Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:19])[N:8]2[C@H:11]2[CH2:16][CH2:15][C@H:14]([O:17][CH3:18])[CH2:13][CH2:12]2)=[C:4]([Cl:20])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:74]1[CH:75]=[C:76]([CH:79]=[CH:80][C:81]=1[N+:82]([O-:84])=[O:83])[C:77]#[N:78]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:20][C:4]1[N:3]=[C:2]([NH:1][C:80]2[CH:79]=[C:76]([CH:75]=[CH:74][C:81]=2[N+:82]([O-:84])=[O:83])[C:77]#[N:78])[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:19])[N:8]2[C@H:11]1[CH2:12][CH2:13][C@H:14]([O:17][CH3:18])[CH2:15][CH2:16]1
Reactant: CO[C@H]1CC[C@H](n2c(=O)[nH]c3c(Cl)nc(N)nc32)CC1
Reactant: N#Cc1ccc([N+](=O)[O-])c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CO[C@H]1CC[C@H](n2c(=O)[nH]c3c(Cl)nc(Nc4cc(C#N)ccc4[N+](=O)[O-])nc32)CC1
Temperature: 100 °C

Procedure:
To an oven-dried 250 mL round bottom flask was added 2-amino-6-chloro-9-(trans-4-methoxycyclohexyl)-7H-purin-8(9H)-one (crude, 3.65 g, 12.28 mmol, 1 equiv.) in anhydrous toluene (50 mL), then freshly grounded cesium carbonate (6 g, 18.43 mmol, 1.5 equiv.) with stirring at room temperature under Ar. Pd(OAc)2 (1.24 g, 1.84 mmol, 0.15 equiv.), racemic BINAP (2.67 g, 4.3 mmol, 0.35 equiv.) and 3-bromo-4-nitro-benzonitrile (3.6 g, 15.96 mmol, 1.3 eq) were all added as solids. The reaction was performed under a flow of Argon, with heating at 100° C. for two days. The reaction mixture was cooled to room temperature, then concentrated in vacuo and the resulting residue was purified using flash chromatography (silica gel, gradient elution 10% EtOAc in hexanes to 50% EtOAc in hexanes) to give the desired product as an orange solid (50% yield). MS (EI) m/z 444 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([NH:23][NH2:24])=[N:21][CH:22]=1)[CH:14]=[CH:13][O:12]2.[CH3:25][CH:26]([CH3:29])[CH:27]=O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:25]([CH:26]([CH3:29])[CH3:27])=[N:24][N:23]=3)[CH:22]=1)[CH:14]=[CH:13][O:12]2
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3occn23)cn1
Reactant: CC(C)C=O
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: CO
Product: CC(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)cn12
Temperature: 60 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
In a round bottom flask {5-[6-(2,4-difluorophenyl)-imidazo[2,1-b]oxazol-5-yl]-pyridin-2-yl}-hydrazine (0.35 g, 1.1 mmol) and 2-methylpropionaldehyde (0.1 mL, 1.1 mmol) was dissolved in MeOH (5 mL) followed by heating to about 60° C. for about 1 h. The reaction was allowed to cool to ambient temperature and then iodobenzene diacetate (0.35 g, 1.1 mmol) was added followed by stirring for about 1 h. The reaction was then purified directly by flash chromatography using DCM/MeOH (90:10) as eluent followed by titration with Et2O to provide the title compound (0.075 g, 18%) as an off-white solid: LC/MS (Table 1, Method a) Rt, =2.12 min; MS m/z: 380.2 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:12]([OH:14])=O)([CH3:8])[CH3:7].[NH2:23][CH:24]1[C:39](=[O:40])[N:26]2[C:27]([C:36]([OH:38])=[O:37])=[C:28]([CH2:31][O:32][C:33](=[O:35])[NH2:34])[CH2:29][S:30][C@H:25]12.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.CC(C)=O.CN(C)C=O>[CH:6]([O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:12]([NH:23][CH:24]1[C:39](=[O:40])[N:26]2[C:27]([C:36]([OH:38])=[O:37])=[C:28]([CH2:31][O:32][C:33](=[O:35])[NH2:34])[CH2:29][S:30][C@H:25]12)=[O:14])([CH3:7])[CH3:8]
Reactant: CC(C)ON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
Phosphorus oxychloride (0.92 g) was added dropwise over 3 minutes at -5° to -10° C. to a solution of dimethylformamide (0.44 g) in ethyl acetate (2 ml). Ethyl acetate (20 ml) was added thereto and after 10 minutes, 2-isopropoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (syn isomer)(1.29 g) was added thereto at -5° to -10° C. The mixture was stirred for 10 minutes to give a clear solution. On the other hand, 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (1.37 g) was dissolved under stirring in a solution of sodium bicarbonate (1.68 g) in water (30 ml), and then acetone (20 ml) was added thereto. To the solution was added dropwise with stirring the ethyl acetate solution obtained above at 0° to 5° C. and at pH 6.5 to 7.5. After stirring for 20 minutes at the same temperature, the aqueous layer was separated and acetone was distilled off. The remaining aqueous layer was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling and stirring. Precipitates were collected by filtration, washed with water and dried to give 7-[2-isopropoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)(1.5 g).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5](/[CH:9]=[C:10](/[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)\[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.C(O)C.C([O-])=O.[NH4+].C(OCC)(=O)C>[Pd].C(O)(=O)C>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)/C(=C\c1cccc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)C(Cc1cccc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Yield: 124 %

Procedure:
A three neck, one liter round bottom flask equipped with condenser, thermometer, nitrogen line and magnetic stirrer was charged with Z-3-(3-trifluoromethylphenyl)-2-(4-trifluoromethylphenyl)-acrylic acid (103, 2.28 g, 6.3 mmol), ethanol (104 mL), palladium black (101.1 mg) and ammonium formate (1.608 g, 25.5 mmol). The reaction mixture was heated to 80° C. for 4 hours. An aliquot was taken and TLC (solvent system was 20% ethyl acetate in hexanes with an acetic acid spike) showed absence of starting material. The solution was cooled to room temperature and vacuum filtered using a glass frit funnel. The solution was concentrated by rotary evaporation and high vaccum, yielding 3-(3-trifluoromethylphenyl)-2-(4-trifluoromethylphenyl)-propionic acid (2.83 g) 105.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)=[CH:5][CH:4]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][CH:11]([O:14][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: OC1CCN(c2ccncc2)C1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Product: O=[N+]([O-])c1ccc(OC2CCN(c3ccncc3)C2)nc1

Procedure:
Sodium hydride (60% dispersion in paraffin oil, 146 mg) 1.2 equivalent) was added to an oven-dried round-bottomed flask and washed under an argon atmosphere with pentane. DMF (5 ml) was then added, followed by 1-(4-pyridyl)-3-hydroxypyrrolidine (1.0 equivalent, 3.05 mmol) and tetra-n-butylammonium bromide (59 mg, 0.18 mmol). The mixture was added as a slurry to 2-bromo-5-nitropyridine (1.5 equivalent) in a second dry flask under argon, with stirring. After the reaction was complete the solvent was evaporated under vacuum. The residue was purified by chromatography on silica, eluting from 1%MeOH/1%NH4OH/CH2Cl2 to 10%MeOH/1%NH4OH/CH2Cl2 (in 1% increments). The crude product was recrystallised from EtOAc to give 1-(4-pyridyl)-3-(5-nitro-2-pyridyloxy)pyrrolidine as a pale brown solid (460 mg);
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12](=[O:13])[C:11]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[NH:10][C:9]2=[O:19])=[CH:5][CH:4]=1.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:30]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12](=[O:13])[C:11]3([CH2:14][CH2:15][N:16]([CH2:30][CH2:29][CH:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:17][CH2:18]3)[NH:10][C:9]2=[O:19])=[CH:20][CH:21]=1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Reactant: O=C1NC2(CCNCC2)C(=O)N1Cc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC2(CCN(CCC(c3ccccc3)c3ccccc3)CC2)C(=O)N1Cc1ccc(Br)cc1
Temperature: 60 °C
Yield: 32.1 %

Procedure:
A mixture of 26.2 mg (70 μmol) of 3-(4-bromo-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride, 21.4 mg (70 μmol) of 3,3-diphenylpropyl bromide and 29 mg (210 μmol) of potassium carbonate in 1 mL of anhydrous DMF was heated overnight at 60° C. After cooling to room temperature, 0.5 mL of water was added and the solution was extracted with DCM (2×2 mL). The crude material was purified by semi-preparative HPLC (method A) yielding 12.8 mg (32.1%) of Compound 3 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]=[N+]=[N-])[CH2:7][N:6]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH2:10])[CH2:7][N:6]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4]
Reactant: COC(=O)C1CC(N=[N+]=[N-])CN1Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CC(N)CN1Cc1ccccc1
Reaction time: 6 h

Procedure:
To a solution of 4-azido-1-benzyl-pyrrolidine-2-carboxylic acid methyl ester (9) in THF under N2 is added triphenylphosphine and water. The mixture is refluxed with stirring for about 6 h. After removal of THF, the residue is dissolved in Et2O, treated with HCl, stirred for 5 min, and extracted with Et2O. The aqueous solution is then treated with NaHCO3 and extracted, dried and concentrated to afford product 4-amino-1-benzyl-pyrrolidine-2-carboxylic acid methyl ester (10).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].O=C1CCC(=O)N1[O:41][C:42](=O)[NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:42]([NH:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)=[O:41])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Nc1ccccn1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4ccccn4)c3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.4 g, 2.4 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) in acetonitrile (50 mL). After stirring for 30 minutes, pyridin-2-yl-carbamic acid 2,5-dioxo-pyrrolidin-1-yl ester (0.7 g, 3.0 mmol) was added, and the mixture was stirred at room temperature overnight. The solid was collected and slurried with hot acetone (20 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-pyridin-2-yl-urea (0.5 g, 64%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.49-2.65 (m, 2H), 2.84-2.79 (m, 1H), 4.83 (d, J=6.1 Hz, 2H), 5.14-5.21 (dd, J=5.5 and 12.7 Hz, 1H), 6.91-6.96 (m, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.64-7.88 (m, 4H), 8.17-8.20 (dd, J=1.3 and 5.0 Hz, 1H), 8.90 (t, J=5.7 Hz, 1H), 9.44 (s, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 21.96, 30.92, 38.67, 48.85, 93.31, 111.57, 116.91, 121.90, 127.20, 131.67, 133.43, 134.80, 138.23, 139.82, 146.69, 153.27, 154.93, 166.97, 167.49, 169.81, 172.75; Anal. calcd. for C20H17N5O5: C, 58.97; H, 4.21; N, 17.19. Found: C, 58.69; H, 4.10; N, 17.05.
Reaction SMILES: Br.[NH2:2][C@@H:3]([CH2:8][C:9]([F:12])([F:11])[CH3:10])[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[C:19](Cl)(Cl)=[O:20].C1(C)C=CC=CC=1>ClCCl>[F:12][C:9]([F:11])([CH3:10])[CH2:8][C@H:3]([N:2]=[C:19]=[O:20])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@@H](N)CC(C)(F)F
Reactant: O=C(Cl)Cl
Agent: Br
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)[C@H](CC(C)(F)F)N=C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
The compound from example 6 (6.76 g, 28.8 mmol) was initially charged and dissolved in 240 ml of dichloromethane and 9.46 ml (117 mmol, 4.05 eq) of pyridine, cooled down to 0° C. in an ice bath for 15 min and admixed with 19.86 ml of a 20% phosgene solution in toluene (37.54 mmol, 1.3 eq) within 20-30 seconds. The mixture was stirred at 0° C. for a further 2 h, then the reaction mixture was extracted with cold half-molar HCl and ice. The water phases were reextracted with dichloromethane, and the combined organic phases were washed with ice and saturated NaCl solution, then dried over MgSO4 and filtered off from the desiccant. Concentration by evaporation under reduced pressure left 5.21 g of brown oil (corresponded to a yield of 94%), which was reacted further directly.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:38])=[C:17]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH3:28])=[C:23]([CH:26]=1)[CH:24]=[O:25]>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:38])=[C:17]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH3:28])=[C:23]([CH:26]=1)[C:24]([OH:11])=[O:25]
Reactant: OO
Reactant: COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C=O
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
An aqueous solution (5 ml) of sodium dihydrogenphosphate (1.06 g, 8.86 mmol), an aqueous solution (7 ml) of sodium chlorite (0.460 g, 5.11 mmol) and aqueous hydrogen peroxide (0.502 ml, 30%) were added to an acetonitrile solution (10 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-methoxybenzaldehyde (0.409 g, 1.14 mmol) and the resulting solution was stirred at room temperature for 5 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the titled compound (0.260 g, 0.691 mmol, 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH2:13])[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](O)=[O:32].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][C:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[O:32])[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(O)c1ccccn1
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(N)C1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NC(=O)c2ccccn2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
To a solution of 0.100 g (0.30 mmol) of (+/−)-9-amino-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester dissolved in 1.50 mL of dimethylformamide was added 0.041 g (0.33 mmol) of 2-pyridine carboxylic acid. To the resulting mixture was added 50 μL (0.33 mmol) of diethyl cyanophosphonate and 130 μL (0.91 mmol) of triethylamine at 0° C. The resulting mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added and the mixture was stirred. The resulting residue was filtered, washed with water, ethyl acetate and diethyl ether to afford 0.098 g (76%) of the pure product as a white powder.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[H-].[Na+].[CH2:11]([S:14](Cl)(=[O:16])=[O:15])[CH2:12][CH3:13].O>O1CCCC1>[CH2:11]([S:14]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:16])=[O:15])[CH2:12][CH3:13]
Reactant: C#CC(O)(CF)CF
Reactant: CCCS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CC(CF)(CF)OS(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An amount (2.4 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol was dissolved in tetrahydrofuran (20 ml); to the solution under cooling with ice, 60% oily sodium hydride (0.96 g) was added under a nitrogen atmosphere. After stirring for 30 minutes under cooling with ice, propanesulfonyl chloride (2.2 ml) was added dropwise. The mixture was stirred for 5 hours while its temperature was raised to room temperature. Water was added to the reaction mixture, followed by extraction with ether. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; 30% ethyl acetate/hexane) to give the titled compound (4.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([Si](C)(C)C)[O:10][N:9]=2)=[CH:4][CH:3]=1.[F-].[Cs+]>CCO.CC#N.[NH4+].[Cl-]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)c1cc(-c2ccc(Br)cc2)no1
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: CC#N
Product: Brc1ccc(-c2ccon2)cc1
Reaction time: 0.08 h

Procedure:
The product from Example 42B (0.103 g) in EtOH (0.7 mL) and MeCN (2.1 mL) was treated with CsF (72 mg, 0.47 mmol), stirred for 5 minutes, diluted with saturated NH4Cl (7 mL), and extracted with CH2Cl2 (2×7 mL). The organic extract was dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (7% ethyl acetate in hexanes) to provide the title compound.
Reaction SMILES: [CH3:1][CH:2]([NH:22][C:23]1[S:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1)[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].CO.Cl>O.O1CCCC1>[CH3:1][CH:2]([NH:22][C:23]1[S:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1)[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)Cc1ccc(OCc2ccc(C(C)Nc3nc(-c4ccccc4)cs3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(Nc1nc(-c2ccccc2)cs1)c1ccc(COc2ccc(CC(=O)O)cc2)cc1

Procedure:
A mixture of methyl 4-[4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzyloxy]phenylacetate (510 mg), a 1N aqueous sodium hydroxide solution (2.5 mL), methanol (5 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 1 hr. Water was added to the reaction mixture, 1N hydrochloric acid (3 mL) was added to the mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of 4-[4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzyloxy]phenylacetic acid. The crystals were recrystallized from diethyl ether-hexane to give colorless prism crystals (427 mg, 87%). melting point: 116-118° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:9]=2[CH2:8][C:7]1=[O:26])[CH3:2].[C:28](N=P(N=P(N(C)C)(N(C)C)N(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)([CH3:31])([CH3:30])[CH3:29].ICC(C)C.Cl>C1COCC1.CCCCCC.O>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:7](=[O:26])[CH:8]([CH2:29][CH:28]([CH3:31])[CH3:30])[C:9]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:10]=2[CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH2:12]1)[CH3:2]
Reactant: CN(C)P(=NP(=NC(C)(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)(N(C)C)N(C)C
Reactant: CCOC(=O)CN1CC(c2ccccc2OC)c2cc(Cl)ccc2CC1=O
Agent: CC(C)CI
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)CN1CC(c2ccccc2OC)c2cc(Cl)ccc2C(CC(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
134 mg of the compound from Example 22A (0.35 mol) are dissolved in 1.35 ml of THF. At −78° C., 0.52 ml of a 1 M solution of 3-tert-butylimino-1,1,1,5,5,5-hexakis(dimethylamino)-3-(tris(dimethylamino)phosphoranylidene)amino-1λ5,3λ5,5λ5-1,4-triphosphazadiene (P4-t-Bu; 328 mg, 0.52 mol) in n-hexane is added drop wise, and the reaction solution is stirred at −78° C. for 30 min. 191 mg of 1-iodo-2-methylpropane (1.04 mol) are added drop wise, and the mixture is stirred at −78° C. for a further 2 h. The reaction solution is mixed with 10 ml of 1 N hydrochloric acid and water and extracted three times with dichloromethane. The combined organic phases are washed with saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water, gradient 20:80→95:5). 87 mg (57% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1CN2C(=NCCC2)C1.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[N:27]=1>CC#N>[Br:25][C:26]1[N:27]=[C:28]([CH2:32][O:1][N:2]=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: Cn1nnnc1C(=NO)c1ccccc1
Reactant: BrCc1cccc(Br)n1
Agent: C1CN=C2CCCN2C1
Solvent: CC#N
Product: Cn1nnnc1C(=NOCc1cccc(Br)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
To a cooled (0° C.) stirred solution of N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (6.47 g, 31.88 mmol, 1.0 eq.) in 250 ml of MeCN, was added dropwise DBN (4.35 g, 35.07 mmol, 1.0 eq.). The reaction was stirred for 5 mins before addition of 2-bromo-6-(bromomethyl)pyridine (8.8 g, 35.07 mmol, 1.1 eq.) portionwise. The mixture was stirred for further 5 mins before removal of the cooling bath and continued at ambient temperature. MeCN was evaporated and the residue was purified by chromatography on silica gel to yield N-[(6-bromopyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (9.4 g, 75% yield, 10:1 mixture of stereoisomers) as a pale yellow oil.