Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:9][CH2:10][O:11][CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O.[NH2:30]/[C:31](/[CH3:37])=[CH:32]\[C:33]([O:35][CH3:36])=[O:34].C(O)(=O)C>C(O)C>[ClH:21].[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]1[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([CH3:37])[NH:30][C:13]([CH2:12][O:11][CH2:10][CH2:9][N:3]2[C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=[C:2]2[CH3:1])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)COCCn1c(C)nc(C)c1C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1=C(COCCn2c(C)nc(C)c2C)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Product: Cl
Yield: 19.6 %

Procedure:
Ethyl 4-[2-(2,4,5-trimethyl-1-imidazolyl)ethoxy]acetoacetate (6.4 g), 2-chlorobenzaldehyde (3.2 g), methyl 3-aminocrotonate (2.6 g) and acetic acid (1 ml) in ethanol (15 ml) were mixed and heated under reflux for 4.5 hours. The cooled reaction mixture was then evaporated to dryness and the residue partitioned between 2N hydrochloric acid (100 ml) and toluene (50 ml). The acid layer was separated, extracted with methylene chloride (3×20 ml) and the extracts were washed with saturated aqueous sodium carbonate (30 ml), dried (Na 2CO3), filtered, and evaporated. The residue in a little toluene was chromatographed on silica (t.l.c. grade, 4 g), eluting with methylene chloride plus 30% v/v petrol. Appropriate fractions were combined, evaporated to dryness and redissolved in ethyl acetate. Addition of ethereal hydrogen chloride precipitated the hydrochloride salt, which was recrystallised from ethyl acetate to give the title compound (1.2 g), m.p. 167°-8° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[I:5][C:6]1[C:7]([OH:32])=[C:8]([O:30][CH3:31])[CH:9]=[C:10]([C:12](=[O:29])[CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[O:16])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[I:5][C:6]1[C:7]([O:32][CH2:1][CH2:2][CH3:3])=[C:8]([O:30][CH3:31])[CH:9]=[C:10]([C:12](=[O:29])[CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[O:16])[CH:11]=1
Reactant: CCCBr
Reactant: COc1cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc(I)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(I)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
n-Propyl bromide (29.2 mL, 0.32 mole) was added to a solution of 1-(5-iodo-4-hydroxy-3-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)butan-1,4-dione (100 g, 0.2 mole) in DMF (400 mL) containing potassium carbonate (96 g, 0.35 mole). The mixture was stirred at 70° C. for 2 hours during which time starting material disappeared. The mixture was cooled, filtered, and extracted with ethyl acetate, and the extract was washed with water and brine, dried over anhydrous MgSO4, and evaporated in vacuo to afford the crude product. Crystallization from ether/hexane gave the title compound as white crystals, m.p. 120°-121° C. NMR (CDCl3) δ 1.08 (t, J=7.5 Hz, CH2CH2CH3) 1.87 (m, CH2CH2CH3), 2.41 (t, J=4 Hz, COCH2CH2CO), 3.90 and 3.94 (s, u Ar OCH3), 4.04 (t, J=8 Hz, OCH2CH2CH3), 7.28 (s, trimethoxyphenyl H-2, H-6), 7.51 (d, J=1.5 Hz, Iodophenyl 'H-6), 8.06 (d, J=1.5 Hz, Iodophenyl 'H-2).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:33][OH:34])[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([Cl:32])[CH:23]=1>>[Cl:32][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:33]=2)[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].[Cl:32][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:34][N:33]=2)[CH:31]=[CH:30][C:25]=1[C:26]([OH:28])=[O:27]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1Cl
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3ccc(C(=O)O)c(Cl)c3)no2)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3ccc(C(=O)OC)c(Cl)c3)no2)ccc1-c1ccccc1C

Procedure:
Methyl 2-chloro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoate was prepared following the general procedure 7 starting from Intermediate 3 and Intermediate 34. It was then hydrolysed following procedure 9, affording the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 13.77 (br s, 1H), 8.34 (d, J=1.5 Hz, 1H), 8.20-8.15 (m, 3H), 8.02 (d, J=7.9 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.37-7.27 (m, 3H), 7.15 (d, J=7.2 Hz, 1H), 4.25-4.14 (m, 2H), 3.25 (s, 3H), 2.04 (s, 3H). LC/MS (Method B): 433.2 (M−H)−, 435.2 (M+H)+. HPLC (Method A) Rt 5.35 min (Purity: 98.5%). CHN analysis: [C24H19N2O4Cl] Calculated: C, 66.29%; H, 4.40%; N, 6.44%; Cl, 8.15%. Found: C, 66.04%; H, 4.52%; N, 6.49%; Cl, 8.23%.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:4]=[CH:5][N:6]=1.[CH2:23]([Br:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(O)(C)C>[Br-:31].[CH2:7]([N:3]1[CH:4]=[CH:5][N:6]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:2]1[CH3:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCn1ccnc1C
Reactant: CCCCCCCCBr
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCN1C=CN(CCCCCCCC)C1C
Product: [Br-]

Procedure:
0.5 mole of 2-methyl-1-n-hexadecylimidazole is dissolved in 250 ml of i-propanol and reacted with 0.6 mole of n-octyl bromide. This is followed by a 10-hour boiling with reflux. Then the i-propanol is distilled off, together with the unreacted n-octyl bromide, and the remaining residue is washed with ether.
Reaction SMILES: CN([CH:4]=[O:5])C.[C:6](Cl)(=[O:10])[C:7](Cl)=O.C[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1>C(Cl)(Cl)Cl>[OH:5]/[CH:4]=[C:7](\[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1)/[CH:6]=[O:10]
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSc1nccc(C)n1
Solvent: ClC(Cl)Cl
Product: CSc1nccc(/C(C=O)=C\O)n1
Temperature: 30 °C
Reaction time: 1 h
Yield: 244.1 %

Procedure:
To a solution of DMF (114.9 g, 1.57 mol) in CHCl3 (800 mL) was added dropwise oxalyl chloride (190.3 g, 1.50 mol) at 0° C. After the addition, the resulting mixture was warmed at 30° C. and stirred for 1 h. The mixture was allowed to cool to 0° C. and 4-methyl-2-(methylthio)pyrimidine (2) (100 g, 0.714 mol) was added to the mixture. The resulting mixture was warmed to 40° C. and stirred for 16 h. The reaction mixture was cooled to room temperature and filtered. The cake was washed with CHCl3 (150 mL×3) and dried in vacuum to give (E)-3-hydroxy-2-(2-(methylthio)pyrimidin-4-yl)acrylaldehyde (3) (342.0 g, 100%) as a yellow solid.
Reaction SMILES: CN1C(C)=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=N1.Br[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:28]([Cl:38])[CH:27]=2)[N:25]=1)=[O:19].[H-].[Na+]>CN(C=O)C>[Cl:38][C:28]1[CH:27]=[C:26]([C:24]2[N:25]=[C:21]([NH:20][C:18](=[O:19])[CH2:17][N:25]3[C:9]4[C:8](=[O:12])[N:7]([CH3:13])[C:6](=[O:14])[N:5]([CH3:15])[C:4]=4[CH:23]=[C:24]3[CH3:26])[S:22][CH:23]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Reactant: CC(C)(C)COc1ccc(-c2csc(NC(=O)CBr)n2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c(=O)n(C)c(=O)n2C)n1CC(=O)Nc1nc(-c2ccc(OCC(C)(C)C)c(Cl)c2)cs1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 2 (50 mg, 0.258 mmol) with 2-bromo-N-{4-[3-chloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}acetamide (129 mg, 0.308 mmol) in the presence of NaH (15 mg, 0.375 mmol) in dry DMF (5.0 mL) to give 85 mg of the product as a white solid; 1H-NMR (δ ppm, DMSO-d6, 300 MHz): 1.04 (s, 9H), 2.27 (s, 3H), 3.17 (s, 3H), 3.36 (s, 3H), 3.76 (s, 2H), 5.32 (s, 2H), 6.07 (s, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.62 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.96 (s, 1H), 12.69 (br s, 1H, exchangeable with D2O); APCI-MS (m/z) 530.26 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24](N)[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(NC1SC=C(/C(=N/OC(C(OC(C)(C)C)=O)(C)C)/C(O)=O)N=1)=O)(C)(C)C.CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O.Cl>ClCCl.O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[CH2:24][C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SC(Sc2c[nH]nn2)C(c2ccccc2)(c2ccccc2)c2ccccc2)CS[C@@H]2CC(=O)N12
Temperature: -30 °C
Reaction time: 0.83 h
Yield: 109.2 %

Procedure:
To a solution of 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester (800 mg : 1.06 mMol.) and (Z)-2-(2-t-butoxycarbonylaminothiazol -4-yl)-2-(1 t-butoxycarbonyl-1methylethoxyimino)acetic acid (479 mg : 1.12 mMol.) in dichloromethane (8 ml) cooling at -30° C., are added N-methylmorpholine (0.27 ml) (2.46 mMol.) and phenyl dichlorophosphate (0.19 ml : 1.27 mMol.), and the mixture is stirred at -30° C. for 50 minutes. The reaction mixture is mixed with 10% hydrochloric acid (1 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (toluene : ethyl acetate=10:1 to 5:1) to give 7β-(Z)-2-(2-t-butoxycarbonylaminothiazol-4 yl)-2-(1-t-butoxycarbonyl -1-methylethoxyimino)acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4carboxylic acid diphenylmethyl ester (855 mg) as yellow foam. Yield : 69%.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][NH:8][C:9]([CH2:11][N:12]([S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)(=[O:35])=[O:34])[C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[NH:26])=[CH:23][CH:22]=3)=[N:19][C:15]=2[CH:14]=1)=[O:10])=[O:6])[CH3:3].Cl[C:47]([O:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)=[O:48]>O1CCCC1.O>[CH2:2]([O:4][C:5]([CH2:7][NH:8][C:9]([CH2:11][N:12]([S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)(=[O:34])=[O:35])[C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:27])=[N:26][C:47]([O:49][CH:50]4[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]4)=[O:48])=[CH:28][CH:29]=3)=[N:19][C:15]=2[CH:14]=1)=[O:10])=[O:6])[CH3:3]
Reactant: CCOC(=O)CNC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: O=C(Cl)OC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CNC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(N)=NC(=O)OC3CCCCC3)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 97 from 4-[(5-(N-ethoxycarbonylmethylaminocarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and cyclohexyl chloroformate in tetrahydrofuran/water.
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH2:33][CH2:34][NH2:35].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH2:33][CH2:34][NH:35][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH3:21])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=1)[CH3:16])=[O:19]
Reactant: COc1ccc(OC)c(CCN)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: COc1ccc(OC)c(CCNC(=O)C(C)(C)Oc2ccc(C[C@H](OC)C(=O)O)cc2)c1

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 2-(2,5-dimethoxy-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H31NO7 [M−H]−: 445.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:21](=[O:24])(=[O:23])[NH2:22])[C:12]=1[NH:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([OH:9])=[O:8])([O-])=O.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:21](=[O:24])(=[O:23])[NH2:22])[C:12]=1[NH:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccccc1Nc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Cc1ccccc1Nc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
By substituting 3-nitro-5-sulphamyl-4(o-toluidino)-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:9][OH:10])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)O1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:26]3[CH:27]=[N:28][NH:29][CH:30]=3)=[CH:3][CH:4]=2)[CH2:9][OH:10])=[CH:12][CH:13]=1
Reactant: OCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: OCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
2,2-Bis-(4-chloro-phenyl)ethanol was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-A2) Rt 2.72 [M+H]+ 299.00.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11].C(O)(=O)C.[Br:17]Br>ClCCl>[Br:17][C:8]1[C:9]([OH:10])=[C:4]([C:5]([OH:11])=[CH:6][CH:7]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1c(O)cccc1O
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1c(O)ccc(Br)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a mixture of methyl-2,6-dihydroxybenzoate (1.68 g, 10.0 mmol) in dichloromethane (10 mL) was added acetic acid (1 mL), followed by drop-wise addition of bromine (515 μL, 10.0 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at ambient temperature for 1 hour, concentrated under reduced pressure, co-evaporated with ethyl acetate (2×). The resulting solid was triturated with hexane/ethyl acetate and re-crystallized from hot hexane/ethyl acetate to provide the titled compound (1.45 g). MS ESI(−,) m/e 244, 246 (M−H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 10.19 (s, 1H), 7.46 (d, 1H), 6.41 (d, 1H), 3.84 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:12][NH:13][O:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:13]([O:14][CH3:15])[CH3:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-bromophenyl)acetic acid (4.4 g, 20.56 mmol) in N,N-dimethylformamide (125 ml) was successively added N,O-dimethylhydroxyamine (4.5 g, 46.26 mmol), triethylamine (10 ml), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (8.9 g, 46.26 mmol) and 1-hydroxybenzotriazole (6.24 g, 46.26 mmol). The reaction mixture was stirred at room temperature overnight, and partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated. The residue was purified by flash chromatography on silica gel (50% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 258 (M+H)+.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[OH:30][C:31]1([C:38]2[CH:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1>>[OH:30][C:31]1([C:38]2[CH:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[CH2:32][CH2:33][CH:34]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:35][CH2:36]1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4noc5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexanone, using the procedure described in Step E of Example 1.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]([C:14]1[C:15]([NH2:23])=[N:16][N:17]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=12)([CH3:13])[CH3:12]>C(Cl)Cl.N1C=CC=CC=1>[CH:1]1([CH2:6][CH2:7][C:8]([NH:23][C:15]2[C:14]([CH:11]([CH3:13])[CH3:12])=[C:18]3[N:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1c(N)nn2cccnc12
Reactant: O=C(Cl)CCC1CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1c(NC(=O)CCC2CCCC2)nn2cccnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-cyclopentylpropionyl chloride (0.048 mL, 0.31 mmol) in CH2Cl2 (0.2 mL) was added to a stirring solution of the product from Example 112C (35 mg, 0.20 mmol) in pyridine (1.2 mL) in a 4 mL vial. The yellow solution was stirred at room temperature for 3 hours, and then concentrated under vacuum. The residue was dissolved in CH2Cl2 (3 mL) and concentrated under vacuum (repeated three times) to remove excess pyridine. The off-white solid residue was crystallized from 60% ethanol-water (8 mL) to provide the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 1.10-1.27 (m, 2H) 1.41 (d, J=7.1 Hz, 6H) 1.48-1.98 (m, 9H) 2.47 (t, J=7.6 Hz, 2H) 3.01-3.22 (m, 1H) 6.91 (dd, J=7.1, 4.1 Hz, 1H) 8.42 (dd, J=4.1, 2.0 Hz, 1H) 8.70 (dd, J=7.1, 1.7 Hz, 1H); MS (ESI) m/z 301 (M+H)+; Anal. Calculated for C17H24N4O: C, 67.97; H, 8.05; N, 18.65. Found: C, 68.03; H, 8.03; N, 18.60.
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][C:6]2[C:7]([N:14]=1)=[N:8][C:9](=O)[C:10](=O)[N:11]=2)=C.[C:15](O)(C)(C)C.I([O-])(=O)(=O)=O.[Na+].[OH2:26]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[N:8]1[CH:9]=[C:10]([CH:15]=[O:26])[N:11]=[C:6]2[CH:7]=[N:14][CH:3]=[CH:4][C:5]=12
Reactant: O
Reactant: CC(C)(C)O
Reactant: C=Cc1ccc2c(n1)=NC(=O)C(=O)N=2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=Cc1cnc2ccncc2n1
Reaction time: 3 h
Yield: 40 %

Procedure:
A suspension of the vinylpyridopyrazinedione above (0.14 g, 0.74 mMol) in dioxane (6 mL) and water (3 mL) was treated with 2.5% osmium tetroxide solution in t-butanol (0.38 mL, 37 μMol) and sodium periodate (0.48 g, 2.2 nMol). After stirring for 3 h the reaction mixture was diluted with water (20 mL) and the product was purified by reversed phase HPLC (method F) using nonbuffered mobile phase. The pure product was isolated as a solid (56 mg, 40%). 1H-NMR (DMSO-d6), δ=12.80 (bs, 1H), 12.20 (bs, 1H), 10.01 (s, 1H), 8.62 (d, 1H, J=1.8 Hz), 7.78 (d, 1H, J=1.8 Hz).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CN=C1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].O>CN(C=O)C.C(OCC)C>[Si:10]([O:4][CH2:3][CH2:2][Br:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCBr
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
Following a published procedure,24 2-bromoethanol (10.0 mL, 141 mmol) was added to a mixture of imidazole (12.5 g, 184 mmol) and tert-butyldimethylsilyl chloride (21.1 g, 140 mmol) in anhydrous DMF (25 mL). The reaction mixture was stirred at room temperature for 12 h. Water and diethyl ether were added. The phases were separated. The aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water and brine. The solution was dried (Na2SO4). Evaporation of the solvent followed by bulb-to-bulb distillation (40-45° C./0.05 mmHg) yielded a colorless liquid (32.5 g, 97%): IR (film, νmax cm−1) 2951, 2859, 1471; 1H NMR δ 0.07 (s, 6H), 0.89 (s, 9H), 3.36-3.41 (m, 2H), 3.85-3.90 (m, 2H); 13C NMR δ −5.06, 18.49, 26.04, 33.45, 63.74; EI-MS 137/139, 181/183, calcd 238.0389 (C8H19BrOSi); Anal. Calcd C, 40.17; H, 8.01. Found: C, 40.55; H, 8.25.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1Cl.[CH3:20][NH:21][NH2:22].O>CO>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1[N:21]([CH3:20])[NH2:22]
Reactant: CNN
Reactant: O=c1c(Cl)c(Cl)cnn1-c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CO
Product: CN(N)c1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1Cl
Temperature: 45 °C

Procedure:
To a solution consisting of 15.5 grams of 4,5-dichloro-2-(3-trifluoromethylphenyl)-pyridazine-3(2H)-one in 120 grams of methanol is added 9.2 grams methylhydrazine. The reaction mixture is heated to 45° C for three hours, cooled and poured onto 250 grams of water. The resulting precipitate is separated by filtration, washed with water and dried. The solid is crystallized from benzene to yield 4-chloro-2-(3-trifluoromethylphenyl)-5-(1-methylhydrazino)-pyridazin-3(2H)-one (m.p. 140° to 141° C, with decomposition).
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:16])[N:7]([CH2:8][CH2:9][OH:10])[C:6](=[O:11])[C:5]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:4]12.Cl[CH2:18][C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][C:19]([CH2:18][O:10][CH2:9][CH2:8][N:7]1[C:6](=[O:11])[C:5]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:4]2[C:3]1=[O:16])=[O:26])[CH3:25]
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a slurry of sodium hydride (57% dispersion in oil, 66.1 g; 1.57M), in tetrahydrofuran (500 ml) cooled to 0° under nitrogen was added B 2-phthalimidoethanol (150 g; 0.785M) followed by ethyl 4-chloroacetoacetate (129 g; 0.785M) in tetrahydrofuran (250 ml) over 1 hour. The mixture was stirred at room temperature overnight then poured into a mixture of 1M hydrochloric acid (800 ml) and ethyl acetate (750 ml). The organic phase was separated and the solvent was evaporated at reduced pressure. The residue separated into two layers and the upper layer of mineral oil was removed to leave the title compound (243 g) as a crude product which was used without further purification.