Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC1C=CC(S(O[C@@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc(O[C@H]2CCOC2)cc1
Temperature: 85 °C
Yield: 29.9 %

Procedure:
A mixture of 4-bromophenol (1.8 g, 10.5 mmole), (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (2.3 g, 9.5 mmole) and K2CO3 (4.0 g, 29 mmole) in DMF (15 mL) was heated at 85° C. for 15 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by ISCO (silica gel, eluting with 5% ethyl acetate in hexane) to give the title compound (690 mg). MS (ESI) m/z: Found: 244.3 (M++1). Calc. 243.1 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:9]([Li])[CH2:8][CH2:7]3.[Si:21]([CH3:25])([CH3:24])(Cl)[Cl:22]>C1COCC1>[Cl:22][Si:21]([CH3:25])([CH3:24])[CH:3]1[C:4]2[C:12](=[CH:11][C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:2]1[CH3:1]
Reactant: C[Si](C)(Cl)Cl
Reactant: [Li]C1CCc2cc3c(cc21)C(c1ccccc1)=C(C)C3
Solvent: C1CCOC1
Product: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Temperature: 22.5 °C
Yield: 96.1 %

Procedure:
(6-Methyl-7-phenyl-1,2,3,5-tetrahydro-s-indacenyl) lithium (17.8305 g, 0.07068 moles) in THF (50 mL) was added dropwise to a solution of Me2SiCl2 (21.3694 g, 0.1656 moles) in THF (100 mL) at 0° C. This mixture was then allowed to stir at 20-25° C. 16 hours. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. The removal of the hexane resulted in the isolation of the desired product as a viscous yellow oil (23.0231 g, 96.1 percent).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=3)[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:9][N:8]2[CH:27]=1)=[O:4].[NH:28]1[CH2:31][CH:30]([C:32]2[NH:36][N:35]=[C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:33]=2)[CH2:29]1>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:28]4[CH2:29][CH:30]([C:32]5[N:33]=[C:34]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=6)[NH:35][N:36]=5)[CH2:31]4)=[CH:15][CH:14]=3)[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:9][N:8]2[CH:27]=1)=[O:4]
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Reactant: COC(=O)c1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Product: COC(=O)c1cn2cc(-c3ccccc3)c(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)nc2n1
Yield: 17.5 %

Procedure:
The title compound has been prepared in analogy to the aforementioned descriptions by reacting 500 mg (1.4 mmol) 7-(4-formylphenyl)-6-phenyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid methyl ester with 383.6 mg (1.4 mmol) 2-(5-azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl, yielding 132.6 mg (15.7%) of the desired product after purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[C:6]([Br:8])[CH:7]=1.I[CH3:13].[H-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][O:11][CH3:13])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: OCCc1cc(Br)cc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COCCc1cc(Br)cc(Br)c1
Yield: 86 %

Procedure:
In analogy to the procedure described for Building Block AW, the alkylation of 2-(3,5-dibromo-phenyl)-ethanol with iodomethane using sodium hydride as the base yielded the title compound 86% yield as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12][CH3:13].ClN1C(=O)CCC1=O.[OH-].[Na+]>C(N(CC)CC)C.ClCCl>[CH3:11][S:12][CH2:13][C:5]1[C:6]([F:10])=[C:7]([F:9])[CH:8]=[C:2]([F:1])[C:3]=1[NH2:4]
Reactant: Nc1cc(F)c(F)cc1F
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCc1c(N)c(F)cc(F)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 2,4,5-trifluoroaniline (35.0 g) are added anhydrous dichloromethane (530 ml) and dimethyl sulfide (24.6 ml) and the mixture is cooled to 0° C. Thereto N-chlorosuccinimide (38.2 g) is gradually added below 5° C. After the mixture is stirred at the same temperature for 15 minutes, triethylamine (47.7 ml) is gradually added. After reflux for 12 hours, the resultant is made alkaline with 5 % aqueous sodium hydroxide solution, extracted with dichloromethane, and the extract is dried over sodium sulfate and concentrated. The residue is purified with column chlomatography (silica-gel, dichloromethane: n-hexane=1:4) to give 2-methylthiomethyl-3,4,6-trifluoroaniline (22.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20].C(N(CC)CC)C>C1COCC1>[C:19]([NH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: Nc1ccc(Oc2cc(Br)ccc2C(=O)O)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Oc2cc(Br)ccc2C(=O)O)cc1
Reaction time: 2.5 h
Yield: 85.7 %

Procedure:
Compound 2f (500 mg, 1.6 mmol) in 10 mL of THF was treated with acetyl chloride (0.15 mL, 2.08 mmol) and triethylamine (0.22 mL, 2.08 mmol). After stirring for 2.5 h the solid was collected. The filtrate was evaporated in vacuo to give 0.48 g of Compound 3f. MS m/z=331 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:29]([NH2:31])[CH3:30])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH:29]([C:19]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[C:17]([CH3:16])[CH:18]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)ccc1OCC(F)(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)(F)F
Yield: 97 %

Procedure:
The title compound is prepared in 97% yield (467 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (350 mg, 1.26 mmol) and 1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (373 mg, 1.38 mmol, Amine-69, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]>C(#N)C>[CH3:7][N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])[S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CNS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN(c1ccccc1[N+](=O)[O-])S(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.3 %

Procedure:
To a suspension of cesium carbonate (20.2 g, 0.065 mol) in acetonitrile (500 mL) at room temperature was added N-methylmethanesulfonamide (5.33 g, 0.049 mol) and 1-fluoro-2-nitrobenzene (4.59 g, 0.033 mol) dropwise over 10-15 minutes. The reaction was stirred at room temperature for 12 hours. Upon completion, the mixture was filtered and then concentrated. The residue was purified by silica gel chromatography (dichloromethane) to afford the product N-methyl-N-(2-nitrophenyl)methanesulfonamide (4.2 g, yield 56.1%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.94 (dd, 1H, J=1.2 Hz, 8.0 Hz), 7.74-7.81 (m, 2H), 7.57-7.62 (m, 1H), 3.27 (s, 3H), 3.03 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([NH:10][C:8]([C:3]1[C:2]([OH:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:9])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1nccnc1O
Product: CC(=O)NC(=O)c1nccnc1O
Temperature: 110 °C
Reaction time: 1 h

Procedure:
In 5 mL of acetic anhydride is suspended 0.5 g of 3-hydroxy-2-pyrazinecarboxamide. The resulting solution is stirred at 110° C. for 1 hour. The deposited crystals are collected by filtration to obtain 0.5 g of N2-acetyl-3-hydroxy-2-pyrazinecarboxamide.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1.[C:18](Cl)(=[O:20])[CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:18]([O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1)(=[O:20])[CH3:19]
Reactant: COC(=O)CCCCCCC1=CC(O)CC1=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCCCCC1=CC(OC(C)=O)CC1=O
Reaction time: 8 h
Yield: 97.9 %

Procedure:
4-Hydroxy-2-(6-methoxycarbonylhexyl)-2-cyclopentenone (24 g) was dissolved in chloroform (200 ml), followed by addition of acetyl chloride (7.9 g) thereto. Triethylamine [10.1 g) was dropwise added thereto while stirring at 0° to 10° C. After completion of the addition, stirring was continued at 25° C. for 8 hours. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-acetoxy-2-(6-methoxycarbonylhexyl)-2-cyclopentenone (27.6 g). Yield, 98%.
Reaction SMILES: [CH2:1]([C:4]1[C:5](Cl)=[N:6][CH:7]=[N:8][C:9]=1[CH3:10])[CH2:2][CH3:3].O.[NH2:13][NH2:14]>C(O)C>[CH3:10][C:9]1[N:8]=[CH:7][N:6]=[C:5]([NH:13][NH2:14])[C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1c(C)ncnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCc1c(C)ncnc1NN
Temperature: 80 °C

Procedure:
A mixture of 5-propyl-4-chloro-6-methyl-pyrimidine (10 mmol) and hydrazine monohydrate (30 mmol) in ethanol (20 mL) is heated at 80° C. overnight. Solvent is removed in vacuo and the residue solid is in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:8][C:6]1[CH:7]=[CH:2][C:3]2[C:9]3[C:10]([CH:15]([CH3:16])[N:17]([S:18]([C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)(=[O:19])=[O:20])[C:4]=2[CH:5]=1)=[CH:11][CH:12]=[CH:13][CH:14]=3
Reactant: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(F)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2c3cc(F)ccc3-c3ccccc3C2C)cc1
Temperature: 100 °C
Yield: 98.3 %

Procedure:
N-[1-(2′,4′-Difluoro-1,1′-biphenyl-2-yl)ethyl]4-methoxybenzenesulfonamide (347 mg, 0.86 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL) and potassium carbonate (238 mg, 1.72 mmol) was added as a solid in one portion. The mixture was heated at 100° C. with stirring until a single product had formed as gauged by LCMS (5-6 hours). Water (10 mL) was added and a white solid precipitated from the cloudy solution. The mixture was allowed to stand until the solution was clear, and the precipitated solid was filtered and washed with additional water to afford the desired compound (324 mg, 98%) as a white solid, m.p. 137.5-139° C.;
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:18][CH2:19][CH2:20][CH2:21][SH:22].CN(C)C=O>O>[CH2:21]([S:22][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH2:20][CH2:19][CH3:18]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCSc1ccc(C=O)cc1
Temperature: 100 °C

Procedure:
A mixture of 4-nitrobenzaldehyde (10.0 g), potassium carbonate (10.0 g), n-butylthiol (12.5 ml) and dimethylformamide (12.5 ml) was heated at 100° C. for a period of 16 hours, cooled and poured into water (250 ml). The aqueous mixture was extracted with diethyl ether (4×250 ml) and the combined organic phases were washed with aqueous 2% sodium hydroxide solution (5×100 ml) and finally with water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed by distillation to give 4-(n-butylthio)benzaldehyde (10.8 g) as a reddish coloured oil. The product was characterized by proton nuclear magnetic resonance spectroscopy. Pmr (CDCl3 ; δ in ppm): 0.97 (3H, t); 1.60 (4H, m); 3.03 (2H, t); 7.32 (2H, d); 7.77 (2H, d); 9.89 (1H, s).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[NH:33]1[CH2:38][CH2:37][S:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:33]1([C:15]([N:13]2[CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:31])[F:1])=[CH:8][CH:7]=3)[CH2:10][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:12]2)=[O:16])[CH2:38][CH2:37][S:36][CH2:35][CH2:34]1
Reactant: C1CSCCN1
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Temperature: 150 °C

Procedure:
10.0 g (22.1 mmol) of the compound from Example 48A, 6.84 g (66.3 mmol) of thiomorpholine and 9.17 g (66.3 mmol) of potassium carbonate were added to 150 ml of DMF and heated in 10 portions in a single-mode microwave (Emrys Optimizer) at 150° C. for 1 h. For workup, the reaction solutions were combined and filtered, and the residue was purified by means of preparative HPLC. Yield: 5.16 g (55% of theory)
Reaction SMILES: C1(=O)[O:6][C@H:4]([CH3:5])[CH2:3]O1.[N:8]1[C:16]([NH2:17])=[C:15]2[C:11]([N:12]=[CH:13][NH:14]2)=[N:10][CH:9]=1.[OH-].[Na+]>CN(C)C=O>[OH:6][C@H:4]([CH3:5])[CH2:3][N:12]1[CH:13]=[N:14][C:15]2[C:11]1=[N:10][CH:9]=[N:8][C:16]=2[NH2:17]
Reactant: C[C@@H]1COC(=O)O1
Reactant: Nc1ncnc2nc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C[C@@H](O)Cn1cnc2c(N)ncnc21

Procedure:
To a reaction vessel containing inert atmosphere, e.g., nitrogen, was added carbonate (A), adenine, N,N-dimethylformamide (DMF) and catalytic amount of base such as sodium hydroxide, then (R)-9-(2-hydroxypropyl)adenine (B) was obtained;
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2].[P:22](Cl)(Cl)[Cl:23]>>[C:11]([C:9]1[CH:8]=[C:7]2[C:6](=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=1)[O:21][P:22]([Cl:23])[C:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C:15]2=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(C2=CCCCC2)c(O)c(C(C)(C)C)c1
Reactant: ClP(Cl)Cl
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP(Cl)C1=C2CCCC1
Yield: 87.8 %

Procedure:
A mixture consisting of 28.7 g (0.10 mol) of 2,4-di-tert-butyl-6-cyclohexen-1-yl-phenol (compound 102, Example 1b) and 17.5 ml (0.20 mol) of phosphorus trichloride is refluxed under nitrogen for 5 hours. Excess phosphorus trichloride is removed by distillation and the residue is then distilled under vacuum at 165-167° C./0.01 mbar, giving 30.8 g (88%) of 6,8-di-tert-butyl-10-chloro-2,3,4,10-tetrahydro-l H-9-oxa-10-phosphaphenanthrene, a colourless thick liquid which slowly crystallises when standing; 31P--NMR (CDCl3): δ=130.5 ppm (s); 1H--NMR (CDCl3): δ(ppm): 1.34 (s, 9H, (CH3)3C--), 1.44 (s, 9H, (CH3)3C--), (compound (202), Table 2).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:23])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[C:7]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:49])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:49][CH2:23][C:3]1[C:2]([F:1])=[C:11]2[C:6]([C:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c2ccc(C)c(F)c2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CBr)c(F)c2n1
Yield: 84.7 %

Procedure:
Methyl 8-fluoro-4-(4-fluorophenyl)-7-methylquinoline-2-carboxylate 7-9 (991 mg, 3.16 mmol), Benzoyl peroxide (102 mg, 0.316 mmol), and NBS (591 mg, 3.32 mmol) were heated at reflux in CCl4 for 5 hours. The solvent was removed in vacuo and the residue purified by column chromatography on a silica gel column, eluting with EtOAc/hexane (0-50%) to afford Methyl 7-(bromomethyl)-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylate 7-10 (1.05 g, 85% yield) as a white solid, LCMS shows the compound is 67% pure, LRMS m/z (M+H)+ 392.0 found, 392.1 required.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11]/[CH:12]=[C:13](\[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)/[C:14](OCC)=[O:15].CO.Cl>O>[F:11]/[CH:12]=[C:13](\[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)/[CH2:14][OH:15]
Reactant: CCOC(=O)/C(=C/F)CCc1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: CO
Product: OC/C(=C/F)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cool to 0° C. a solution of diisobutylaluminum hydride (7.64 kg, 25% by weight in toluene, 13.42 mol). Add a solution of ethyl (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyrate (1.74 kg, 74.1% by weight in toluene, 5.37 mol) at such a rate that the temperature of the reaction mixture does not rise above 20° C. After the addition is complete, warm to ambient temperature. After 2 hours, cool to 0° C. Slowly, add methanol (7.73 kg) at such a rate that the temperature of the reaction mixture does not rise above 15° C. Cool to 0° C. Slowly, add water (7.96 kg) at such a rate that the temperature of the reaction mixture does not rise above 20° C. Add a concentrated aqueous solution of hydrochloric acid (7.59 kg). Warm to ambient temperature. Separate the organic layer and dry azeotropically by distillation in vacuo until the volume of the organic layer is about one half of its original volume to give the title compound as a solution in toluene.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=2)[N:14]=1.C(O)CC>N1C=CC=CC=1>[Cl:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:1](=[O:10])[CH:2]=[CH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: CCCO
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Nc1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
Cinnamoyl chloride (7.3 g) is added to a suspension of 2-amino-7-chloro-1,8-naphthyridine (7.2 g) in pyridine (80 cc). After stirred for 2 hours at 20° C., the suspension obtained is poured into distilled water (500 cc). The suspension is filtered, washed with water (3×50 cc) and dried at 50° C. under reduced pressure (0.07 kPa). The solid obtained (10.6 g; m.p. 263° C.) is dissolved in boiling 1-propanol (1200 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with 1-propanol (3×50 cc), diethyl ether (2×50 cc) and dried at 50° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-3-phenylpropenamide (11.4 g), m.p. 263° C., is obtained.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3].[NH2:19][C:20]1[CH:25]=[C:24]([NH2:26])[N:23]=[C:22]([SH:27])[N:21]=1>O.C(=O)(O)[O-].[Na+]>[OH2:3].[OH2:3].[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:27][C:22]3[N:23]=[C:24]([NH2:26])[CH:25]=[C:20]([NH2:19])[N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Nc1cc(N)nc(S)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1cc(N)nc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n1
Temperature: 60 °C
Yield: 82.5 %

Procedure:
2.7 g (0.01 mole) of 7-aminocephalosporanic acid are dissolved in 50 ml of water with the required amount of sodium bicarbonate. 1.7 g (0.013 mole) of 4,6-diamino-2-mercaptopyrimidine and the equivalent amount of sodium bicarbonate are added and the reaction solution is heated to 60° C. for 4 hours, whilst stirring and keeping the pH value constant (pH=7). The mixture is allowed to cool, undissolved material is filtered off and the filtrate is concentrated in vacuo at 30° C. to half its volume. The aqueous solution which remains is extracted several times with ethyl acetate and the aqueous phase is adjusted to a pH of 2 with 2 N hydrochloric acid. The precipitate is filtered off, washed with water until free from chloride and dried in vacuo at 37° C. over potassium hydroxide. 1.61 g of the title compound are obtained. Rf : 0.27 (acetone:glacial acetic acid =10:1) IR (KBr): 1,745 cm-1 (β-lactam band) NMR (d6 -DMSO, 60 MHz):
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([C@H:20]2[CH2:22][C@@H:21]2[CH2:23]O)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([C@H:20]2[CH2:22][C@@H:21]2[CH:23]=[CH2:25])[CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2CO)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=C[C@H]1C[C@@H]1c1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (1S,2S)-2-[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl]cyclopropylmethanol (3.00 g, 8.97 mmol) in CH2Cl2 (25 mL) was treated with 3 equiv. of NaHCO3 followed by Dess-Martin periodinane (7.60 g, 18.0 mmol, 2.0 equiv.). The solution was stirred for 2 h at room temperature. Saturated aqueous Na2SO3 (5 mL) and NaHCO3 (5 mL) were then added, and the biphasic mixture was stirred for 15 min and extracted with EtOAc (2×100 mL). The organic phase was washed with brine (50 mL), dried (Na2SO4), and concentrated in vacuo. The resulting aldehyde was purified by CC and directly used in the next reaction.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].Cl.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32]O)[CH2:27][CH2:26]2)=[CH:10][CH:9]=1>ClC(Cl)Cl>[ClH:3].[ClH:5].[Cl:5][CH2:32][CH2:31][N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:16]2[N:15]([CH2:14][C:11]3[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=2)[CH2:26][CH2:27]1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Fc1ccc(Cn2c(NC3CCN(CCCl)CC3)nc3ccccc32)cc1
Yield: 83 %

Procedure:
A mixture of 15 parts of thionyl chloride, 4 parts of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidineethanol dihydrochloride and 375 parts of trichloromethane is stirred and refluxed overnight. The precipitated product is filtered off and dried, yielding 13 parts (83%) of N-[1-(2-chloroethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine dihydrochloride; mp.>260° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]2[CH:6]([NH:9][C:10]3[O:11][CH2:12][C:13]4[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:7][O:8][C:4]=2[CH:3]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>>[Cl:23][CH2:24][C:25]([NH:20][C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:10]([NH:9][CH:6]3[C:5]4[CH:21]=[CH:22][C:2]([F:1])=[CH:3][C:4]=4[O:8][CH2:7]3)[O:11][CH2:12][C:13]=2[CH:19]=1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Product: O=C(CCl)Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Yield: 26.6 %

Procedure:
Prepared from rac-N2-(6-fluoro-2,3-dihydro-benzofuran-3-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 34) (748 mg, 2.5 mmol, HPLC 0.641 min) and chloroacetyl chloride (0.21 ml, 2.625 mmol) according to the procedure described for Example 3 step A. Obtained the title compound as a white solid (250 mg, 27%, HPLC 1.056 min), MS (ISP) m/e=376.1 [(M+H)+] and 378 [(M+2+H)+].