([CH3:37])[O:15][CH2:16][C@@H:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=1)[C:23]([NH:39][C:40]1[CH:44]=[CH:43][N:42]([CH3:45])[N:41]=1)=[O:25])[CH3:18])([CH3:12])[CH3:13]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
DIPEA (4.06 g, 23.4 mmol) was added to a suspension of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid (2.43 g, 5.84 mmol), 3-amino-1-methylpyrazole (0.85 g, 8.76 mmol) and HATU (4.66 g, 12.3 mmol) in DMF (50 mL) and stirred at ambient temperature for 16 hours. The resultant mixture was partially reduced in vacuo, poured onto water (100 mL) and extracted with diethyl ether (2×50 mL). The extracts were washed with water and brine then dried (MgSO4), filtered and reduced to an opaque gum which partially crystallized. The crude product was purified by column chromatography, eluting with 0-100% ethyl acetate in isohexane, to give the title compound as a colourless oil (1.87 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[CH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[C:3]1=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(C=C2Cc3ccccc3C2=O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(C=C2C(=O)c3ccccc3C2Br)cc1

Procedure:
4-(1-Oxoindan-2-ylidenemethyl)benzonitrile (2.18 g, 8.9 mmol) was dissolved in carbon tetrachloride (40 mL). N-bromosuccinimide (1.58 g, 8.9 mmol) and benzoyl peroxide (100 mg) were added in one portion. Reaction mixture was reflux for 9 h, cooled down; precipitate was filtered off and washed with diethyl ether (10×30 mL) for removal of N-hydroxysuccinimide. Precipitate was dried under vacuum, provided pure 15a.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:14][CH:15]=1
Reactant: CCCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCCNC(=O)c1ccc(N)cc1
Yield: 74 %

Procedure:
A solution of 4-nitro-N-propylbenzamide (1.00 g, 4.80 mmoles) in MeOH (25 ml) was hydrogenated in the presence of a 5% palladium-on-charcoal catalyst at about 25° and atmospheric pressure. The catalyst was removed by filtration, and the filtrate was evaporated to dryness in vacuo to give 4-amino-N-propylbenzamide as a gummy residue; yiel 836 mg. This product was dissolved in DMAC (10 ml) containing I (504 mg, 1.50 mmoles), and the whole was stirred at room temperature for 72 hrs. The precipitate of the product was collected by filtration, washed with Et2O and dried in vacuo over P2O5 ; yield 74% (482 mg), mp > 340° (Mel-Temp). This sample was homogeneous on tlc (5:1 CHCl3 --MeOH). Anal. Calcd for C17H20N8O.HBr: C, 47.12; H, 4.88; N, 25.86. Found: C, 47.10; H, 5.18; N, 25.55. Spectral data: λmax, nm (ε × 10-3), 0.1 N HCl, 244 (18.5), 284 (18.3), 337 (10.5), 345 (sh) (9.70); pH 7, 261 (26.9). 279 (24.2), 371 (7.65); 0.1 N NaOH, 261 (27.1), 279 (24.2), 371 (7.73); β 0.96 (t, 3, CH3), 1.50 (m, 2, CH2CH3), 3.17 (m, 2, NHCH2CH2), 4.62 (s, 2, CH2N), 7.23 (m, 4, C6H4), 8.07 (m, 1, NHCO), 8.87 (s, 1, C7 -H), 9.35 (NH). Some of the NH2 peaks were too broad to locate but are observed in the integral.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:8]([N:13]=1)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH3:4].NC1C=NC=CC=1N>>[CH2:1]([C:5]1[NH:13][C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ncccc2[nH]1
Agent: Nc1ccncc1N
Product: CCCCc1nc2cnccc2[nH]1

Procedure:
The title compound was prepared according to the procedure described for the preparation of 2-butylimidazo[4,5-b]pyridine starting with 3,4-diaminopyridine.
Reaction SMILES: [I:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:28][CH:29]1[CH2:31][CH2:30]1>[F-].[K+]>[I:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:28][CH:29]3[CH2:31][CH2:30]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CC1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(I)cccc1-2
Agent: [F-]
Agent: [K+]
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(I)cccc1-2

Procedure:
4.65 g (10 mmol) of tert.butyl (S)-11,12,13,13a-tetrahydro-8-iodo-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c] [1,4]benzodiazepine-1-carboxylate, 24 g (330 mmol) of hydroxymethyl-cyclopropane and 3 g (13 mmol) of tetraethyl crthotitanate are stirred at 115° overnight, the solution is evaporated to dryness and the residue is taken up in chloroform. The solution obtained is stirred for 0.5 hour with 40 ml of a saturated potassium fluoride solution, the resulting emulsion is filtered through siliceous earth, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By crystallization from ethyl acetate and hexane there is obtained cyclopropylmethyl (S)-11,12,13,13a-tetrahydro-8-iodo-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 164°-165°.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][C:17]1([O:50][CH3:51])[C:48](=[O:49])[N:19]2[C:20]([C:32]([O:34][CH:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])=[C:21]([CH2:24][S:25][C:26]3[N:30]([CH3:31])[N:29]=[N:28][N:27]=3)[CH2:22][S:23][C@H:18]12.[CH3:52][O:53][N:54]=[C:55]([C:59]1[N:60]=[N:61][S:62][CH:63]=1)[C:56](O)=[O:57]>O1CCCC1>[CH3:52][O:53][N:54]=[C:55]([C:59]1[N:60]=[N:61][S:62][CH:63]=1)[C:56]([NH:16][C:17]1([O:50][CH3:51])[C:48](=[O:49])[N:19]2[C:20]([C:32]([O:34][CH:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:33])=[C:21]([CH2:24][S:25][C:26]3[N:30]([CH3:31])[N:29]=[N:28][N:27]=3)[CH2:22][S:23][C@H:18]12)=[O:57]
Reactant: CON=C(C(=O)O)c1csnn1
Reactant: COC1(N)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nnnn3C)CS[C@@H]21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1(OC)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nnnn3C)CS[C@@H]21)c1csnn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.1 %

Procedure:
Dicyclohexylcarbodiimide (0.99 g.) was added at ambient temperature to a solution of diphenylmethyl 7-amino-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (2.1 g.) in dry tetrahydrofuran (20 ml.) and then 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer) (0.9 g) was added thereto at ambient temperature to give white precipitates. After stirring for 2 days at ambient temperature, the precipitates were filtered off and the filtrate was concentrated under reduced pressure to give brown oil. The oil as subjected to column chromatography on silica gel, eluted with a mixture of chloroform and ethyl acetate and the eluate was concentrated under reduced pressure to give diphenylmethyl 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (1.78 g.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([C:14](=[C:18](SC)[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:15]([NH2:17])=[O:16])#[N:13]>>[NH2:13][C:12]1[N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[N:11]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:14]=1[C:15]([NH2:17])=[O:16]
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Product: Cc1ccc(-c2nn(-c3ccc([N+](=O)[O-])cc3)c(N)c2C(N)=O)cc1

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)acetamide (464 mg, 2.0 mmol) and 4-nitrophenylhydrazine (337 mg, 2.2 mmol) following the procedure used for the compound of Example 12. The crude product was purified by column chromatography (SiO2, 2% acetic acid, 5% methanol in CH2Cl2) to give the title compound as a yellow solid (14 mg) m.p. 299-3000. δH (d6DMSO) 8.42 (2H, d, J 8.6 Hz), 8.21 (2H, d, J 8.7 Hz), 7.80 (2H, d, J 8.0 Hz) and 7.75 (2H, d, J 7.9 Hz).
Reaction SMILES: CN1C[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2O1.C([O-])(=O)C.[NH4+:17].C[N:19](C)[C:20](=O)[CH3:21]>>[CH3:21][C:20]1[NH:17][C:6](=[O:8])[C:5]2[C:4](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:19]=1
Reactant: [NH4+]
Reactant: CC(=O)N(C)C
Reactant: CN1CC(=O)c2ccccc2O1
Agent: CC(=O)[O-]
Product: Cc1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C

Procedure:
2-Methylbenzoxazin-4-one (0.24 mole) and ammonium acetate (0.30 mole) is given in 50 ml of N,N-dimethylacetamide and then heated to 160° under a nitrogen blanket for 2 h. After cooling to rt, the white solid is collected by filtration and washed with diethyl ether. Air drying give 2-methyl-quinazolin-4-one.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH2:20])[N:3]=1.[H-].[Na+].I[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[O:13][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])=[C:4]([NH2:20])[N:3]=1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CCCCCCCCCCCCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.4 %

Procedure:
2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) and sodium hydride (7 g) in DMF (1 L) were heated to boiling for 2 hr. Iodooctadecane (100 g) was added at 150° C. and the reaction mixture allowed to cool to RT. The reaction mixture was stirred for 11 days at RT. The solyent was evaporated and the residue purified by silica gel chromatography. The product was eluted with 5% MeOH/CH2Cl2. The appropriate fractions were evaporated to yield the product (11 g). 1H NMR (DMSO-d6) δ 0.84 (t, 3, CH2), 1.22 (m, 32, O--CH2 --CH2 --(CH2)16), 1.86 (m, 2, O--CH2CH2), 3.25 (m, 2, O--CH2), 3.93 (d, 1, 4'H), 4.25 (m, 1, 3'H), 4.38 (t, 1, 2' H), 5.08 (d, 1, 3'-OH), 5.48 (t, 1, 5'-OH, 5.75 (s, 2, 6-NH2), 5.84 (d, 1, 1'-H), 6.8 (s, 2, 2-NH2), and 7.95 (s, 1, 8-H).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][N:12]=[C:13]=[S:14]>C(O)C>[SH:14][C:13]1[N:12]([CH3:11])[C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: CN=C=S
Solvent: CCO
Product: Cn1c(S)nc2ccccc2c1=O
Yield: 41.2 %

Procedure:
A mixture of anthranilic acid (22.5 g), methyl isothiocyanate (12.5 g) and ethanol (200 ml) was refluxed for three hours, cooled and the precipitate filtered off and washed with water. Recrystallisation from ethanol gave 2-mercapto-3-methyl-3,4-dihydroquinazolin-4-one (13.0 g, m.p. 265°-266°). A mixture of this material (5.76 g) hydrazine hydrate (20 ml) and ethanol (30 ml) was refluxed for 30 minutes, then cooled. The precipitate was filtered off, washed with water and dried to give the 2-hydrazinoquinazolinone (3.16 g, m.p. 220°-223°). Recrystallisation from ethanol gave material m.p. 223°. A stirred solution of the crude product (1.9 g) in a mixture of hydrochloric acid (20 ml, 2N) and acetic acid (10 ml) was treated dropwise at 0°-5° with a solution of sodium nitrite (0.69 g) in water (5 ml). The mixture was allowed to attain room temperature and, after one hour, was filtered and the precipitate washed with water and dried to give the title compound (1.04 g., m.p. 164°-167°). Recrystallisation from ethanol gave material m.p. 167°.
Reaction SMILES: [O:1]1CC[N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17]CNCC2)=[CH:8]C=1.N[C@H:19]([C:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])C)=[O:25])=[O:23])[CH2:20][OH:21].[C:31]1([C:37]2[O:41][C:40]([C:42]3[CH:47]=[CH:46][C:45]([N:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)=[CH:44][CH:43]=3)=[N:39]N=2)C=CC=CC=1>>[C:24]([OH:26])(=[O:25])/[CH:22]=[CH:19]/[C:20]([OH:21])=[O:1].[NH2:3][CH2:2][CH2:6][C:11]1[C:10]2[C:9](=[CH:8][CH:30]=[C:27]([O:26][CH2:24][C:22]([N:51]3[CH2:50][CH2:49][N:48]([C:45]4[CH:44]=[CH:43][C:42]([C:40]5[O:41][CH2:37][CH2:31][N:39]=5)=[CH:47][CH:46]=4)[CH2:53][CH2:52]3)=[O:23])[CH:29]=2)[NH:12][CH:17]=1
Reactant: CC(C)(C)OC(=O)C(=O)[C@@H](N)CO
Reactant: c1ccc(-c2nnc(-c3ccc(N4CCNCC4)cc3)o2)cc1
Reactant: c1cc(N2CCNCC2)ccc1C1=NCCO1
Product: NCCc1c[nH]c2ccc(OCC(=O)N3CCN(c4ccc(C5=NCCO5)cc4)CC3)cc12
Product: O=C(O)/C=C/C(=O)O

Procedure:
Compound 5 is prepared from intermediate 5B (576 mg; 2.48 mmol) and SerBOC acid (694 mg; 2.07 mmol) according to the procedure described for the preparation of Example 1 from 1C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]([OH:18])=O)[N:11]=2)=[O:8])=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])=[CH:22][C:21]=1[F:33]>>[F:33][C:21]1[CH:22]=[C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])[CH:24]=[CH:25][C:20]=1[NH:19][C:16]([CH2:15][N:12]1[CH:13]=[CH:14][C:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])=[N:11]1)=[O:18]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: O=C(O)Cn1ccc(NC(=O)c2ccc(Cl)s2)n1
Product: O=C(Cn1ccc(NC(=O)c2ccc(Cl)s2)n1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
57.4 According to general method B, {3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrazol-1-yl}-acetic acid was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) to give 5-chloro-thiophene-2-carboxylic acid (1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-1H-pyrazol-3-yl)-amide. White solid. MS 472.4 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[N:11]([C@H:22]([C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)[CH3:23])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42](B(O)O)[CH:41]=[CH:40]2.C(N(CC)CC)C>C(COC)OC>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:13]=[C:12]([C:42]3[CH:41]=[CH:40][C:39]4[C:44](=[CH:45][CH:46]=[C:37]([O:36][CH3:35])[CH:38]=4)[CH:43]=3)[N:11]([C@H:22]([C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)[CH3:23])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Reactant: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2OS(=O)(=O)C(F)(F)F)cc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc3cc(OC)ccc3c2)cc1
Temperature: 100 °C

Procedure:
Ethyl 4-[(1S)-1-(3-(3,5-dichlorophenyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoate (2.15 g, 4.0 mmol), 6-methoxy-2-naphthylboronic acid (1.18 g, 6.0 mmol), and triethylamine (1.2 ml, 8.0 mmol) were dissolved in dimethoxyethane (40 ml) in a thick-wall tube. The reaction mixture was purged with N2 for 15 min. Catalyst Pd(PPh3)4 (350 mg, 8%) was added, and the test tube was heated in a microwave reactor to 100° C. for 15 min. The solvent was removed under reduced pressure, and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was washed with 0.5 NH4Cl2×, brine 2×, dried over Na2SO4, and filtered through a Celite pad. The crude product was purified by column chromatography (SiO2, 10-15% ethyl acetate in hexanes) to give ethyl 4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoate as a dry film. NMR (500 MHz, CDCl3) δ: 1.38 (t, J=7.1 Hz, 3H); 1.96 (d, J=7.0 Hz, 3H); 3.95 (s, 3H); 4.37 (q, J=7.1 Hz, 2H); 5.59 (q, J=7.0 Hz, 1H); 6.65 (s, 1H); 7.17 (d, J=2.6 Hz, 1H); 7.20 (dd, J=2.6, 8.9 Hz, 1H); 7.28 (d, J=8.4 Hz, 2H); 7.29 (dd, J=1.8, 8.5 Hz, 1H); 7.30 (t, J=1.9 Hz, 1H); 7.63 (d, J=1.8 Hz, 1H); 7.67 (d, J=8.9 Hz, 1H); 7.76 (d, J=8.5 Hz, 1H); 7.80 (d, J=1.9 Hz, 2H); 7.99 (d, J=8.4 Hz, 2H); MS C31H26Cl2N2O3 Cald: 544.13; Obsd: 545.15.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22](I)[S:23][C:16]=34)=[C:10]([F:25])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[C:26]([N:33]1[CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34]1)([O:28][C:29]([CH3:32])(C)C)=[O:27].C([O-])(O)=O.[Na+].CO[CH2:55][CH2:56]OC.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:36]5[CH2:35][CH2:34][N:33]([C:26]([O:28][CH2:29][CH2:32][CH2:55][CH3:56])=[O:27])[CH2:38][CH:37]=5)[S:23][C:16]=34)=[C:10]([F:25])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: COCCOC
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1)NC1CC1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCOC(=O)N1CC=C(c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
Iodide 269 (2 g, 4.26 mmol), 1-N-Boc-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (1.85 g, 5.96 mmol), NaHCO3 (1.1 g, 12.8 mmol) and tetrakis(triphenylphosphine)palladium (0.49 g, 0.43 mmol) were suspended in a mixture of DME/water (80 mL/16 mL). The mixture was degassed with an Ar flow, heated at 80° C. and stirred for 16 hours. The mixture was then cooled and filtered through a pad of Celite and washed with EtOAc. The filtrate was diluted with water and extracted with EtOAc. The extract was washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (eluent 3% MeOH in DCM) to afford title compound 270 (1.7 g, 78% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.73 (s, 1H), 8.45 (d, J=5.4 Hz, 1H), 7.72 (dd, J=13.5, 2.4 Hz, 1H), 7.55 (s, 1H), 7.35 (t, J=9.0 Hz, 1H), 7.24-7.16 (m, 1H), 6.60 (br, 1H), 6.57 (d, =5.4 Hz, 1H), 6.40 (br, 1H), 4.15-4.00 (m, 2H), 3.63-3.54 (m, 2H), 2.70-2.40 (m, 3H), 1.44 (s, 9H), 0.70-0.60 (m, 2H), 0.48-0.35 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11].O.CC(=O)OCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[N:12]([CH2:13][CH3:14])[CH2:10][CH3:11]
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: CCNCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN(CC)c1cc(Cl)nnc1Cl
Reaction time: 72 h

Procedure:
3,4,6-Trichloropyridazine (2 g) and diethylamine (2.4 ml) were initially charged in toluene (10 ml) and left to stand at RT for 3 days. Then the mixture was admixed with water and EA, and the EA phase was removed. The EA phase was washed three times with water, dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (70 g cartridge, n-heptane/EA gradient 0-50% within 60 min). 1.1 g of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1F.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[F:17]
Reactant: Nc1ccccc1F
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1F
Temperature: 140 °C
Yield: 51.7 %

Procedure:
4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4 (1.50 g, 6.46 mmol) is suspended in xylenes (7.5 mL) and 2-fluoro-phenylamine (6.24 mL, 64.6 mmol) is added. The reaction mixture is stirred at 140° C. under N2. After stirring for 6 days, the reaction is complete. The reaction mixture is cooled to room temperature and diluted with methylene chloride and filtered through a silica gel plug eluting with methylene chloride (1L) to give an orange filtrate. The filtrate is concentrated to dryness and then triturated with diethyl ether to yield a bright yellow solid. The trituration is repeated. The yellow solid is collected to yield 1.08 g (52%) of the pure desired product. MS APCI (−) m/z 322 (M−1) detected.