Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:22]([OH:24])=[O:23])=[N+:15]=[N-:16]>C(#N)C>[N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:22]([O:24][CH2:2][C:1]#[N:4])=[O:23])=[N+:15]=[N-:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN=[N+]=[N-])C(=O)O
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN=[N+]=[N-])C(=O)OCC#N
Reaction time: 3.75 h
Yield: 109.4 %

Procedure:
N,N-Diisopropylethylamine (99 μL, 0.566 mmol) and subsequently bromoacetonitrile (179 μL, 2.57 mmol) were added to a solution of (S)-6-azido-2-((tert-butoxycarbonyl)amino)hexanoic acid (Compound tk48) (140 mg, 0.514 mmol) in acetonitrile (0.6 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 3.75 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 6-azido-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk49) (175 mg, quant.).
Reaction SMILES: C1(C(O)C(Cl)(Cl)Cl)CCCC=C1.O=O.[Na].[CH:16]1([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1>CO.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[C:16]1([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: COC(=O)C1C=CCCC1
Agent: O=O
Agent: OC(C1C=CCCC1)C(Cl)(Cl)Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)C1=CCCCC1
Yield: 59 %

Procedure:
1-(2-Cyclohexen-1-yl)-2,2,2-trichloroethanol (20 g; 87.3 m. moles) was added to a solution of cupric chloride dihydrate (0.25 g; 1.47 m. moles) and a 1,10-phenanthroline hydrate (0.75 g; 3.8 m. moles) in methanol (150 ml). A rapid stream of oxygen was passed through the vigorously stirred solution and a solution of sodium (2.5 g; 108.5 m. moles) in methanol (50 ml) was added over a period of 41/4 hours. A solution of cupric chloride dihydrate (0.125 g; 0.733 m. moles) and 1,10-phenanthroline hydrate (0.375 g; 1.9 m. moles) in methanol (10 ml) was then added and the reaction allowed to proceed for a further 11/4 hours at a temperature of 20°-25° C. The reaction mixture was poured into ice-cold dilute hydrochloric acid, extracted with ether (4×100 ml) and the combined extracts washed twice with dilute aqueous sodium carbonate. The dried (MgSO4) extract was evaporated and the residue distilled to give a mixture of methyl 2-cyclohexene-1-carboxylate and methyl 1-cyclohexene-1-carboxylate (7.2 g; yield 59%), b.p. 80°-85° C./12 mm, containing about 90% of the former as indicated by G.L.C.
Reaction SMILES: [C:1]([N:4]([CH3:47])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]4[N:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]3[C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([C:35]3([NH:39]C(=O)OC(C)(C)C)[CH2:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[ClH:48].O1CCOCC1>CO>[ClH:48].[ClH:48].[ClH:48].[NH2:39][C:35]1([C:32]2[CH:33]=[CH:34][C:29]([C:28]3[N:14]4[C:15]5[CH:27]=[CH:26][CH:25]=[N:24][C:16]=5[NH:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[C:13]4=[N:12][C:11]=3[C:8]3[CH:7]=[CH:6][C:5]([N:4]([CH3:47])[C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=3)=[CH:30][CH:31]=2)[CH2:38][CH2:37][CH2:36]1
Reactant: CC(=O)N(C)c1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)N(C)c1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 93 %

Procedure:
tert-Butyl {1-[4-(2-{4-[acetyl(methyl)amino]phenyl}-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (30 mg, 0.048 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at room temperature for 20.5 hours. The mixture was concentrated to afford the desired product (28 mg, 93%) as a yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.68 (br s, 2H), 8.62 (s, 1H), 8.10 (dd, J=4.9 Hz and 1.4 Hz, 1H), 7.96 (dd, J=7.7 Hz and 1.4 Hz, 1H), 7.56 (d, J=8.6 Hz, 3H), 7.37 (d, J=8.6 Hz, 2H), 7.31-7.26 (m, 2H), 7.13 (t, J=8.6 Hz, 1H), 6.88 (dd, J=8.0 Hz and 1.1 Hz, 1H), 6.73 (dd, J=8.0 Hz and 4.6 Hz, 1H), 3.73-3.65 (m, 1H), 3.51-3.45 (m, 1H), 3.17-3.13 (m, 2H), 2.59-2.47 (m, 3H), 2.23-2.15 (m, 2H), 1.88-1.75 (m, 3H). LCMS: 527 [M+H].
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([Cl:24])=[C:16]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[S:17][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].ClC(OC(Cl)C)=O>ClC(Cl)C.C(Cl)Cl.CO>[Cl:24][C:15]1[C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[S:17][C:16]=1[C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)C(=O)c1sc2c(c1Cl)CCN(Cc1ccccc1)CC2
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)C(=O)c1sc2c(c1Cl)CCNCC2
Temperature: 22 °C

Procedure:
A solution of the product from step (h) (assumed 0.35 mmol) in anhydrous dichloroethane (2 ml) was cooled to 0° C., treated with K2CO3 (˜50 mg) and 1-chloroethyl chloroformate (0.38 ml, 3.5 mmol). The reaction was allowed to warmed to 22° C. for 18 hours. The reaction diluted with CH2Cl2 (50 ml) and washed with sat. NaHCO3 (2×50 ml), brine (50 ml), dried (MgSO4) and solvent evaporated in vacuo providing an oily residue, which was dissolved in anhydrous MeOH (10 ml) and refluxed for 1.5 hours. The MeOH was evaporated in vacuo to give the crude product. A portion of the crude was purified by preparative HPLC-MS to give the title compound. 1H NMR (300 MHz, CDCl3) δ 6.25 (br s, 1 H); 3.05-3.19 (m, 8 H); 1.34 (s, 9 H); MS: ESI (positive): 272, 274 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH2:7][CH2:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1>[OH-].[Na+].[Pd]>[CH3:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:5]2=[CH:4][N:3]=1
Reactant: Cc1ncc2n1CCC=C2c1ccc(NS(C)(=O)=O)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Cc1ncc2n1CCCC2c1ccc(NS(C)(=O)=O)cc1

Procedure:
Dissolve 5 g (16.5 mmol) of the product from Example VI in 100 ml of in sodium hydroxide and hydrogenate over 2 g of 10% palladium on carbon at 50 psi for 16 hr. Remove the catalyst and neutralize the filtrate with ammonium chloride. Extract with 2×100 ml of methylene chloride. Dry the combined extracts over sodium sulfate and remove the solvent in vacuo. Crystallize the residue from ethyl acetate to provide the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:8]=[C:9]([C:14](=[O:38])[CH2:15][NH:16][C:17](=O)[CH2:18][CH2:19][C:20]2[N:21](S(N(C)C)(=O)=O)[CH:22]=[C:23]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28])[N:24]=2)[CH:10]=[CH:11][C:12]=1[F:13].C(=O)(O)[O-].[Na+]>C(#N)C.C(Cl)Cl>[F:6][C:7]1[CH:8]=[C:9]([C:14]2[O:38][C:17]([CH2:18][CH2:19][C:20]3[NH:24][C:23]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28])=[CH:22][N:21]=3)=[N:16][CH:15]=2)[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCC(=O)NCC(=O)c2ccc(F)c(F)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: CCC(C)(C)Cc1cnc(CCc2ncc(-c3ccc(F)c(F)c3)o2)[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (190 mg, 1.2 mmol) was added to a solution of N-[2-(3,4-difluorophenyl)-2-oxoethyl]-3-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]propanamide (for synthesis see example 234) (30 mg, 0.06 mmol) in dry acetonitrile (4 mL) at rt. After stirring at 80° C. overnight, saturated sodium bicarbonate (ca. 3 mL) was added. The aqueous phase was washed with 1:5 ethyl acetate/diethyl ether, basified with 5N aqueous sodium hydroxide and extracted with ethyl acetate. Combined extracts were washed with brine, dried (sodium sulfate) and concentrated to give a residue. The residue was dissolved in methylene chloride to give the title compound, which was acidified with 1M HCl in diethyl ether. Additional diethyl ether and hexane were added, and concentration afforded the HCl salt of the title compound. LC-MS: m/e 360 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]=1[S:12]([OH:15])(=O)=[O:13])=[O:5])[CH3:2].S(Cl)([Cl:18])=O>>[Cl:18][S:12]([C:7]1[CH2:8][O:9][CH2:10][CH2:11][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:15])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C1=C(S(=O)(=O)O)COCC1
Product: CCOC(=O)C1=C(S(=O)(=O)Cl)COCC1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
4-(Ethoxycarbonyl)-5,6-dihydro-2H-pyran-3-sulfonic acid (27.5 g) was dissolved in thionyl chloride (82.6 ml) and the mixture was stirred at room temperature →85° C. for 3 h. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in ethyl acetate (100 ml). The obtained solution was partitioned by adding diluted brine (120 ml). The ethyl acetate layer was washed twice with saturated brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/7→1/5). The objective product was concentrated under reduced pressure and the crystals produced by freezing were washed with hexane to give ethyl 5-(chlorosulfonyl)-3,6-dihydro-2H-pyran-4-carboxylate (7.81 g) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([C:4]([CH2:15][CH:16]=[CH2:17])(C(OCC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].[C-]#N.[Na+].CS(C)=O>O>[C:5]([CH:4]([CH2:1][CH:2]=[CH2:3])[CH2:15][CH:16]=[CH2:17])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C=CCC(CC=C)(C(=O)OCC)C(=O)OCC
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCC(CC=C)C(=O)OCC
Temperature: 160 °C
Yield: 78.1 %

Procedure:
A mixture of diethyl diallylmalonate (701; 50 g, 208 mmol), sodium cyanide (20.7 g, 422 mmol) and DMSO (166 mL) was heated at 160° C. for 6 h. After being cooled to r.t., the mixture was added to 400 mL of water and the product was extracted into hexane (4×100 mL). After evaporation of the solvent at reduced pressure, the residue was distilled (42-43° C./1 Torr) to give 27.34 g (78%) of 702 as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 5.80-5.70 (m, 2H, 2 CH═CH2), 5.10-5.02 (m, 4H, 2 CH═CH2), 4.14 (q, 2H, J=7.2 Hz, OCH2), 2.54-2.48 (m, 1H, CH), 2.41-2.34, 2.29-2.23 (2m, 4H, 2CH2), 1.25 (t, J=7.2 Hz, 3H, CH3).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[O:14]=[C:15]1[C:20]2=[CH:21][NH:22][C:23]([CH:24]=O)=[C:19]2[CH2:18][CH2:17][NH:16]1.N1CCCCC1>C(O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:24][C:23]1[NH:22][CH:21]=[C:20]3[C:19]=1[CH2:18][CH2:17][NH:16][C:15]3=[O:14])[C:7](=[O:13])[NH:8]2
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2c(CCO)cccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cccc(CCO)c2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (35.4 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (32.8 mg, 0.2 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[C:25]2[O:26][C@H:27]([CH2:30]C3C=C(C)C=CC=3S([O-])(=O)=O)[CH2:28][O:29][C:24]=2[CH:23]=[CH:22][CH:21]=1>CN(C)C=O.O1CCCC1.C(=O)(O)[O-].[Na+]>[CH3:18][O:19][C:20]1[C:25]2[O:26][CH:27]([CH2:30][N:1]3[CH2:2][CH:3]=[C:4]([C:7]4[C:15]5[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=5)[NH:9][CH:8]=4)[CH2:5][CH2:6]3)[CH2:28][O:29][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: COc1cccc2c1O[C@H](Cc1cc(C)ccc1S(=O)(=O)[O-])CO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc2c1OC(CN1CC=C(c3c[nH]c4ccc(C#N)cc34)CC1)CO2
Yield: 56.6 %

Procedure:
3-(1,2,3,6-Tetrahydro-4-pyridinyl)1H-indole-5-carbonitrile (0.70 g, 3.1 mmole) and [(2R)-8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl-4-methylbenzenesulfonate (040 g, 1.1 mmole) were dissolved in a mixture of dimethylformamide/tetrahydrofuran (1:1 v/v, 50 mL) and sodium bicarbonate (1.0 g) added. The reaction mixture was refluxed under nitrogen for 18 hours. The solvent was evaporated in vacuum and the residue partitioned between 400 mL each of methylene chloride and water. The organic phase was separated, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuum to give a solid which was purified by column chromatography on silica gel. Elution with 2% methanol in chloroform, concentration of the product fractions in vacuum and treatment of an ethereal solution of the residue with 4 N isopropanolic HCl gave the (S)-enantiomer of the title compound (250 mg, 54% ) as a yellow solid hydrochloride, one-quarter hydrate, m.p. 235-238° C.
Reaction SMILES: Br[C:2]1[NH:3][C:4](=[O:11])[C:5]2[NH:6][CH:7]=[N:8][C:9]=2[N:10]=1.[N:12]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>COCCO>[N:12]1([CH2:18][CH2:19][NH:20][C:2]2[NH:3][C:4](=[O:11])[C:5]3[N:6]=[CH:7][NH:8][C:9]=3[N:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=c1[nH]c(Br)nc2nc[nH]c12
Reactant: NCCN1CCCCC1
Solvent: COCCO
Solvent: O
Product: O=c1[nH]c(NCCN2CCCCC2)nc2[nH]cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A mixture of 2-bromohypoxanthine (6 g, 28 mmol) and 2-piperidinoethylamine (7 ml, 56 mmol) in 2-methoxyethanol (30 ml) was heated to reflux overnight. The mixture was cooled to ambient temperature, giving rise to a yellow precipitate. Additional precipitate was generated on addition of water (50 ml). After stirring for 1 hour, the suspension was filtered and the solid obtained was washed with water and dried under vacuum to give the title compound (5.6 g). LC/MS SYSTEM C Rt=0.82 mins, m/z=263 MH+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH2:11][O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)[CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[C:14]3[C:15]([F:20])=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][CH2:11][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1COc1cc(F)cc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1c2ccc(Br)cc2COc2cc(F)cc(F)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
[step 2] 4-Bromo-2-[(3,5-difluorophenoxy)methyl]benzoic acid (11.4 g, 33.2 mmol) obtained in step 1 was dissolved in dichloromethane (111 mL), trifluoroacetic anhydride (9.4 mL, 66.4 mmol) and trifluoroborane diethyl ether complex (4.2 mL, 33.2 mmol) were added, and the mixture was stirred at room temperature for 4 hr. To the mixture were added 2 mol/L aqueous sodium hydroxide solution (100 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted 3 times with dichloromethane (300 mL). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained brown solid (12.6 g) was suspended in isopropylalcohol (100 mL), and the suspension was stirred at room temperature for 13 hr. The suspension was suction filtered, and the obtained solid was dried under reduced pressure to give 8-bromo-1,3-difluorodibenzo[b,e]oxepin-11(6H)-one (9.3 g, 86%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:14][C:15](=[O:46])[C@H:16]([CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])[NH:17][C:18](=[O:38])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[C:35]3[C:34](=[O:36])[N:33]=[C:32]([NH2:37])[NH:31][C:30]=3[NH:29][CH:28]=2)=[CH:21][CH:20]=1)C.[OH-].[Na+:48]>>[CH:21]1[C:22]([CH2:25][CH2:26][C:27]2[C:35]3[C:34]([NH:33][C:32]([NH2:37])=[N:31][C:30]=3[NH:29][CH:28]=2)=[O:36])=[CH:23][CH:24]=[C:19]([C:18]([NH:17][C@@H:16]([C:15]([O-:46])=[O:14])[CH2:39][CH2:40][C:41]([O-:43])=[O:42])=[O:38])[CH:20]=1.[Na+:48].[Na+:48]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2c[nH]c3[nH]c(N)nc(=O)c23)cc1)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@H](CCC(=O)[O-])C(=O)[O-])cc3)c2c(=O)[nH]1

Procedure:
reacting N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl-L-glutamic acid diethyl ester p-toluenesulfonate salt with sodium hydroxide to give pemetrexed disodium.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][CH:25]=1)[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C.ClCCl>C(#N)C.O>[F:26][C:11]([F:10])([F:27])[C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][CH:25]=1)[CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([NH:22][C:2]2[N:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=2)[CH2:20][CH2:21]1
Reactant: NC1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Reactant: N#Cc1ccc(Cl)nn1
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC2CCN(Cc3cccc(C(F)(F)F)c3)CC2)nn1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
A mixture of 6-chloro-pyridazine-3-carbonitrile (D4) (0.130 g, 0.931 mmol), 1-(3-trifluoromethyl-benzyl)-piperidin-4-ylamine (D6) (0.241 g, 0.931 mmol) and diisopropylethylamine (0.243 ml, 1.4 mmol) in acetonitrile (3 ml) was stirred at 120° C. for 30 min., under microwave irradiation (Biotage MW-oven). Dichloromethane and water were added, and then the mixture washed with a saturated solution of sodium carbonate. The organic phase was filtered over cotton and the solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel; 0-2% ammonia in methanol (7M)/dichloromethane) to yield E16 (0.215 g, 64%) as a solid. C18H18F3N5 requires 361. Found 362 (MH+); mp: 170.3° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:16][CH:15]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.5 %

Procedure:
Following procedure A, 2-chloro-5-nitropyridine (303 mg, 1.91 mmol, 1.00 eq) and 4-iso-propylphenol (331 mg, 2.43 mmol, 1.27 eq) were dissolved in DMF (6.0 mL). Anhydrous K2CO3 (398 mg, 2.88 mmol, 1.51 eq) was added and the reaction mixture was stirred at room temperature for 24 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100) to afford the title compound as pale yellow solid (490 mg, 1.90 mmol, 99% yield). Rf=0.40 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C14H15N2O3+ [M+H]+ 259.1077. found: 259.1072. 1H NMR (400 MHz, CDCl3) δ 9.04 (d, J=3.4 Hz, 1H, aromatic H), 8.44 (dd, J=9.1, 2.8 Hz, 1H, aromatic H), 7.37-7.28 (m, 2H, aromatic H), 7.12-7.06 (m, 2H, aromatic H), 7.03-6.97 (m, 1H, aromatic H), 2.96 (hept, J=6.9 Hz, 1H, CH(CH3)2), 1.30 (d, J=7.0 Hz, 6H, CH(CH3)2). 13C NMR (101 MHz, CDCl3) δ 167.08, 150.67, 146.49, 145.02, 140.18, 134.81, 127.84, 121.11, 111.24, 33.62, 24.03.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:20][CH2:19][C:13]2([O:17][C:16](=[O:18])[NH:15][CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:24]=1[CH2:25]Br.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]2([O:17][C:16](=[O:18])[N:15]([CH2:25][C:24]3[CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[CH:29]=[CH:30][C:23]=3[O:22][CH3:21])[CH2:14]2)[CH2:19][CH2:20]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1CN1CC2(CCN(C(=O)OC(C)(C)C)CC2)OC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
Sodium hydride (82 mg, 60% dispersion in mineral oil, weight percent) was suspended under a nitrogen atmosphere in DMF (5 mL). Compound A3 (0.5 g, 1.95 mmol) was added thereto and the reaction mixture was stirred for 10 min at RT. 2-Methoxy-5-nitrobenzyl bromide (485 mg, 1.97 mmol) was added thereto. The reaction mixture was stirred for 18 h at RT, combined with water and extracted with EtOAc. The combined organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. The residue was dissolved in a mixture of ether and heptane. After removal of the ether, the desired product 3-(2-methoxy-5-nitrobenzyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (A87) (670 mg, 81% of theoretical) was obtained as a white solid by filtration.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[N:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[N:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Solvent: Cc1ccccc1C
Product: Cc1nccc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from 4,5-dichlorophenylenediamine (89 mg 0.5 mmol) and 3-[3-(2-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K42) (172 mg, 0.55 mmol) by refluxing in xylene according to the general procedure M. Obtained as a light yellow solid (131 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1.[B].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.[F:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48]Cl)=[CH:46][CH:45]=1>CN(C)C=O>[F:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][N:10]2[C:11]3[C:12](=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:16]=3)[N:23]=[C:9]2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:46][CH:45]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3[nH]2)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: [B]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2Cc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A mixture of 2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridine (Compound of Example 1) (80 mg), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine resin (PS-BEMP, 2.2 mmol/g) (181 mg) and N,N-dimethyl formamide (3.2 ml) was shaken at room temperature for 1 hour. To the mixture was added 4-fluorobenzyl chloride (46 mg), and the mixture was further shaken at room temperature for 15 hours. The resin was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to a preparative HPLC, and the desired fraction was concentrated. The concentrate was distributed into dichloromethane and a saturated aqueous solution of sodium bicarbonate. The organic layer was filtered by means of a PTFE filter tube, and concentrated under reduced pressure to obtain 1-(4-fluorobenzyl)-2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridine (84 mg, 78%).