Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1.C1COCC1>[CH2:33]([O:32][C:30]([CH2:29][CH2:28][C:8](=[CH2:1])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:12])=[O:31])[CH3:34]
Reactant: CC(C)(C)[O-]
Reactant: CCCCCCCCCCCCCCOC(=O)CCC(=O)CCC(=O)OCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: C=C(CCC(=O)OCC)CCC(=O)OCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 156.5 %

Procedure:
Potassium t-butoxide (0.195 g, 1.73 mmol) was added to a stirred suspension of methyl triphenylphosphonium bromide (0.618 g, 1.73 mmol) in dry benzene (8 mL), which was maintained under argon at room temperature. After stirring for 30 min, the reaction mixture was cooled to 0° C. and a solution of ketone 3.17 (0.46 g, 1.16 mmol) in dry THF was added rapidly. The reaction mixture was quenched after 30-60 minutes at 0° C. with brine (~10 mL), extracted with EtOAc (3×20 mL), and the combined organic layer was washed with water (1×10 mL) and dried (Na2SO4). The residue obtained after concentration was purified by flash column chromatography over silica gel using hexane:EtOAc (95:5) giving 3.18 as a liquid (0.72g, 71.5%); IR (neat) 1738 (C=O) and 1647 cm-1 ; 1H NMR (CDCl3) δ 0.85(distorted t, 3H, CH3 (CH2)13), 1.20-1.40 (m, 25 H, CH3 (CH2)11CH2CH2OCO, CH3CH2OCO), 1.60 (m, 2 H, CH3 (CH2)11CH2CH2OCO), 2.35 (m, 4 H, OCCH2CH2 (C=CH2)CH2CH2CO), 2.45 (m, 4 H, OCCH2CH2 (C=CH2)CH2CH2CO), 4.00-4.15 (m, 4H, CH3 (CH2)11CH2CH2OCO, CH3CH2O), 4.75 (s, 2 H, =CH2); 13C NMR (CDCl3) δ 14.09, 14.20, 22.66, 25.89, 28.60, 29.23, 29.33, 29.50, 29.56, 29.62, 31.00, 31.03, 31.89, 32.64, 60.35, 64.61, 109.75, 146.37, 173.08, 173.181. Anal. Calcd for C24H44O4 : C, 72.67; H, 11.19. Found: C, 72.63; H, 11.23.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:25]([OH:27])=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:28](=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[CH3:28][O:26][C:25](=[O:27])[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 10.45 g of Nα -Boc-Nε -Cbz-L-lysine in 125 ml methanol and 17 ml water. Neutralize the solution with 27.5 ml of 0.5M cesium carbonate solution and concentrate the resulting solution to a syrup at aspirator pressure and 35° C. Dissolve the syrup in 100 ml. dimethylformamide and concentrate; repeat once more. Dissolve the residue in 75 ml. dimethylformamide and 2.7 ml. methyi iodide. Stir the reaction mixture overnight at room temperature then remove the dimethylformamide under vacuum (oil pump). Add 250 ml. water to the residue and extract into 150 ml. ethyl acetate. Wash the ethyl acetate extract twice with 100 ml. portions of water then dry the organic phase over MgSO4. Filter and concentrate the dried solution in vacuo to obtain Nα -Boc-Nε -Cbz-L-lysine methyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].N.[CH3:25][N:26]1CCCC1=O>>[O:23]=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:13]1[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:25]#[N:26])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(Br)cc12
Reactant: CN1CCCC1=O
Agent: N
Product: N#Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reaction time: 0.75 h

Procedure:
A mixture of 2-[2-(5-bromo-1H-indol-3-yl) ethyl]-1H-isoindole-1,3(2H)-dione (4.0 g), cuprous cyanide (1.1 g) and N-methyl-2-pyrrolidinone (10 ml) was heated at reflux for 1 hour. The reaction mixture was poured onto ice (30 g) and concentrated ammonia (15 ml) was added and the suspension was stirred for 0.75 hour. The solid was filtered off, washed with water and methanol and was crystallised from aqueous acetone to give the title compound (2.7 g) as a fawn solid m.p. 217°-221° C. T.L.C. Silica ether Rf 0.44.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21]C)=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([NH:30]C(=O)C(F)(F)F)[CH2:26][CH2:25]2)[CH:3]=1.[NH3:37]>CO>[NH2:30][C@H:27]1[CH2:26][CH2:25][C@H:24]([O:23][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:37])=[O:21])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:29][CH2:28]1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](NC(=O)C(F)(F)F)CC3)c2c1C
Reactant: N
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](N)CC3)c12

Procedure:
0.100 g methyl 4-(4-fluoro-2-(trans-4-(2,2,2-trifluoroacetamido)cyclohexyloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (cpd.15.1) and 2 ml 7 M ammonia in MeOH were stirred in a pressure tube overnight at 70° C. and 8 days at 90° C. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography to give the desired compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][NH:3]1.[H-].[Na+].[CH2:14](I)[CH3:15].O>CN(C=O)C>[CH2:14]([N:3]1[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:7][C:2]1=[O:1])[CH3:15]
Reactant: COC(=O)c1ccc(=O)[nH]c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(C(=O)OC)ccc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
Methyl 2-oxo-1,2-dihydropyridine-5-carboxylate (400 mg, 2.61 mmol) obtained in Step 3 was dissolved in DMF (3 mL), and 55% sodium hydride (125 mg, 2.87 mmol) and ethyl iodide (0.230 mL, 2.87 mmol) were added thereto, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford methyl 1-ethyl-2-oxo-1,2-dihydropyridine-5-carboxylate (375 mg, 79%).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(Cl)=[S:20]>ClCCl>[CH2:1]([C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[N:5]=[C:19]=[S:20])[CH3:2]
Reactant: S=C(Cl)Cl
Reactant: CCc1cc(OC)ccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(OC)ccc1N=C=S
Temperature: 0 °C
Yield: 83.3 %

Procedure:
To solution of 2-ethyl-4-methoxyaniline (4.5 g, 30 mmol) and triethylamine (6.0 g, 60 mmol) in dichloromethane (31 mL) was added thiophosgene (3.4 g, 30 mmol) was added drop wise at 0° C. over the period of 1 hour. After completion, the reaction mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (3×200 mL) and washed with ice water (2×100 mL), followed by brine (2×50 mL). The organic phase was dried over sodium sulfate, filtered, and evaporated under reduced pressure. Purification by flash column chromatography using 0-10% ethyl acetate/hexanes as eluent provided 2-ethyl-1-isothiocyanato-4-methoxybenzene as yellow oil (4.9 g, 25 mmol), which was taken onto the next step immediately.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[OH-].[Na+].[CH:17]1C=CC=CC=1.CI>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH3:17])[C:4]=2[CH:3]=1
Reactant: c1ccccc1
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1c2ccccc2c2ccc(O)cc21
Reaction time: 2 h

Procedure:
To a mixture comprising 20 g of 2-hydroxycarbazole, 3 g of benzyltriethyl ammonium chloride, 70 ml of a 50% aqueous solution of sodium hydroxide and 10 ml of benzene was added dropwise 25 g of methyl iodide. After the dropwise addition, the mixture was stirred for 2 hours. The mixture was poured into hot water and the mixture was allowed to stand at room temperature overnight. The precipitated solid was recovered by filtration, washed with water and dried to obtain a yellowish brown solid of 2-hydroxy-9-methylcarbazole.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][C:13]([NH:15][C:16]1[C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]([CH3:24])[N:17]=1)=[O:14].I[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C=O)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][N:15]([C:16]1[C:20]([C:21](=[O:22])[NH2:23])=[CH:19][N:18]([CH3:24])[N:17]=1)[C:13](=[O:14])[CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=1[F:3])[CH3:31]
Reactant: Cn1cc(C(N)=O)c(NC(=O)CCc2cccc(F)c2F)n1
Reactant: CCOC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C(=O)CCc1cccc(F)c1F)c1nn(C)cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 279.5 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 260 mg, 6.5 mmol) in anhydrous DMF (5 ml) under argon at 0° C. was added a solution of 3-[3-(2,3-difluorophenyl)-propanoylamino]-1-methyl-1H-pyrazole-4-carboxylic acid amide (Int. B58) (2.0 g, 6.49 mmol) in anhydrous DMF (5 ml). The reaction mixture was allowed to warm to room temperature over 30 min and then ethyl iodoacetate (0.15 ml, 1.27 mmol) was added at 0° C. The mixture was stirred at ambient temperature overnight, washed with brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (fine silica, dichloromethane-methanol) to give the title compound as a cream solid (1.4 g, 55%). 1H-NMR (DMSO) δ 1.18 (3H, t), 2.41 (2H, t), 2.87 (2H, t), 3.82 (3H, s), 4.10 (2H, q), 4.26 (2H, s), 6.99-7.24 (4H, m), 7.55 (1H, s), 8.16 (1H, s); MS (APCI+) found (M+1)=395; C18H20F2N4O4 requires 394.
Reaction SMILES: [S:1]([C:5]1[C:6](C(OC)=O)=[CH:7][S:8][CH:9]=1)(=[O:4])(=[O:3])[NH2:2].[CH3:14][O-:15].[Na+].Cl>CO>[O:4]=[S:1]1(=[O:3])[C:5]2[CH:6]=[CH:7][S:8][C:9]=2[C:14](=[O:15])[NH:2]1
Reactant: C[O-]
Reactant: COC(=O)c1cscc1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1NS(=O)(=O)c2ccsc21
Temperature: 25 °C

Procedure:
A mixture of methyl 4-sulfamoylthiophene-3-carboxylate (2.7 g, 12.2 mmol), methanol (12 mL), and a 25% methanolic solution of sodium methylate (3.6 mL) was refluxed for 48 h. The reaction mixture was cooled to room temperature and acidified with concentrated hydrochloride acid, and the precipitated product was collected and washed with water. Recrystallized from water, yielded 400 mg of the title compound. MS: 187.8 (M−1), 189.5 (M+1). 1H NMR (DMSO-d6): 8.34 (d, J=4.4 Hz, 1H), 7.705 (d, J=4.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]3[CH2:37][CH2:36][CH2:35][C@H:34]3[C:38](=[O:44])[NH:39][CH:40]3[CH2:43][CH2:42][CH2:41]3)=[O:32])[N:26]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:25]=2)=[O:23])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:52](Cl)[CH2:53]Cl.C(O)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]3[CH2:37][CH2:36][CH2:35][C@H:34]3[C:38](=[O:44])[NH:39][CH:40]3[CH2:43][CH2:42][CH2:41]3)=[O:32])[N:26]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:25]=2)=[O:23])[CH2:16][CH2:17][C:18]([O:20][CH2:52][CH3:53])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCCl
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OCC)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 1.30 g 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester in 22 ml dichloromethane were added 421 mg EDC, 268 mg DMAP and 541 μl ethanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 550 mg MS (ES+): m/e=738.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:12][C:13]([OH:15])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]([NH:35][NH2:36])=[O:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]([NH:35][NH:36][C:13](=[O:15])[CH2:12][C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11]1)=[O:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1(CC(=O)O)CC1
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Yield: 71.3 %

Procedure:
A solution of 2-(1-(tert-butoxycarbonylamino)cyclopropyl)acetic acid (1.5 g, 6.9 mmol), (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide (3.1 g, 7.6 mmol), DIPEA (2.7 g, 21.0 mmol), and HATU (3.9 g, 10.45 mmol) in DMF (20 mL) was stirred at 0° C. for 1 hr. The mixture was quenched with saturated sodium chloride (150 mL) and EtOAc (150 mL). The organic layer was separated and washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (0˜80% gradient elution EtOAc/petroleum ether) to afford tert-butyl 1-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclopropylcarbamate (2.4 g, 70%) as a white solid. ESI-MS (EI+, m/z): 488 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C@@H:35]4[CH2:40][CH2:39][C@H:38]([C:41](O)=[O:42])[CH2:37][CH2:36]4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:44]([F:47])([F:46])[F:45])=[CH:19][N:18]=2)=[C:12]([O:48][CH3:49])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH3:50][N:51](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl-].C[NH3+].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:49][O:48][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C@H:35]3[CH2:36][CH2:37][C@@H:38]([C:41](=[O:42])[NH:51][CH3:50])[CH2:39][CH2:40]3)=[C:28]3[C:32]=2[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]3)[C:20]([C:44]([F:47])([F:46])[F:45])=[CH:19][N:18]=1)[CH2:9][P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](C(=O)O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: C[NH3+]
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](C(=O)NC)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
cis-4-(7-{[2-({4-[(Diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylic acid (10.0 mg, 0.0142 mmol), TBTU (9.1 mg, 0.0283 mmol) and DMF (0.8 mL) were mixed and the mixture was stirred at room temperature for 30 minutes. Methylammonium chloride (9.6 mg, 0.142 mmol) and DIPEA (24.7 μL, 0.142 mmol) were added and the mixture was stirred at room temperature for 2 hours. The crude was purified by MDP to obtain the title compound (4.4 mg, 43% yield). 1H NMR (400 MHz, methanol-d4) δ=1.29 (t, J=7.1 Hz, 6H), 1.67-1.81 (m, 4H), 1.87-2.01 (m, 2H), 2.15 (d, J=12.4 Hz, 2 H), 2.60 (br. s., 1H), 2.71 (t, J=11.2 Hz, 1H), 2.79 (s, 3H), 3.18 (s, 3H), 3.37 (d, J=21.7 Hz, 2H), 3.90 (s, 3H), 4.10 (quin, J=7.3 Hz, 4H), 4.53 (s, 2H), 6.99 (d, J=7.8 Hz, 1H), 7.13 (s, 1H), 7.34 (br. s., 1H), 7.67 (d, J=8.1 Hz, 1H), 8.33 (br. s., 2H). MS (ES+): m/z 719.36 (100) [MH+]; HPLC: tR=1.04 min (UPLC, purity).
Reaction SMILES: [OH:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[C:8]([O:10][CH3:11])=[O:9]>[Pd].CCOC(C)=O>[NH2:15][C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:4][CH2:3][C:2]([OH:1])([CH3:18])[CH3:19]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(NCC(C)(C)O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(NCC(C)(C)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.4 %

Procedure:
To a mixture of methyl 3-[(2-hydroxy-2-methylpropyl)amino]-4-nitrobenzoate (2.69 g, 10.03 mmol) and 10% palladium on carbon (2.13 g, 2.005 mmol, 10%) was added EtOAc (20.0 mL). Reaction was vacuumed and then filled with nitrogen (3×), ending with vacuuming and was then put under a hydrogen balloon. Reaction stirred at ambient temperature for 3 h. Mixture filtered through celite, washing with MeOH. Filtrate concentrated and used without further purification, giving the title compound (2.59 g): LC-MS [M+1]=239.3.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][OH:11].[ClH:12]>C1(C)C=CC=CC=1>[ClH:12].[C:2]1([CH2:1][C:8](=[NH:9])[O:11][CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1ccccc1
Reactant: CO
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=N)Cc1ccccc1
Yield: 88.3 %

Procedure:
The same equipment as described in Example 3 was used. Benzyl cyanide (38.0 grams; 0.325 mole) was mixed with absolute methanol (10.3 grams; 0.322 mole) and toluene (195 ml). With cooling and agitation HCl gas (16 grams; 0.44 mole) was introduced from a weighed cylinder and the mixture was maintained under the same conditions overnight (26 hours). The resulting white slurry was filtered cold and the solid methyl phenylacetimidate hydrochloride (52.8 grams; 88.4% yield) was collected and a portion of it used directly in the next step.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH2:22][C:23]([F:26])([F:25])[F:24])=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[I-].[Li+]>N1C=CC=CC=1>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([CH2:22][C:23]([F:26])([F:24])[F:25])[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(CC(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1c(CC(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 20 step D from 6-chloro-4-phenyl-2-(2,2,2-trifluoro-ethyl)-quinoline-3-carboxylic acid methyl ester (60 mg, 0.16 mmol) and lithium iodide (212 mg, 1.58 mmol) in pyridine. Off white solid (9.5 mg, 16%). LC-MS: 364 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][N:9]=[C:10]2[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:26])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH:16]3[C:11]2=[CH:12][C:13](=[O:39])[CH:14]([CH3:38])[CH:15]3[CH2:27][CH2:28][C:29](=[O:37])[CH2:30][CH:31]([OH:36])[CH2:32][C:33]([OH:35])=[O:34])=[C:5]([CH3:40])[O:4][N:3]=1.[OH-].[Na+:42]>O1CCOCC1.O>[CH3:1][C:2]1[C:6]([CH2:7][O:8][N:9]=[C:10]2[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:26])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH:16]3[C:11]2=[CH:12][C:13](=[O:39])[CH:14]([CH3:38])[CH:15]3[CH2:27][CH2:28][C:29](=[O:37])[CH2:30][CH:31]([OH:36])[CH2:32][C:33]([O-:35])=[O:34])=[C:5]([CH3:40])[O:4][N:3]=1.[Na+:42]
Reactant: CCC(C)C(=O)OC1CCC(=NOCc2c(C)noc2C)C2=CC(=O)C(C)C(CCC(=O)CC(O)CC(=O)O)C21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC(C)C(=O)OC1CCC(=NOCc2c(C)noc2C)C2=CC(=O)C(C)C(CCC(=O)CC(O)CC(=O)[O-])C21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
139 mg of 7-[5-(3,5-dimethylisoxazol-4-yl)methoxyimino-2-methyl-8-(2-methylbutyryloxy)-3-oxo-1,2,3,5,6,7,8,8a-octahydro-1-naphthyl]-3-hydroxy-5-oxoheptanoic acid (prepared as described in Example 11b) were dissolved in 2.7 ml of a 1:1 by volume mixture of dioxane and water. 2.35 ml of a 0.1N aqueous solution of sodium hydroxide were added dropwise over a period of minutes at 0° C. to the solution, which was then stirred for 1 hour at room temperature. At the end of this time, the solution was freeze-dried, to obtain 140 mg of the title compound as a colorless moisture sensitive powder.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:16]=[CH:15][NH:14][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:7]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC.CCO>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:2]2[C:3]3[CH:16]=[CH:15][NH:14][C:4]=3[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[N:7]=2)[CH:18]=1
Reactant: OB(O)c1cccnc1
Reactant: Clc1nc(-c2ccccn2)nc2[nH]ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: COCCOC
Solvent: CCO
Product: c1ccc(-c2nc(-c3cccnc3)c3cc[nH]c3n2)nc1

Procedure:
4-Chloro-2-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 1) (1 eq, 1.17 mmol, 285 mg) and pyridine-3-boronic acid (ABCR GmbH & Co. KG, Karlsruhe, Germany) (2 eq, 2.35 mmol, 294 mg) are dissolved in MeCN (8 ml). Then an aqueous Na2CO3 solution (2 M, 4 eq, 4.7 mmol, 2.3 ml) and PdCl2(PPh3)2 (0.1 eq, 0.117 mmol, 84 mg) are added and the resulting mixture is heated using microwave radiation at 150° C. for 20 min. Alternatively Pd(PPh3)4 and DME/EtOH (1:1) can be used instead of PdCl2(PPh3)2 and MeCN. The solvents are removed in vacuo, then aqueous NaOH solution (1 M) is added, and the solution is extracted with DCM. The organic layer is dried with MgSO4, filtered, and concentrated. The crude product is recrystallized from EtOAc affording the title compound; [M+H]+=274; 1H-NMR (400 MHz, DMSO): δ 12.52 (s, 1H), 9.46 (dd, 1H), 8.76 (m, 2H), 8.66 (td, 1H), 8.57 (td, 1H), 7.97 (dt, 1H), 7.80 (d, 1H), 7.65 (ddd, 1H), 7.48 (ddd, 1H), 7.01 (d, 1H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][P:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:17])[OH:16])=O)C1C=CC=CC=1>Cl>[NH2:11][CH2:12][CH2:13][CH2:14][P:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:16])[OH:17]
Reactant: CCCCCCCCCCCCP(=O)(O)CCCNC(=O)OCc1ccccc1
Agent: Cl
Product: CCCCCCCCCCCCP(=O)(O)CCCN
Temperature: 25 °C

Procedure:
A solution of 2.4 g of 3-benzyloxycarbonylaminopropyl(dodecyl) phosphinic acid in 50 ml of 36% hydrochloric acid is refluxed for 3 hours. During this time, a white precipitate is formed. After cooling to room temperature the acid is removed by co-evaporation with 6×50 ml of water on a rotary evaporator. The crude product is then dissolved in 50 mlof ethanol and stirred with 5 ml of propylene oxide. Filtration and drying gives 3-aminopropyl(dodecyl) phosphinic acid as a white solid m.p. 175°-7°. 31P-NMR=43.0 ppm. (NaOD).