Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][C:5](O)=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:36][NH:37][S:38]([CH3:41])(=[O:40])=[O:39]>O.C(OCCCC)(=O)C>[Br:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][C:5]([N:37]([CH3:36])[S:38]([CH3:41])(=[O:40])=[O:39])=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)c1nc(O)nc(-c2ccc(F)cc2)c1Br
Reactant: CNS(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOC(C)=O
Solvent: O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1Br
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 38.1 %

Procedure:
5-Bromo-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-ol (62.2 g, 199 mmol), potassium carbonate (35.83 g, 259 mmol) and butyl acetate (435.4 mL) were charged to a 2 L multi-neck flask and stirred/heated to 42° C. p-Toluenesulfonyl chloride (41.83 g, 219 mmol) was then added in portions over 50 minutes, maintaining the temperature at ≦45° C. The reaction was stirred at this temp for 2.5 hours, at which point LCMS showed only the desired intermediate (MH+=467) present. Potassium carbonate (41.25 g, 299 mmol) and butyl acetate (186.6 mL) were then added and reaction heated to 120° C. Once at this temperature N-methylmethanesulfonamide (28.21 g, 259 mmol) was added over 30 mins. The reaction was held at this temperature for 18 hours, then butyl acetate (330 mL) and water (412 mL) were added, reducing the reaction temperature to 75° C. Stirring was continued at this temperature for 20 minutes, then the reaction mixture was transferred to a separating funnel, and allowed to stand for 10 mins to separate. The aqueous layer was separated off and re-extracted with butyl acetate (250 mL) by stirring at 60° C. for 15 mins. The organic layers were combined and 1 M aqueous NaOH (330 mL) added. This mixture was stirred at 60° C. for 20 minutes, then the lower aqueous phase separated off. The organic layer was concentrated in vacuo to 20% original volume, then allowed to cool and crystallize. The crude solid was isolated by filtration (50.5 g slightly damp), and this material recrystallized from methanol (500 mL), filtered and dried at 50° C. to constant weight to give the title compound (30.54 g, 38% yield) as a white crystalline solid.
Reaction SMILES: CN(C(O[N:9]1N=N[C:11]2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:27]=1[C:28]([OH:30])=O.C(N(C(C)C)CC)(C)C.C(N)C>C(#N)C.C1COCC1>[Br:25][C:26]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:27]=1[C:28]([NH:9][CH2:10][CH3:11])=[O:30]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)c1cc([N+](=O)[O-])ccc1Br
Reaction time: 15 h
Yield: 43 %

Procedure:
To a stirred solution of HATU (501 mg, 1.32 mmol), 2-bromo-5-nitrobenzoic acid (325 mg, 1.32 mmol) and diisopropyl ethylamine (642 μl, 3.90 mmol) in anhydrous acetonitrile (20 ml) at room temperature was added ethylamine (725 μl of a 2.0M solution in THF, 1.45 mmol) and the reaction stirred for 15 hrs. The solvent was evaporated in vacuo and the crude residue purified by flash column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound as a pale yellow solid (155 mg, 43%). HPLC retention time 3.72 min. Mass spectrum (ES+) m/z 273 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[S:23][C:24]=1[C@H:25](O)[CH3:26].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C@@H:25]([C:24]3[S:23][C:22]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=4)=[N:21][C:20]=3[CH3:19])[CH3:26])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1[C@@H](C)O
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1[C@@H](C)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with (S)-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol [ee=95%; PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to obtain (R)-(6-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless oil. The configuration was tentatively assigned as R according to R. Cadilla et al., PCT Int. Appl. (2002), WO 02/062774 A1 and the generally accepted SN2-type mechanism of the Mitsunobu reaction.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([S:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[F:17])([CH3:7])[CH3:6])C.C[Si](C)(C)[O-].[K+]>C1COCC1>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([S:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:18])=[O:3])=[C:10]([F:17])[CH:11]=1)#[N:16]
Reactant: CCOC(=O)C(C)(C)Sc1ccc(C#N)cc1F
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(Sc1ccc(C#N)cc1F)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 106 %

Procedure:
To a solution of 1.1 g (4.1 mmol) of 2-(4-cyano-2-fluoro -phenylsulfanyl)-2-methyl-propionic acid ethyl ester in THF (50 mL) were added 1.58 g (12.3 mmol) of potassium trimethylsilanolate. The reaction was stirred at room temperature for 3 h. The solvent was removed under reduced pressure. The residue was partitioned between DCM (50 mL) and water (50 mL). The aqueous layer was acidified with 1 M aqueous HCl solution and extracted with DCM (4×50 mL). The combined organic extracts were dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford 1.04 g of 2-(4-cyano-2-fluoro-phenylsulfanyl)-2-methyl-propionic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[N:10]2[CH3:33])=[C:5]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.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>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:11](=[O:32])[N:10]2[CH3:33])=[C:5]([S:34]([CH3:37])(=[O:35])=[O:36])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
The reaction was carried out under argon. Allyl (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (157 mg, 0.294 mmol) and morpholine (1.5 eq., 38 mg, 0.441 mmol) were initially charged in dry THF (5 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 17 mg, 0.015 mmol) was added, and the reaction mixture was stirred at RT for 16 h (HPLC control). The mixture was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a solid (120 mg, 83% of theory).
Reaction SMILES: Br[C:2]1[N:16]([Si](C(C)(C)C)(C)C)[C:15]2[C:24]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([CH3:25])[CH2:7][N:6]1[CH3:26].C([Li])(C)(C)C.CCCCCC.O>C1(C)C=CC=CC=1>[CH3:26][N:6]1[C@H:5]2[C@@H:10]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:24]=3[C:3]([CH2:4]2)=[CH:2][NH:16]4)[CH:9]=[C:8]([CH3:25])[CH2:7]1
Reactant: CC1=C[C@@H]2c3cccc4c3c(c(Br)n4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: CC1=C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: -90 °C
Reaction time: 5 h

Procedure:
800 mg of 2-bromo-1-(tert-butyldimethylsilyl)-8,9-didehydro-6,8-dimethylergoline was dissolved in 50 ml of anhydrous toluene; the solvent was distilled off under vacuum and the mixture taken up in 75 ml of anhydrous, freshly distilled toluene under an argon atmosphere. To this solution was added 1 ml of anhydrous tetramethylethylenediamine and the mixture was cooled to -90° C. Then the mixture was combined with 6.0 ml of 1.4-molar tert-butyllithium solution in hexane (8.4 mmol) and agitated for 5 hours. Water was then added, the mixture was extracted with methylene chloride, the organic phase was dried with sodium sulfate and evaporated. In a quantitative yield, 8,9-didehydro-6,8-dimethylergoline was isolated. The desired 8,9-didehydro-6,8-dimethyl-2-trimethylsilylergoline could not be detected by NMR.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][C:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:14][C:15]1[C:20]([O:21][C:2]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Reactant: Cc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1Oc1cc(C(F)(F)F)ccc1C#N
Temperature: 50 °C
Yield: 93.4 %

Procedure:
A mixture of 2-fluoro-4-(trifluoromethyl)benzonitrile (0.19 g, 1.0 mmol), 2-methylpyridin-3-ol (0.11 g, 1.0 mmol), and cesium carbonate (0.33 g, 1.0 mmol) in anhydrous DMF (5 mL) was heated at 50° C. for 16 h. The reaction was diluted with water and extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (0%-30% EtOAc-hexanes) to obtain 2-(2-methylpyridin-3-yloxy)-4-(trifluoromethyl)benzonitrile (0.26 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=4.7, 1.4 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.44 (dd, J=8.1, 0.7 Hz, 1H), 7.35 (dd, J=8.1, 1.4 Hz, 1H), 7.28-7.25 (m, 1H), 6.87 (s, 1H), 2.50 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][CH3:8])=[C:4]([S:11][CH3:12])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:22][C:23]1([CH3:33])[O:27][C:26](=[CH:28][C:29](Cl)=[O:30])[C:25](=[O:32])[O:24]1>C(Cl)Cl>[CH3:22][C:23]1([CH3:33])[O:27][C:26](=[CH:28][C:29]([N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=2[S:11][CH3:12])[CH3:8])=[O:30])[C:25](=[O:32])[O:24]1
Reactant: CNCc1ccc(F)cc1SC
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1cc(F)ccc1CN(C)C(=O)C=C1OC(C)(C)OC1=O
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred solution of (4-fluoro-2-methylsulfanyl-benzyl)-methyl-amine (1.3 g) and diisopropylethylamine (1.74 mL, 10 mmol) in CH2Cl2 (60 mL) was added (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (1.1 g, 6 mmol). After 1 h, the reaction mixture was concentrated and the resulting residue was taken up in ether (100 mL), washed with 1N HCl (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give a viscous yellow oil. Flash chromatography on a silica gel column with 3:2 hexanes/EtOAc followed by 2:3 hexanes/EtOAc gave the desired product as a 1:1 mixture of E and Z isomers 1.8123 g, 89% yield). 1HNMR (500 MHz, CDCl3) δ: 7.17 (0.5H, dd, J=8.54, 6.11 Hz), 7.00 (0.5H, dd, J=8.55, 5.8 Hz), 6.94–6.89 (1H, m), 6.83–6.77 (1H, m), 6.17 (0.5H, s), 6.04 (0.5H, s), 4.68 (1H, s), 4.51 (1H, s), 2.98 (1.5H, s), 2.97 (1.5H, s), 2.48 (1.5H, s), 2.45 (1.5H, s), 1.72 (3H, s), 1.67 (3H, s). MS calcd for C16H19FNO4S (M+H): 340.1. found: 340.3.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:29][CH2:30][CH:31]2[CH2:33][O:32]2)=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[CH:24]=1>C(O)(C)C.CCO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:29][CH2:30][CH:31]([OH:32])[CH2:33][N:13]2[CH2:12][CH2:11][CH:10]([N:6]3[C:5]4[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=4[NH:8][C:7]3=[O:9])[CH2:15][CH2:14]2)=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[CH:24]=1
Reactant: CC(=O)Nc1cc(Cl)ccc1OCC1CO1
Reactant: O=c1[nH]c2cc(F)ccc2n1C1CCNCC1
Solvent: CC(C)O
Solvent: CCO
Product: CC(=O)Nc1cc(Cl)ccc1OCC(O)CN1CCC(n2c(=O)[nH]c3cc(F)ccc32)CC1
Yield: 100.6 %

Procedure:
A solution of 5-fluoro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (480 mg, 2.0 mmol) and N-(5-chloro-2-oxiranylmethoxy-phenyl)-acetamide (490 mg, 2.0 mmol) in isopropanol (i-PrOH) (10 mL) and EtOH (10 mL) were stirred at 80° C. for 17 h, after which the solvent was removed in vacuo. The residue was purified using gradient flash chromatography (CH2Cl2 to MeOH), yielding the desired product as a white solid (960 mg, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][S:24][CH2:25][CH2:26][O:27][C:28]([NH:30][C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[N:33]=[CH:34][N:35]2[CH2:40][C:41](O)=[O:42])=[O:29]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:41](=[O:42])[CH2:40][N:35]1[CH:34]=[N:33][C:32]2[C:36]1=[N:37][CH:38]=[N:39][C:31]=2[NH:30][C:28]([O:27][CH2:26][CH2:25][S:24][CH3:23])=[O:29])[CH3:2]
Reactant: CSCCOC(=O)Nc1ncnc2c1ncn2CC(=O)O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(NC(=O)OCCSC)ncnc21
Yield: 87 %

Procedure:
The title compound (2.77 g, 85%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [6-N-(2-methylthioethoxycarbonyl)-adenin-9-yl]-acetic acid (1.56 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 10.59 (s, 1H), 8.97 (brs, 0.6H), 8.76 (brs, 0.4H), 8.57 (s, 0.4H), 8.52 (s, 0.6H), 8.28 (d, 1H), 8.17 (d, 1H), 7.65 (m, 2H), 5.35 (s, 1.2H), 5.14 (s, 0.8H), 4.46 (s, 0.8H), 4.17 (q, 0.8H), 4.06 (s, 1.2H), 4.02 (q, 1.2H), 3.70 (t, 1.2H), 3.47 (t, 1.2H), 3.42 (t, 0.8H), 3.21 (t, 0.8H), 2.12 (s, 3H), 1.23 (t, 1.2H), 1.12 (t, 1.8H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5](Cl)=[N:6][CH:7]=1.[NH2:11][NH2:12]>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH2:10])=[N:12][NH:11][C:5]2=[N:6][CH:7]=1
Reactant: N#Cc1cc(Br)cnc1Cl
Reactant: NN
Solvent: CCCCO
Product: Nc1n[nH]c2ncc(Br)cc12
Temperature: 25 °C

Procedure:
(Step 7-i) To a solution of 5-bromo-2-chloropyridine-3-carbonitrile (2 g, 9.22 mmol) in 30 mL n-butanol was added 2 mL anhydrous hydrazine. The reaction mixture was heated under reflux for 14 hrs and allowed to cool to room temperature. The solvent was removed by evaporation and the residue was poured into a saturated NaHCO3 solution. The resulting precipitate was collected and washed with water. After drying in vacuo, the product, 5-bromo-1H-pyrazolo[3,4-b]pyridin-3-amine, can be used directly without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C(O)(=O)C>[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Nc1ccccc1Cl
Reactant: CCc1ccc2ncc([N+](=O)[O-])c(Cl)c2c1
Solvent: CC(=O)O
Product: CCc1ccc2ncc([N+](=O)[O-])c(Nc3ccccc3Cl)c2c1

Procedure:
The title compound is prepared in analogy to Example 19d starting from 0.7 g (2.957 mmol) of 4-chloro-6-ethyl-3-nitro-quinoline (Example 49e) and 0.37 g (3.55 mmol) 2-chloroaniline in 3 ml acetic acid. Crystallization from ethyl acetate-hexane. mp: 134-136° C.; MS: 328 (M++1); HPLC: tret=10.61 min (Grad 1).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10](Cl)=[O:11]>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:11]
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Reactant: CC(C)CN
Solvent: ClCCl
Product: CC(C)CNC(=O)c1ccc(F)c(Cl)c1
Reaction time: 2 h

Procedure:
Isobutyl amine (2 molar equivalent) was added to a solution of 3-chloro-4-fluorobenzoyl chloride (1 g) in DCM (10 ml) and stirred for 2 h. The reaction was diluted with DCM, washed with water, dried (MgSO4) and evaporated under reduced pressure to give a white solid (1.2 g).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[Br:1][CH:2]([CH3:6])[C:3]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15])=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: Nc1cccc(Br)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(Br)C(=O)Nc1cccc(Br)c1O
Yield: 99.9 %

Procedure:
2-Bromopropionyl chloride (1.47 ml, 14.6 mmol) was added dropwise to a vigorously stirred and ice-cooling mixture of 2-amino-6-bromophenol (2.74 g, 14.6 mmol) and sodium bicarbonate (3.06 g, 36.4 mmol) in ethyl acetate (50 ml)/water (15 ml). The mixture was stirred at 0° C. for 3 h and diluted with water. The aqueous layer was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue used for the following step without further purification to afford 4.71 g (99%) of the title compound.
Reaction SMILES: CN1CCOCC1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][C:10]=1[S:22][C@@H:23]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C@@H:24]([OH:28])[C:25](O)=[O:26].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C.O>[OH:28][C@H:24]1[C:25](=[O:26])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][C:10]=2[S:22][C@H:23]1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1
Reactant: COc1ccc([C@H](Sc2cc(Oc3ccccc3)ccc2N)[C@@H](O)C(=O)O)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Oc4ccccc4)ccc3NC(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
1,5 ml of N-methylmorpholine was added, whilst ice-cooling, to a solution of 1.74 g of (2S, 3S)-3-(2- amino-5-phenoxyphenyl)thio-2-hydroxy-3-(4-methoxyphenyl)propionic acid [prepared as described in step (b) above] and 1,5 g of diphenylphosphorylaZide dissolved in 19 ml of dimethylformamide, and the mixture was stirred at room temperature for 16 hours. At the end of this time, ethyl acetate and water were added to the reaction mixture, and the resulting mixture was shaken to mix it thoroughly The ethyl acetate layer was then separated and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure. The crystalline residue was collected by filtration using diethyl ether and diisopropyl ether to afford 0.90 g of the title compound melting at 181-183° C.
Reaction SMILES: C([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=O)=[CH:15][CH:14]=2)[N:8]=1)CCCCC.[CH2:22](Cl)[CH2:23]Cl.P(Cl)(Cl)(Cl)=O>CCOCC>[CH2:9]([C:12]1[CH:11]=[N:10][C:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]#[N:19])=[CH:20][CH:21]=2)=[N:8][CH:7]=1)[CH2:13][CH2:14][CH2:15][CH2:22][CH3:23]
Reactant: ClCCCl
Reactant: CCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCCCCc1cnc(-c2ccc(C#N)cc2)nc1

Procedure:
15.58 g. of 4-(4-n-hexylpyrimid-2-yl)benzoic acid amide are left in a mixture of 350 ml. of ethylene chloride and 5.58 ml. of phosphorus oxychloride for 90 minutes under reflux, with stirring. The reaction mixture, diluted with ether, is washed with 2N sodium hydroxide solution and then with water until neutral. After evaporation of the organic phase, drying over sodium sulfate, 14.6 g. of 5-n-hexyl-2-(4-cyanophenyl)pyrimidine result, which are distilled in high vacuum, m.p. 53.5° - 54.5°; cl.p. 35.5° - 36.5°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][CH:7]([C:9]2[CH2:10][S:11][C@@H:12]3[C@H:28]([NH:29]C(=O)COC4C=CC=CC=4)[C:27](=[O:40])[N:13]3[C:14]=2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:6][CH2:5]1.CN1CCOCC1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>ClCCl.O>[NH2:29][C@@H:28]1[C:27](=[O:40])[N:13]2[C:14]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[O:16])=[C:9]([C@@H:7]3[CH2:6][CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[O:8]3)[CH2:10][S:11][C@H:12]12
Reactant: COCC1CCC(C2=C(C(=O)OCc3ccc(OC)cc3)N3C(=O)[C@@H](NC(=O)COc4ccccc4)[C@H]3SC2)O1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN1CCOCC1
Solvent: CO
Solvent: ClCCl
Product: COC[C@H]1CC[C@@H](C2=C(C(=O)OCc3ccc(OC)cc3)N3C(=O)[C@@H](N)[C@H]3SC2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
A solution of 4-methoxybenzyl (6R,7R)-3-[(2RS,5SR)-5-methoxymethyltetrahydrofuran-2-yl]-7-phenoxyacetamidoceph-3-em-4-carboxylate (1.93g) in dichloromethane (25ml) was cooled to -15 to -20° C., N-methylmorpholine (0.75ml) was added followed by a solution of phosphorus pentachloride in dichloromethane (26.5ml of a solution containing 40mg.ml-1). The mixture was stirred at the same temperature for 0.5h and then methanol (6.8ml) was added and the mixture stirred at room temperature for 0.5h. Water (10ml) was then added and the mixture vigorously stirred for 0.5h. The dichloromethane was then removed on a rotary evaporator and the residue was partitioned between ether and water. The aqueous phase was stirred with ethyl acetate and the pH was adjusted to 6.2 with 1N aqueous ammonia. The organic phase was washed with water and brine, dried over magnesium sulphate and evaporated. The products were separated by column chromatography of the residue using gradient elution is (silica gel, 1:1 hexane : ethyl acetate going to neat ethyl acetate). The following were obtained in order of elution 4-methoxybenzyl (6R,7R)-7-amino-3-[(2S,5R)-5-methoxymethyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (388mg); vmax (CHCl3) 3410, 1776 and 1725cm-1 ; δH (CDCl3) 1.59-1.78 (2H,m), 1.93-2.08 (1H,m), 2.18-2.32 (1H,m), 2.54 (2H, br s), 3.33-3.54 (3H,m), 3.38 (3H,s), 3.80 (3H,s), 4.00-4.11 (1H,m), 4.76 (1H,d, J 4.99Hz), 4.90 (1H,d, J 4.97Hz) 4.96 (1H,t, J 8.23Hz) 5.17 (2H,s), 6.88 (2H,d, J 8.60Hz) and 7.33 (2H,d, J 8.61Hz). [Mass spectrum: M+ (434)]; 4-methoxybenzyl (6R,7R)-7-amino-3-[(2R,5S)-5-methoxymethyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (305mg); vmax (CHCl3) 3409, 1776 and 1725cm-1 ; δH (CDCl3) 1.60-1.81 (2H, m), 1.85-2.01 (2H, m), 3.30-3.50 (2H, m), 3.38 (3H, s), 3.44 (1H,d, J 17.78Hz), 3.69 (1H, d, J 17.75Hz), 3.80 (3H, s), 4.00-4.17 (1H,m), 4.70 (1H, d, J 4.92Hz), 4.93 (1H, d, J 4.95Hz), 5.10-5.20 (1H, m), 5.18 (1H, d, J 11.88Hz), 5.24 (1H, d, J 11.89Hz), 6.88 (1H,d, J 8.65Hz) and 7.35 (1H, d, J 8.64Hz). [Mass spectrum: M+ (434)].