Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([CH:21]3[C:25](=[O:26])[CH2:24][CH2:23][C:22]3=[O:27])[N:16]=2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[C:22](=[O:27])[CH2:23][CH2:24][C:25]=3[O:26][CH3:5])[N:16]=2)=[CH:11][CH:10]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(-c2ccc(Cl)cc2)nn1C1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC1=C(n2nc(-c3ccc(Cl)cc3)cc2C)C(=O)CC1
Temperature: 60 °C
Yield: 64.3 %

Procedure:
Neat dimethyl sulfate (0.12 ml, 1.3 mmol) was added at room temperature to a vigorously stirred suspension of 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-cyclopentane-1,3-dione (374 mg, 1.3 mmol) and potassium carbonate (180 mg, 1.3 mmol) in acetone (10 ml). The mixture was then heated to 60° C. for 3 h with continued stirring, then cooled and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (30 ml) and 1M sodium hydroxide solution (20 ml), the layers were separated, and the aqueous phase was further extracted with ethyl acetate (2×20 ml). The combined organics were washed with brine (20 ml), dried over magnesium sulfate and concentrated. The crude product was then purified by flash chromatography (using 20% to 100% EtOAc in DCM) to give 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-3-methoxy-cyclopent-2-enone (253.2 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[C:6]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:15]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[C:26]1(=O)[CH:31]=[CH:30][C:29](=[O:32])[CH:28]=[CH:27]1>CC#N>[CH2:1]([O:3][C:4]([C:5]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=2)[N:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[CH:16][CH:15]=2)[C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:25])[CH3:2]
Reactant: O=C1C=CC(=O)C=C1
Reactant: CCOC(=O)C=C(CC(=O)OCC)Nc1ccc(N(CC)CC)cc1
Solvent: CC#N
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N(CC)CC)cc1
Temperature: 4 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(4-diethylaminophenylamino)pent-2-enedioic acid diethyl ester (11.9 g, 34.2 mmol, see step (a) above), 1,4-benzoquinone (4.62 g, 42.8 mmol) and anhydrous MeCN (70 mL) was stirred at 70° C. for 2 d and at 4° C. for 1 d. The solid was collected and recrystallized from MeCN. Yield 4.5 g (30%).
Reaction SMILES: [NH2:1][C:2]1([CH2:18][OH:19])[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:17])=[CH:6][CH:7]=2.Br[CH2:21][C:22]#[N:23].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[NH2:1][C:2]1([CH2:18][O:19][CH2:21][C:22]#[N:23])[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:17])=[CH:6][CH:7]=2
Reactant: NC1(CO)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Reactant: N#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCOCC1(N)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Reaction time: 0.08 h

Procedure:
A 4-neck 3000-mL RBF with a mechanical stirrer was charged with (5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methanol (29.43 g, 86 mmol), tetrabutylammonium hydrogen sulfate (5.85 g, 17.23 mmol), THF (431 mL), and bromoacetonitrile (30.0 mL, 431 mmol) to give a clear, brown solution. The resulting solution was stirred vigorously for 5 min, then a 2N aq. solution of NaOH (431 mL, 862 mmol) was added in one portion. The mixture was stirred overnight and concentrated under vacuum. The remaining material was partitioned between EtOAc (500 mL) and water (500 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×250 mL). The combined organic layers were washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was taken up in DCM and filtered through a short pad of silica gel. The filtrate was concentrated and purified by silica gel chromatography (0.5% MeOH/DCM) to provide 2-((5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)acetonitrile.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C:5](=O)[CH2:4]1)[CH3:2].Cl.[CH:22]1([CH2:25][O:26][NH2:27])[CH2:24][CH2:23]1>CCO>[CH:22]1([CH2:25][O:26][N:27]=[C:5]2[CH2:6][C@H:7]([C:8]3[N:12]4[C:13]5[CH:19]=[CH:18][NH:17][C:14]=5[N:15]=[CH:16][C:11]4=[N:10][N:9]=3)[C@H:3]([CH2:1][CH3:2])[CH2:4]2)[CH2:24][CH2:23]1
Reactant: NOCC1CC1
Reactant: CC[C@@H]1CC(=O)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Agent: Cl
Solvent: CCO
Product: CC[C@@H]1CC(=NOCC2CC2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
To a solution of (3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (0.05 g, 0.19 mmol, Example #AA.1.59) in EtOH (1 mL) was added TEA (0.04 mL, 0.28 mmol) and O-(cyclopropylmethyl)hydroxylamine hydrochloride (0.02 g, 0.19 mmol, Huhu Technologies). The reaction mixture was stirred for about 18 h at ambient temperature. Additional O-(cyclopropylmethyl)hydroxylamine hydrochloride (0.02 g, 0.19 mmol, Huhu Technologies) was added. The reaction was stirred at ambient temperature for about 5 h. The solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 1-10% MeOH in DCM to afford (3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone O-cyclopropylmethyl oxime (0.051 g, 80%): LC/MS (Table 1, Method a) Rt=1.94 min; MS m/z: 339 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=3)=[N:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCCCCCCc1ccc(-c2ncc(-c3ccc(OC)cc3)cn2)cc1
Agent: Br
Solvent: CC(=O)O
Product: CCCCCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)cn2)cc1
Yield: 56.4 %

Procedure:
A mixture of 5-(4-methoxyphenyl)-2-(4-nonylphenyl)-pyrimidine (60 g), hydrobromic acid (240 g) and acetic acid (1 l ) was refluxed for 40 hours, followed by distilling off most part of the acetic acid, pouring the residue into 2N-NaOH aqueous solution and recrystallizing the deposited crystals from ethyl acetate to obtain 5-(4-hydroxyphenyl)-2-(4-nonylphenyl)pyrimidine (32.6 g). This product had a C-SA point of 98.4° C. and a SA-I point of 138.6° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[S:18][C:17]([N+:19]([O-])=O)=[C:16]([C:22]([NH2:24])=[O:23])[CH:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.BrC1SC([N+]([O-])=O)=C(C(N)=O)C=1>>[NH2:19][C:17]1[S:18][C:14]([C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:4][CH2:3][S:2](=[O:25])(=[O:1])[CH2:7][CH2:6]3)=[CH:13][CH:12]=2)=[CH:15][C:16]=1[C:22]([NH2:24])=[O:23]
Reactant: NC(=O)c1cc(-c2ccc(N3CCS(=O)(=O)CC3)cc2)sc1[N+](=O)[O-]
Agent: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Product: NC(=O)c1cc(-c2ccc(N3CCS(=O)(=O)CC3)cc2)sc1N

Procedure:
The title compound was prepared from 5-[4-(1,1-dioxidothiomorpholin-4-yl)phenyl]-2-nitrothiophene-3-carboxamide (366 mg, 0.96 mmol) according to the general procedure described in Intermediate 10 Step 6 (nitro reduction method A).
Reaction SMILES: [C:1]1(=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][C:3](=[O:11])O1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1>C(Cl)Cl>[N:25]1[CH:26]=[CH:27][CH:28]=[N:29][C:24]=1[N:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:3](=[O:11])[CH2:4][C:5]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:1]2=[O:12])[CH2:19][CH2:20]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: ClCCl
Product: O=C1Cc2ccccc2C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
0.02 mol of 2-benzopyran-1,3(4H)dione and 0.02 mol of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine are heated at 160°-170° C. for 1 hour under an atmosphere of N2, with stirring. The mixture is then allowed to cool and the substance is dissolved in methylene chloride. The substancw is purified over a silica gel column (mobile phase: CH2Cl2 /iprOH (10:0.5)).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:24][C:25]1([CH3:31])[O:29][C:28](=[O:30])[NH:27][CH2:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:27]4[CH2:26][C:25]([CH3:31])([CH3:24])[O:29][C:28]4=[O:30])=[N:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC1(C)CNC(=O)O1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CC(C)(C)OC4=O)cn3)CC2)c(C)c1
Yield: 52.7 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (113 mg) described in Preparation Example 232 and 5,5-dimethyloxazolidin-2-one (52 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (65 mg) was obtained.
Reaction SMILES: Cl.[NH2:2][OH:3].[N+:4]([C:7]1[CH:23]=[CH:22][C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=O)=[CH:9][CH:8]=1)([O-:6])=[O:5]>C(O)C>[N+:4]([C:7]1[CH:23]=[CH:22][C:10]([C:11](=[N:2][OH:3])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C(=NO)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A solution of hydroxylamine hydrochloride (10.2 g, 147 mmol) was added to a suspension of 4,4'-dinitrobenzophenone (19 g, 70 mmol) in 100 ml of ethanol. The reaction mixture was heated to reflux for 2 hours, cooled to room temperature, and the solid collected by filtration. Recrystallization from ethanol provided the title compound (14.0 g, 70%) as pale yellow crystals. mp 194° C.; 1H NMR (D6 -DMSO) 12.25 (s, 1H), 8.35 (d, 2H), 8.20 (d, 2H), 7.60 (d, 4H).
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH3:15])=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N.[N:34]1([CH2:40][C@H:41]2[NH:45][C:44](=[O:46])[CH2:43][CH2:42]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>O1CCOCC1.ClCCl.[Cu](I)I>[CH3:15][CH:11]1[CH2:12][CH2:13][CH2:14][N:10]1[CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:16]=[CH:17][C:2]([N:45]2[C@H:41]([CH2:40][N:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)[CH2:42][CH2:43][C:44]2=[O:46])=[CH:3][CH:4]=1
Reactant: O=C1CC[C@@H](CN2CCCCC2)N1
Reactant: CC1CCCN1CCCOc1ccc(I)cc1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1CCCN1CCCOc1ccc(N2C(=O)CC[C@H]2CN2CCCCC2)cc1
Temperature: 110 °C
Yield: 46 %

Procedure:
A suspension of 1-[3-(4-iodophenoxy)propyl]-2-methylpyrrolidine a5 (0.245 g, 0.71 mmol, 1 eq) in dioxan (4 ml), potassium phosphate (0.3 g, 1.42 mmol, 2 eq), copper iodide (0.001 g, 0.007 mmol, 1 mol %), trans-1,2-diaminocyclohexane (0.008 g, 0.07 mmol, 10 mol %) and (5S)-5-(piperidin-1-ylmethyl)pyrrolidin-2-one a15 (0.155 g, 0.85 mmol, 1.2 eq) is placed in a sealed tube under argon atmosphere and heated at 110° C. until reaction completion. The mixture is diluted with dichloromethane and is washed twice with a solution of 1 M sodium hydroxide. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give 279 mg of a brown oil. This oil is purified by chromatography on silicagel (dichloromethane/ethanol/ammonia 95/5/0.5) to afford 130 mg of (5S)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxyl]phenyl}-5-(piperidin-1-ylmethyl)pyrrolidin-2-one 48 as a pink oil.
Reaction SMILES: Cl.[CH:2]1([O:6][C:7]2[CH:8]=[C:9]([F:15])[C:10]([F:14])=[C:11]([NH2:13])[CH:12]=2)[CH2:5][CH2:4][CH2:3]1.Cl.[C:17]1(Cl)[C:23](=O)C([Cl:25])=C(Cl)[C:19](=O)[C:18]=1Cl.C(=O)/C=C/C>C(O)CCC.O1CCCC1>[ClH:25].[CH:2]1([O:6][C:7]2[CH:8]=[C:9]([F:15])[C:10]([F:14])=[C:11]3[C:12]=2[CH:23]=[CH:17][C:18]([CH3:19])=[N:13]3)[CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cc(OC2CCC2)cc(F)c1F
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: C/C=C/C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCO
Product: Cc1ccc2c(OC3CCC3)cc(F)c(F)c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A mixture of 5-cyclobutoxy-2,3-difluorobenzenamine hydrogen chloride (9.9 g, 42.1 mmol), concentrated hydrochloric acid (36 mL), chloranil (12.32 g, 49.8 mmol) in n-butanol (60 mL) stirred for 1 h at 100° C. (E)-Crotonaldehyde (19.8 mL, 239 mmol) was added dropwise, and the resulting solution stirred for 1 h at 100° C. and was then cooled to 70° C. Tetrahydrofuran (600 mL) was added, and the mixture stirred for another 30 min at 70° C. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was poured into water (300 mL) and the pH of the mixture was adjusted to 7-8 with saturated aqueous potassium carbonate solution. The resulting mixture was extracted with ethyl acetate (3×300 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 25% ethyl acetate/petroleum ether) to afford 5-cyclobutoxy-7,8-difluoro-2-methylquinoline hydrochloride (6 g, 57%) as a yellow solid. MS (ESI, pos. ion) m/z 250 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:33])[CH2:18][CH2:19][C:20]2[CH:21]=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=2)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:42])C=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:33])[CH2:18][CH2:19][C:20]2[CH:21]=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:32])=[O:42])=[CH:27][CH:26]=2)=[CH:14][CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccc(SC)cc2)cc1)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccc(S(C)=O)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 16 %

Procedure:
A mixture of N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-methylthiophenyl)-4-isoxazolyl]propionamide (98 mg), m-chloroperbenzoic acid (60 mg) and tetrahydrofuran (5 ml) was stirred at room temperature for 4 hr. 10% aqueous sodium sulfite solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous potassium carbonate solution, and then with saturated brine, dried (MgSO4) and concentrated. The residue was purified by preparative HPLC to give N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-methylsulfinylphenyl)-4-isoxazolyl]propionamide.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]3[C:23](=[O:29])[NH:24][CH:25]=[C:26]([F:28])[CH:27]=3)=[N:13][C:12]=12)=[O:7].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:28][C:26]1[CH:27]=[C:22]2[C:23](=[N:24][CH:25]=1)[O:29][CH2:2][CH2:3][O:4][NH:5][C:6](=[O:7])[C:8]1=[C:12]3[N:13]=[C:14]([CH:15]=[CH:16][N:11]3[N:10]=[CH:9]1)[N:17]1[C@@H:18]2[CH2:19][CH2:20][CH2:21]1
Reactant: O=C(NOCCCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1NOCCOc2ncc(F)cc2[C@H]2CCCN2c2ccn3ncc1c3n2
Temperature: 90 °C

Procedure:
A mixture of (R)-N-(2-chloroethoxy)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (60 mg, 0.14 mmol) and Cs2CO3 (232 mg, 0.71 mmol) in DMF (1.4 mL) was heated at 90° C. for 20 minutes to reach completion. The reaction mixture was filtered (GF/F paper) and diluted with water (10 mL), then extracted with EtOAc (3×10 mL). The organic layers were combined, washed with brine and dried (Na2SO4). The crude material was purified on reverse phase column chromatography (Biotage SP4 system C18 12+M, acetonitrile/water 5 to 55%) to yield a mixture of the desired final product and impurities. This mixture was again purified by preparative TLC (10% MeOH/DCM) to yield the pure title product as white solid (1 mg, 1% yield). MS (apci) m/z=385.1 (M+H).
Reaction SMILES: [CH:1](=[N:4][OH:5])[CH2:2][CH3:3].BrBr.BrC(=NO)CC.[O-:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+].Br>C(Cl)(Cl)(Cl)Cl>[O:14]([CH:2]([CH3:3])[CH:1]=[N:4][OH:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCC=NO
Reactant: [O-]c1ccccc1
Agent: Br
Agent: BrBr
Agent: CCC(Br)=NO
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C=NO)Oc1ccccc1

Procedure:
Using the procedure of Example I, propionaldehyde oxime in carbon tetrachloride is brominated with bromine introduced at -5° to 0° C. To the resulting solution of 1-bromo-propionaldehyde oxime is added dropwise with stirring a suspension of sodium phenoxide in carbon tetrachloride. The reaction is allowed to go to completion and any residual sodium phenoxide is neutralized with hydrogen bromide gas. The precipitated sodium bromide is collected by filtration, and the filtrate concentrated under reduced pressure to provide the desired α-phenoxy propionaldehyde oxime.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:34][C:35](=[O:46])[CH2:36][C:37]1[CH:38]=[N:39][C:40]([O:44][CH3:45])=[C:41](Br)[CH:42]=1)C>>[C:9]([N:8]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[CH:15][C:14]=1[C:41]1[CH:42]=[C:37]([CH2:36][C:35]([OH:46])=[O:34])[CH:38]=[N:39][C:40]=1[O:44][CH3:45])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)N(Cc1ccccc1)Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)Cc1cnc(OC)c(Br)c1
Product: COc1ncc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1ccccc1)C(C)=O

Procedure:
Prepared according to the procedure described in Example 17, Step 4 and Step 5, using the following starting materials: N-benzyl-N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-acetamide and (5-bromo-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH2:29]C)[N:19]=[CH:18][N:17]=1>CN(C=O)C>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]1[N:19]=[CH:18][N:17]=[C:16]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH:21]=1
Reactant: CN(C)S(=O)(=O)Cc1cccc(N)c1
Reactant: CCOc1ccccc1-c1cc(Cl)ncn1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(Nc2cccc(CS(=O)(=O)N(C)C)c2)ncn1
Temperature: 80 °C

Procedure:
A mixture of (3-aminophenyl)-N,N-dimethylmethanesulfonamide (0.107 g, 0.50 mmol) and 4-chloro-6-(2-ethoxyphenyl)-pyrimidine (0.110 g, 0.10 mmol) in DMFA (3 mL) was stirred at 80° C. till the reaction completion (TLC control), then concentrated in vacuo and the residue was recrystallized from isopropanol to give C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N,N-dimethyl-methanesulfonamide (Compound 20)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=O.[OH:13][CH2:14][C:15]([NH:18][C:19]([NH2:21])=[S:20])([CH3:17])[CH3:16]>C(O)C>[OH:13][CH2:14][C:15]([NH:18][C:19]1[S:20][CH:2]=[C:3]([C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)[N:21]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(CO)NC(N)=S
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: CC(C)(CO)Nc1nc(-c2ccc(C#N)cc2)cs1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
This compound was prepared in the same manner as described in step 3 of Example 81. 4-(2-bromoacetyl)benzonitrile (1.7 g, 7.4 mmol) and N-(2-hydroxy-1,1-dimethylethyl)thiourea (1.1 g, 7.4 mmol), prepared in step 2 of Example 52, were heated to reflux in 45 mL of ethanol for 30 min. The reaction mixture was cooled to room temperature and the crude product was collected by suction filtration to give 4-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (2.0 g, 100%), MS (ES) m/z 274 [M+H]+. No further purification was performed on this compound.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:46]/[OH:47])/[C:19]([NH:21][CH:22]2[C:44](=[O:45])[N:24]3[C:25]([C:32]([O:34][CH:35]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:36])=[O:33])=[C:26]([CH2:29][O:30][CH3:31])[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1.COC(C)(C)C>CC(C)=O>[C:3]1([CH3:13])[C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=[CH:1][CH:2]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:46]/[OH:47])/[C:19]([NH:21][CH:22]2[C:44](=[O:45])[N:24]3[C:25]([C:32]([O:34][CH:35]([O:37][C:38](=[O:43])[C:39]([CH3:41])([CH3:42])[CH3:40])[CH3:36])=[O:33])=[C:26]([CH2:29][O:30][CH3:31])[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COCC1=C(C(=O)OC(C)OC(=O)C(C)(C)C)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: Cc1ccccc1S(=O)(=O)O

Procedure:
A solution of 2.1 g (11 mmol) of p-toluenesulfonic acid in 5 ml of acetone was added dropwise to a solution of 5 g (9.3mmol) of α-(2,2-dimethylpropanoyloxy)ethyl 7-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyimino-acetamido]-3-methoxymethyl-3-cephem-4-carboxylate in 35 ml of acetone. After stirring briefly, a precipitate formed, which process was completed by slowly adding 250 ml of t-butyl methyl ether. After stirring for 15 minutes, the crystalline product was filtered off with suction, washed with a little t-butyl methyl ether and dried in vacuo over calcium chloride/paraffin. 4.6 g of the desired crystalline title compound were obtained, which consisted of an approximately 1:1 ratio of the two diastereomers and was identical in its physical and chemical properties with the product from working example 2.
Reaction SMILES: [CH2:1]([C:13]1[CH:14]=[C:15]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:22]=2)[S:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1C(=O)N([Br:42])C(=O)C1.O>C(Cl)(Cl)Cl.CC(O)=O>[Br:42][C:20]1[S:19][C:18]([C:15]2[S:16][CH:17]=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:14]=2)=[CH:22][C:21]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCCCc1csc(-c2cc(CCCCCCCCCCCC)cs2)c1
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCc1csc(-c2cc(CCCCCCCCCCCC)c(Br)s2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 4,4′-didodecyl-2,2′-bithiophene (0.100 g, 0.199 mmol) in CHCl3/HOAc (1:1) (Vt=2.0 mL) at 0° C. was added N-bromosuccimide (NBS, 35.7 mg, 0.199 mmol) in portions over a period of 45 minutes. The reaction mixture was stirred for 1 hour at 0° C. and overnight at room temperature. The reaction mixture was poured into water (50.0 mL) and extracted with chloroform (3×50.0 mL). The combined organic phases were washed with water (50.0 mL), NaOH solution, and dried over MgSO4. After filtration through Celite, the filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (hexanes) to provide 5-bromo-4,4′-didodecyl-2,2′-bithiophene (29A) as a colorless oil (98.0 mg, 85% yield). 1H NMR (CDCl3): δ 0.84-1.54 (m, 46H), 2.57 (m, 4H), 6.81 (s, 1H), 6.84 (s, 1H), 6.94 (s, 1H).