Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:17]([CH3:19])[CH3:18]>CN(C=O)C>[CH:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:19])[CH3:18]
Reactant: CC(C)I
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of 2 g (16.38 mmol) of 4-hydroxybenzaldehyde in 100 mL of DMF, 2.72 g (19.69 mmol) of K2CO3, 2.74 g (16.52 mmol) of KI and 3.94 mL (39.38 mmol) of 2-iodopropane was added under argon. The mixture was stirred at 80° C. overnight, concentrated and the residue obtained was partitioned between CHCl3 and H2O. The phases were separated, the aqueous phase was extracted with CHCl3 and the combined organic phases were dried over MgSO4 and concentrated. The crude product obtained was purified by chromatography on silica gel using EtOAc/hexane mixtures of increasing polarity as eluent, to give 2.08 g of the title compound of the example as an oil (77% yield).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH:14]([OH:18])[CH2:15][CH2:16][OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19]C1C2C(Cl)=CN(COC(O)CCO)C=2N=CN=1>>[NH2:19][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH:14]([OH:18])[CH2:15][CH2:16][OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCCC(O)OCn1cc(I)c2c(Cl)ncnc21
Reactant: Nc1ncnc2c1c(Cl)cn2COC(O)CCO
Product: Nc1ncnc2c1c(I)cn2COC(O)CCO

Procedure:
Compound 22c was prepared from 4-chloro-5-iodo-7-[(1,3-dihydroxypropoxy)methyl]pyrrolo[2,3-d]pyrimidine by the method described for 22a to yield 0.20 g (51%). mp=177°-177.5° C. 1H NMR (DMSO-d6): δ3.22-3.52 (m, 5); 4.58 (t, 2, exchanges with D2O, OH); 5.57 (s, 2, C-1'); 6.66 (bs, 2, exchanges with D2O, NH2); 7.55 (s, 1, C-6); 8.11 (s, 1, C-2). Anal. for C10H13N4O3I. (C,H,N).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:29][O:28][C:22]1[CH:23]=[C:24]([O:26][CH3:27])[N:25]=[C:20]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:9]=[CH:10][C:11]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:13]=3)[CH2:2][CH2:3]2)[N:21]=1
Reactant: CC(=O)NCc1ccc(CN2CCNCC2)cc1
Reactant: COc1cc(OC)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(N2CCN(Cc3ccc(CNC(C)=O)cc3)CC2)n1
Temperature: 0 °C
Yield: 64.2 %

Procedure:
A solution of N-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide (5.0 g) obtained in Example 88(2), 2-chloro-4,6-dimethoxypyrimidine (3.9 g) and potassium carbonate (4.2 g) in acetonitrile (50 ml) was refluxed under heating for 5 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-brown solid. The obtained pale-brown solid was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) and crystallized from diisopropyl ether to give the title compound (5.0 g) as white crystals.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[F:30][C@H:31]1[CH2:35][CH2:34][N:33]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:39]4[CH2:40][CH2:41][CH:36]([N:33]5[CH2:34][CH2:35][C@H:31]([F:30])[CH2:32]5)[CH2:37][CH2:38]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: F[C@H]1CCN(C2CCNCC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N4CC[C@H](F)C4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.1 g, 0.255 mmol), 4-((S)-3-fluoropyrrolidin-1-yl)piperidine (0.053 g, 0.307 mmol) and 4 Å molecular sieves (0.25 g) in DCE (4 mL) was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.109 g, 0.51 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 40:60) to give 565 as a white solid (0.121 g, 87%). LCMS (Method I): RT=2.26 min, [M+H]+ 548.2 1H NMR (400 MHz, DMSO-d6): δ 8.04-8.00 (m, 1 H), 7.65-7.61 (m, 1 H), 7.26-7.21 (m, 2 H), 5.16 (dt, J=56.0, 5.5 Hz, 1 H), 4.50-3.96 (m, 4 H), 3.82 (s, 3 H), 3.79-3.74 (m, 4 H), 3.75 (s, 2 H), 3.32-3.19 (q, J=7.4 Hz, 2 H), 2.89-2.74 (m, 4 H), 2.69-2.55 (m, 1 H), 2.37-2.28 (m, 1 H), 2.15-1.97 (m, 4 H), 1.90-1.74 (m, 3 H), 1.45-1.34 (m, 2 H), 1.34 (t, J=7.4 Hz, 3 H)
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[CH3:7][O:8][C:9]([C@H:11]1[C@H:16]([CH3:17])[O:15][C@@H:14]([CH3:18])[CH2:13][N:12]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[O:10]>>[CH3:7][O:8][C:9]([C@H:11]1[C@H:16]([CH3:17])[O:15][C@@H:14]([CH3:18])[CH2:13][N:12]1[S:19]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:2][C:3]#[C:4][CH2:5][CH3:6])=[CH:26][CH:27]=1)(=[O:21])=[O:20])=[O:10]
Reactant: CCC#CCCl
Reactant: COC(=O)[C@H]1[C@H](C)O[C@@H](C)CN1S(=O)(=O)c1ccc(O)cc1
Product: CCC#CCOc1ccc(S(=O)(=O)N2C[C@H](C)O[C@@H](C)[C@@H]2C(=O)OC)cc1

Procedure:
The title compound was prepared in a manner similar to Preparation 3 from 1-chloro-pent-2-yne and (2S,3R,6S)-4-(4-Hydroxy-benzenesulfonyl)-2,6-dimethyl-morpholine-3-carboxylic acid methyl ester. 1HNMR (400 MHz, CDCl3): δ=7.70 (d, J=8.9 Hz, 2H), 7.0 (d, J=8.9 Hz, 2H), 4.71 (bs, 2H), 4.52 (q, J=7.0 Hz, 1H), 4.27 (s, 1H), 3.97 (m, 1H), 3.54 (s, 3H), 2.98 (dd, J=12.1 and 10.8, 1H), 2.21 (m, 2H), 1.44 (d, J=6.9 Hz, 3H), 1.11 (t, J=7.5 Hz, 3H), 1.05 (d, J=6.0 Hz, 3H).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[S:18][CH:19]=[C:20]([C:22](=[O:25])[CH2:23]Br)[N:21]=1.C([SiH](CC)CC)C>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][N:4]2[CH2:3][CH2:2][O:25][CH:22]([C:20]3[N:21]=[C:17]([C:16]([F:27])([F:26])[F:15])[S:18][CH:19]=3)[CH2:23]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(CCNCCO)cc1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Agent: CC[SiH](CC)CC
Product: COc1ccc(CCN2CCOC(c3csc(C(F)(F)F)n3)C2)cc1

Procedure:
Prepared analogously to Example 32 by reaction of N-(2-hydroxyethyl)-2-(4-methoxyphenyl)ethanamine with 2-trifluoromethyl-4-bromoacetyl-thiazole followed by reduction with triethylsilane.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:27]([F:30])([F:29])[F:28])=[C:21]([S:23](Cl)(=[O:25])=[O:24])[CH:22]=3)[N:16]=2)[N:13]=1)[CH3:6]>C(#N)C>[CH:1]1([NH:4][S:23]([C:21]2[CH:22]=[C:17]([C:15]3[N:16]=[C:11]4[CH:10]=[CH:9][C:8]([O:7][CH2:5][CH3:6])=[N:13][N:12]4[CH:14]=3)[CH:18]=[CH:19][C:20]=2[C:27]([F:30])([F:28])[F:29])(=[O:24])=[O:25])[CH2:3][CH2:2]1
Reactant: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(S(=O)(=O)Cl)c3)cn2n1
Reactant: NC1CC1
Solvent: CC#N
Product: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(S(=O)(=O)NC4CC4)c3)cn2n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 66.7 %

Procedure:
A solution of cyclopropanamine (0.025 mL, 0.369 mmol) in acetonitrile (1 mL) is added 5-(6-ethoxyimidazo[1,2-b]pyridazin-2-yl)-2-(trifluoromethyl)benzene-1-sulfonyl chloride (0.123 mmol). The mixture is stirred at 60° C. for 12 hours. The mixture is concentrated to dryness and then purified via chromatography using a gradient of hexanes to EtOAc to afford 0.035 g (67%) of the title compound as a white solid: LCMS (m/z)=427.4 [M+H]+, tR=2.76 min. (compound same as Example 212)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C(O)CO>O>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1cccc(C(F)(F)F)c1
Solvent: OCCO
Solvent: O
Product: CCOC(=O)Cn1c(-c2cccc(C(F)(F)F)c2)nc2cccnc21
Yield: 88.3 %

Procedure:
A mixture of N-[3-[[3-(trifluoromethyl)benzoyl]amino]-2-pyridinyl]glycine ethyl ester (22.0 g, 0.06 mole) and ethylene glycol (100 ml) was heated at reflux for 40 minutes. The reaction mixture was poured into water (300 ml) and cooled. The solid was collected by filtration, washed with water (200 ml), and dried. The solid was recrystallized from isopropyl ether/tetrahydrofuran to give in 2 crops 18.4 g (0.053 mole) of crude 2-(3-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester. This solid together with potassium hydroxide pellets (4.7 g, 0.084 mole), 95% ethanol (150 ml), and water (10 ml) was refluxed for 21/2 hrs. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (100 ml) and extracted wth methylene chloride (2×30 ml). The aqueous portion was acidified with glacial acetic acid and filtered after precipitation was complete. The filter cake was suspended in water (200 ml) and filtered. Recrystallization from tetrahydrofuran-isopropyl ether gave 15.3 g (91%). A 1.6-g sample was recrystallized from tetrahydrofuranisopropyl ether to give 1.0 g of an off-white solid, mp 240°-241.5° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][OH:24])[CH2:19][CH2:18]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][OH:24])[CH2:19][CH2:18]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: N[C@H]1CC[C@H](CO)CC1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CO)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (200 mg, 0.83 mmol) was reacted with (trans-4-aminocyclohexyl)methanol (130 mg, 1.0 mmol) to afford the desired product (180 mg, 65%) as an orange-yellow solid: 1H NMR (500 MHz, CDCl3) δ 10.90 (s, 1H), 8.94 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 5.10-4.92 (m, 1H), 3.58-3.47 (m, 2H), 2.68 (s, 3H), 2.37-2.23 (m, 2H), 2.01-1.89 (m, 2H), 1.65-1.51 (m, 1H), 1.42-1.30 (m, 2H), 1.29-1.18 (m, 2H); ESI MS m/z 334 [M+H]+
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>>[Cl:23][CH2:24][C:25]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:26]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)CCl
Product: O=C(CCl)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 7 step A from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 180 step C) and chloroacetyl chloride. White solid. MS (ESI): 391.1 (MH+).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:13]=[CH:12][C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)([OH:4])=[O:3].[CH2:14](O)[CH3:15]>S(=O)(=O)(O)O>[CH2:14]([O:3][C:2]([C:5]1[CH:13]=[CH:12][C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4])[CH3:15]
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2nc[nH]c2c1

Procedure:
According to a method similar to that described in Zhur. Obschei Khim., vol. 32, pp 835-41 (1953), 3,4-diaminobenzoic acid was prepared. A formic acid solution (200 ml) of 3,4-diaminobenzoic acid (8 g) thus prepared was refluxed for 4 hrs to yield 5-carboxybenzimidazole.hydrochloride (8.9 g). The carboxylic acid (8.9 g) was refluxed with heating for 3.5 hrs in a mixture of sulfuric acid (4 ml) and absolute ethanol (140 ml) to yield 5-ethoxycarbonylbenzimidazole (mp. 93°-94° C., 7.8 g). An anhydrous tetrahydrofuran solution (20 ml) of the ester (7.5 g) was added to an anhydrous tetrahydrofuran suspension (50 ml) of lithium aluminium hydride (6.5 g) while cooling. The mixture was stirred for 3 hrs at room temperature to yield 5-hydroxymethylbenzimidazole (mp. 128.4° C., 3.62 g). A 47% aqueous hydrobromic acid solution (33 ml) containing the benzimidazole derivative (2.2 g) and cysteamine hydrochloride (1.9 g) was refluxed with heating for 7 hrs to yield 5-[(2-aminoethyl)thiomethyl]benzimidazole.2 hydrobromide (mp. 224°-225° C., 4.2 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[C:15]([CH3:20])=[N:16][O:17][C:18]=2[CH3:19])(=[O:13])=[O:12])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1.S(OC)(O[CH3:28])(=O)=O.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:28])[S:11]([C:14]2[C:15]([CH3:20])=[N:16][O:17][C:18]=2[CH3:19])(=[O:13])=[O:12])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(C)c1S(=O)(=O)N(C)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 35.3 %

Procedure:
To a suspension of sodium hydride (65%, 0.05 g (1.36 mmol)) in DMF (3.0 ml), N-(4-chloro-2-nitrophenyl)-3,5-dimethyl-4-isoxazolesulfonamide (0.30 g (0.90 mmol)) was added with stirring at room temperature. To the mixture, after stirring for one hour at room temperature, dimethyl sulfate (0.13 ml (1.36 mmol)) was added dropwise, and the mixture was stirred for 16 hours. Water (20.0 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with acetone-hexane (1:4) as eluent, to give 0.11 g (35%) of the title compound as white crystals.
Reaction SMILES: C[O:2][P:3]([CH2:7][NH:8][CH:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[O:11])([O:5]C)=[O:4]>Br>[P:3]([CH2:7][NH:8][CH:9]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][CH:28]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])([OH:5])([OH:4])=[O:2]
Reactant: COP(=O)(CNC(Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC(=O)OC(C)(C)C)OC
Agent: Br
Product: O=C(O)CCNC(=O)C(Cc1ccc(-c2ccccc2)cc1)NCP(=O)(O)O

Procedure:
A solution of t-butyl N-[2-(dimethylphosphonomethylamino)-3-(4-biphenylyl)propionyl]-3-aminopropionate (0.38 g, 0.78 mmol) in 30% HBr/glacial HOAc is stirred at room temperature for 6.5 hours. After concentration to about 1/10 volume, ether (40 mL) is added and the solid filtered. The solid is then suspended in water (3 mL), filtered off and washed with water to obtain N-[2-(phosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionic acid, m.p. 242°-244° dec.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:11])[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+]>CO>[CH3:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1csc(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.6 %

Procedure:
A solution of 2-methyl-thiazole-4-carboxylic acid ethyl ester (3.14 g, 20.00 mmol) in methanol (50.00 ml) was treated with 2N NaOH (30.00 ml) and stirred at room temperature for 45 min. Methanol was removed in vacuo and the resulting slurry was neutralized with HCl 2N (30.00 ml). The aqueous phase was then extracted three times with ethyl acetate. The combined organic layers were dried with sodium sulphate and evaporated. 2-Methyl-thiazole-4-carboxylic acid (2.48 g, 87%) was obtained as a yellow solid, MS (ISP): m/e=142.1 (M−H), which was used crude.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:21][C:22]1([CH3:32])[N:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:25]2[C:24](=[O:31])[NH:23]1.C(N(CC)CC)C>CN(C)C=O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][N:26]3[C:22]([CH3:32])([CH3:21])[NH:23][C:24](=[O:31])[CH:25]3[CH2:30]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(C(=CCCCBr)c2ccc(F)cc2)cc1
Reactant: CC1(C)NC(=O)C2CNCCN21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)C2CN(CCCC=C(c3ccc(F)cc3)c3ccc(F)cc3)CCN21
Temperature: 70 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of 51 parts of 1,1'-(5-bromo-1-penten-1-ylidene)bis[4-fluorobenzene], 25.4 parts of hexahydro-3,3-dimethylimidazo-[1,5-a]pyrazin-1(5H)-one, 35.5 parts of N,N-diethylethanamine and 270 parts of N,N-dimethylformamide was stirred overnight at 70° C. After evaporation, the residue was taken up in trichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 60 parts (94.0%) of 7-[5,5-bis(4-fluorophenyl)-4-pentenyl]hexahydro-3,3-dimethylimidazo[1,5-a]pyrazin-1(5H)-one as a residue (int. 24).
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([CH2:53][OH:54])[CH:49]=[C:50]([NH2:52])[CH:51]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1>>[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:51]=[C:50]([NH:52][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:18][CH2:19][N:20]([C:23]6[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=6)[CH2:21][CH2:22]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH:49]=[C:48]([CH2:53][OH:54])[CH:47]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(Cl)cc(Cl)c3)CC2)cc1C(=O)O
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(Cl)cc(Cl)c3)CC2)cc1C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 71.2 %

Procedure:
The same reaction procedure to the example 18 were carried out using 2-ethyl-5-{[4-(3,5-dichlorophenyl)-piperazine-1-carbonyl]-amino}-6-methoxynicotinic acid and [3-(acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[C:24]1([N:30]=[C:31]=[S:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:31](=[S:32])[NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: S=C=Nc1ccccc1
Reactant: O=C1c2ccccc2OCCC1(CO)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2OCCC1(CO)COC(=S)Nc1ccccc1

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]oxepin-5-one (500 mg, 2.25 mmol) in 28 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.34 ml, 2.5 mmol) and phenyl isothiocyanate (672 μl, 5.63 mmol). The mixture was heated to reflux for 72 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:1 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 149 mg (19%).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].[CH:6]([C:8]1[C@H:13]([C:14]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[N:12]2[C:30](=[O:42])[C@@H:31]([NH:32][C:33](=[O:41])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:11]2[S:10][CH:9]=1)=[O:7].[Cl-].[Li+].Cl>O1CCCC1.C(OCC)(=O)C>[OH:7][CH:6]([C:8]1[C@H:13]([C:14]([O:16][CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])[N:12]2[C:30](=[O:42])[C@@H:31]([NH:32][C:33](=[O:41])[CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:11]2[S:10][CH:9]=1)[CH2:3][CH:2]=[CH2:1]
Reactant: C=CC[Mg]Cl
Reactant: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC(O)C1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
Allylmagnesium chloride (2M in diethyl ether, 4.0 ml, 8 mmol) was added to a solution containing diphenylmethyl (4R, 6R, 7R)-3-formyl-7-phenylacetamidoceph-2-em-4-carboxylate (0.5 g, 1.0 mmol) and lithium chloride (0.35 g, 8 mmol) in tetrahydrofuran (5 ml) at −70° C. After 20 minutes at −70° C., hydrochloric acid (1M, 10 ml, 10 mmol) was added. Ethyl acetate was added and the organic layer was separated, washed with brine, dried (MgSO4), and evaporated. The resulting oil was purified by chromatography (20% to 60% ethyl acetate in hexane, silica gel) giving; first the title compound S-diastereomer, 90 mg (17%), dH (CDCl3) 2.18 (1H, dt, J 15 Hz and 8 Hz), 2.36 (1H, dt, J 17 and 5 Hz), 3.45 (2H, ABq), 4.18 (1H, m), 4.95-5.15 (4H, m), 5.55-5.7 (2H, m), 6.11 (1H, d, J 9 Hz), 6.36 (1H, s), 6.89 (1H, s), 7.3-7.4 (15H, m), and second; the title compound R-diastereomer, 250 mg (45%), dH (CDCl3) 2.28 (2H, t, J 7 Hz), 3.62 (2H, ABq), 4.15 (1H, t, J 7 Hz), 4.95-5.2 (4H, m), 5.5-5.65 (2H, m), 6.16 (1H, d, J 9 Hz), 6.20 (1H, s), 6.89 (1H, s), 7.3-7.4 (15H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][CH:30]=1)[CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=2)=[N:12]1)=[O:5])[CH3:2].[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])=[O:37])([CH3:34])([CH3:33])[CH3:32].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C:7]1[CH:30]=[CH:29][CH:28]=[C:9]([CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25](=[O:26])[NH:43][CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])=[CH:22][CH:23]=3)=[N:12]2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CC(=O)O)cc3)ccc2=O)c1
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CC(=O)NCCCCNC(=O)OC(C)(C)C)cc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
120 mg (0.295 mmol) of 4-[1-(3-ethoxycarbonylaminobenzyl)-6-oxo-1,6-dihydropyridazin-3-yl]phenylacetic acid are suspended in 2 ml of DMF, and 68 μl (0.354 mmol) of N-tert-butyloxycarbonyl-1,4-diaminobutane, 66 μl (0.59 mmol) of 4-methylmorpholine, 41 mg (0.3 mmol) of 1-hydroxybenzotriazole and 114 (0.59 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride are added. The reaction mixture is stirred at room temperature for 24 h and purified by means of preparative HPLC.