Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]=[N+:21]=[N-:22])[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:4][CH2:3]1.C([O:30][C:31](=[O:34])[C:32]#[CH:33])(C)(C)C.C(OCC)(=O)C>O1CCOCC1>[O:25]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:33]=[C:32]([C:31]([OH:34])=[O:30])[N:22]=[N:21]4)[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:6][CH2:7]1
Reactant: C#CC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)c1cn(C[C@H]2CN(c3ccc(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)nn1
Yield: 40.2 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one (6.9 g, 18.83 mmol) (Reference Example 2) was dissolved in dry 1,4-dioxane (15 ml), 2-propynoic acid t-butylester (4.75 g, 37.67 mmol) was added and the resulting mixture was refluxed for 12 hours under vigorous stirring. Ethyl acetate (30 ml) was added and the resulting precipitate was filtered, washed with ethyl acetate and dried as a white solid (5 g). This solid was suspended in dichloromethane (16 ml), followed by drop wise addition of trifluoroacetic acid (8 ml) and the resulting mixture was stirred over night. The solvent was removed under vacuum and the residue was purified by precipitation from dichloromethane to give the title product as an off-white solid (3.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH3:12])=[CH:5][C:3]=1[NH2:4].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O.Cl>N1C=CC=CC=1>[NH2:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH3:12])=[CH:5][C:3]=1[NH:4][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)c(N)c([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2cc(C)cc([N+](=O)[O-])c2N)cc1
Temperature: 45 °C

Procedure:
0.15 mol (25.05 g) of 2-amino-3-nitro-5-methylaniline is dissolved in 75 ml of pyridine, and 0.165 mol (31.4 g) of para-toluenesulphonyl chloride is then added gradually, whilst stirring, at between 40° and 45° C. When the addition has ended, the stirring is maintained for 1 hour at 45° C., the reaction medium is then poured into 450 ml of iced water and ther pyridine is neutralised with the aid of hydrochloric acid. The expected product which has precipitated is filtered off, washed with water and then recrystallised from acetic acid. After drying in vacuo, it melts at 184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[NH2:10])=[CH:5][CH:4]=1.[OH:19][CH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:10][C:20]([C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23][CH2:22]2)=[O:19])=[CH:12][CH:13]=1
Reactant: O=C(O)[C@H]1CC[C@H](CO)CC1
Reactant: COc1ccc(C(N)c2ccc(OC)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(C(NC(=O)[C@H]2CC[C@H](CO)CC2)c2ccc(OC)cc2)cc1
Reaction time: 3 h

Procedure:
To a solution of bis(4-methoxyphenyl)methanamine (846 mg), trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (500 mg), and triethylamine (1.322 mL) in N,N-dimethylformamide (30 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate reagent (1.677 g). The resulting mixture was stirred for 3 hours, diluted with ethyl acetate, washed with water, aqueous NaOH and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was dissolved in dichloromethane and loaded into a silica cartridge, eluted with 0-100% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]1[C:25]([N:33]([CH3:42])[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)=[N:26][C:27]([CH3:32])=[N:28][C:29]=1[NH:30][NH2:31].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([NH:31][NH:30][C:29]2[C:24]([F:23])=[C:25]([N:33]([CH3:42])[CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[N:26]=[C:27]([CH3:32])[N:28]=2)=[O:10])[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc(NN)c(F)c(N(C)CCc2ccncc2)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N(C)CCc2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A mixture of (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (230 mg, 0.76 mmol), 5-fluoro-6-hydrazino-N,2-dimethyl-N-[2-(4-pyridinyl)ethyl]-4-pyrimidinamine (210 mg, 0.76 mmol), EDC (180 mg, 0.91 mmol), HOAt (120 mg, 0.91 mmol), and NMM (0.25 mL, 2.28 mmol) in 5 ml DMF was stirred at room temperature overnight. The reaction mixture was then purified via reverse phase HPLC to provide {(2R)-2-(cyclopentylmethyl)-3-[2-(5-fluoro-2-methyl-6-{methyl[2-(4-pyridinyl)ethyl]amino}-4-pyrimidinyl)hydrazino]-3-oxopropyl}[(phenylmethyl)oxy]formamide (290 mg, 67%). LCMS: (M+H)+: 564.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]([CH3:19])[CH2:16][S:17][CH3:18])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]([CH3:19])[CH2:16][S:17][CH3:18])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(F)c1
Reactant: CSCC(C)Nc1nccc(-c2ccnc(Cl)c2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CSCC(C)Nc1nccc(-c2ccnc(Nc3cccc(F)c3)c2)n1
Temperature: 110 °C
Reaction time: 13 h

Procedure:
To a solution of 4-(2-chloro-4-pyridinyl)-N-[1-methyl-2-(methylthio)ethyl]-2-pyrimidinamine (i.e., the product of Step C) (150 mg, 0.5 mmol) in toluene (6.0 mL) was added 3-fluoroaniline (108 μL, 1.1 mmol), palladium(II) acetate (24 mg, 0.12 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene ((±)-BINAP) (40 mg, 0.06 mmol) and cesium carbonate (700 mg, 2.2 mmol); the resulting mixture was stirred at 110° C. for 13 h. The mixture was allowed to cool and silica gel (300 mg) was added. The excess solvent was removed under reduced pressure, and the resulting solid was chromatographed on silica gel eluted with 5% to 60% ethyl acetate in hexanes to give 60 mg of the title compound as a yellow solid, m.p. 104-107° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][C:6](=O)[C:5]=2[C:4]([CH3:18])=[CH:3]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:6]1[CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][C:10]2[N:2]([CH3:1])[CH:3]=[C:4]([CH3:18])[C:5]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1cn(C)c2c1C(=O)CC(c1ccccc1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cn(C)c2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Yield: 23.3 %

Procedure:
A mixture of 1,3-dimethyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.31 g), aminoguanidine hydrochloride (0.15 g), concentrated hydrochloric acid (0.065 ml), water (0.065 ml) and ethanol (50 ml) was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the mixture was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid. The solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-1,3-dimethyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 8) (0.1 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH2:15][CH3:16])[NH:5]2.[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH2:15][CH3:16])[N:5]2[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:19]=1[O:18][CH3:17]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: CCC1Nc2cc(Br)ccc2-n2cccc21
Product: CCC1c2cccn2-c2ccc(Br)cc2N1C(=O)c1ccc(OC)cc1OC

Procedure:
7-Bromo-5-(2,4-dimethoxybenzoyl)-4-ethyl-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from 7-bromo-4-ethyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (see Example 42) and 2,4-dimethoxybenzoyl chloride according to the procedure of Example 106, Step 2. The product was purified via Biotage Horizon® (25S, silica gradient from 5% EtOAc/Hexane to 40% EtOAc/hexane) and isolated as a white foam. MS (ESI) m/z 441/443 ([M+H]+); HRMS: calcd for C22H21BrN2O3, 440.0736; found (ESI+), 441.08006.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:31][CH2:32]2)[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and methanesulfonyl chloride (Aldrich), to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone. MS (M+H)+, 424.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)[N:18]=[N:19][C:14]3=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([NH:67][CH2:68][CH2:69][CH2:70][NH2:71])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.O>[NH2:67][CH2:68][CH2:69][CH2:70][NH:71][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)[N:18]=[N:19][C:14]3=[CH:13][CH:12]=2)=[CH:10][C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: NCCCNC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Reaction time: 0.08 h
Yield: 93.7 %

Procedure:
To a solution of example 13 (0.150 g, 0.375 mmol) in DMF (1 ml) N-ethyldiisopropylamine (0.048 g, 0.375 mmol) and HATU (0.143 g, 0.375 mmol) were added and stirred for 5 min. N-boc-1,3-diaminopropane (0.130 g, 0.751 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford N-boc-protected amide (0.200 g). The amide was dissolved in dichlomethane (1 ml) and trifluoroacetic acid (0.5 ml) was added and stirred at RT for 1 h. The reaction mixture was quenched with sodium bicarbonate solution, extracted with dichloromethane, dried over sodium sulphate and concentrated to afford the title compound as a pale brown solid (0.160 g, 93%). M.P.: 292-294° C. MS (m/z): 456.270 (M++1).
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:12][CH2:13][NH:14][C:15](=O)[CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>O.C(O)C>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH3:16][C:15]1[C:9]2[N:8]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][CH:10]=2)[CH2:12][CH2:13][N:14]=1
Reactant: CC(=O)NCCn1cccc1-c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: CC1=NCCn2c1ccc2-c1ccccc1
Yield: 57 %

Procedure:
N-[2-(2-Phenylpyrrol-1-yl]-ethyl]acetamide (5.0 g) was added to 30 ml of phosphorus oxychloride under argon and the mixture was boiled under reflux for 1 hour. The cooled mixture was hydrolyzed with 100 ml of 2N sodium hydroxide solution and 230 ml of 28% sodium hydroxide solution (cooling with ice), diluted with 2000 ml of water and extracted with methylene chloride (1×350 ml, 3×200 ml). The organic phases were combined, dried with MgSO4 and freed from solvent. 1.0 g of a total of 4.5 g of crude product was dissolved in a 30-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.9 g (57%) of 3,4-dihydro-1-methyl-6-phenylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 175° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.[CH3:28][N:29]([CH2:31][C:32](O)=[O:33])[CH3:30].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>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:32](=[O:33])[CH2:31][N:29]([CH3:30])[CH3:28])[CH2:2][CH2:3]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: CN(C)CC(=O)O
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCN(C(=O)CN(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a solution of [(S)-1-(1-piperidin-4-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine 113 (97 mg, 0.268 mmol), dimethylaminoacetic acid (30 mg, 0.294 mmol) and DIPEA (230 μL, 1.34 mmol) in DMF (5 mL) was added HATU (153 mg, 0.401 mmol) and the mixture was stirred at RT for 1 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined, then concentrated in vacuo, purified by column chromatography (Si—PCC, gradient 0-20% 2M NH3/MeOH in DCM) and triturated with diethyl ether. The product thus obtained was further purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 5-60% 0.1% NH4OH in acetonitrile/water) and loaded into an Isolute® SCX-2. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The basic fractions were then combined and concentrated in vacuo affording 125 as a white solid (40 mg, 33%). LCMS: RT 1.67 min [M+H]+ 448.1. 1H NMR (CDCl3 plus MeOD, 400 MHz): δ 8.45 (1H, s), 7.94 (1H, s), 7.77 (1H, d, J=7.62 Hz), 7.41 (1H, d, J=7.73 Hz), 7.26-7.17 (3H, m), 6.10 (1H, s), 4.99-4.81 (1.5H, m), 4.64-4.53 (0.5H, m), 4.38-4.27 (0.5H, m), 4.21-4.08 (0.5H, m), 3.32-3.01 (2H, m), 2.87-2.16 (10H, m), 2.05-1.27 (6H, m). Signals split due to presence of rotamers
Reaction SMILES: CN1CCOCC1.Cl[S:9]([C:12]1[CH:17]=[CH:16][N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14](=[O:24])[C:13]=1[N:25](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)(=[O:11])=[O:10].Cl.[CH:41]1([CH2:45][NH2:46])[CH2:44][CH2:43][CH2:42]1>C(Cl)Cl>[NH2:25][C:13]1[C:14](=[O:24])[N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH:17][C:12]=1[S:9](=[O:10])(=[O:11])[NH:46][CH2:45][CH:41]1[CH2:44][CH2:43][CH2:42]1
Reactant: CCOC(=O)Cn1ccc(S(=O)(=O)Cl)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1=O
Reactant: NCC1CCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)Cn1ccc(S(=O)(=O)NCC2CCC2)c(N)c1=O
Temperature: 25 °C

Procedure:
NMM (1.43 mL, 13.0 mmol) was added to a stirred mixture of 4-chlorosulfonyl-3-(N,N-di-t-butoxycarbonylamino)-1-ethyloxycarbonylmethyl-2-pyridinone (as a mixture from Step H, 0.84 g) and cyclobutylmethylamine hydrochloride (348 mg, 2.86 mmol) in methylene chloride (15 mL). After 16 h the reaction was diluted with methylene chloride and washed with 10% citric acid solution. The organic layer was dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography on silica (40% ethyl acetate/hexanes). HCl gas was bubbled through a stirred solution of the resulting compound in ethyl acetate (10 mL) at 0° C. for 15 min. The reaction was warmed to rt and after a further 3 h it was evaporated to give the title compound as a solid;
Reaction SMILES: C(O[K])(C)(C)C.[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C:16]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].F[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28]>O1CCOCC1.[NH4+].[Cl-]>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C:16]([O:23][C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=[O:28])([C:19]([F:20])([F:21])[F:22])[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(F)(F)F)C1
Reactant: O=Cc1ccccc1F
Agent: CC(C)(C)O[K]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)(C(F)(F)F)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
tBuOK (136 mg; 1.2 mmol; 1.5 eq.) was added at 10° C. to a solution of 3-hydroxy-3-trifluoromethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (247 mg; 0.97 mmol; 1.2 eq.) in 1,4-dioxane (10 mL) and the reaction mixture was stirred at room temperature for 15 minutes whereupon 2-fluoro-benzaldehyde (100 mg; 0.81 mmol; 1 eq.) was added. The reaction mixture was stirred at 100° C. for 3 hours then diluted with sat. aq. NH4Cl and extracted with EA (2×). The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (DCM) afforded the title compound (95 mg, 33%) as a colourless oil. HPLC (max plot) 98.2%, Rt 4.87 min.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].[CH3:18][N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][CH2:25]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(OCC)(=O)C.CCCCCCC.C1COCC1>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:25][CH2:24][CH:20]3[CH2:21][CH2:22][CH2:23][N:19]3[CH3:18])=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: CN1CCCC1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CN(C)CC1(c2ccc(OCCC3CCCN3C)cc2)CCOCC1
Yield: 27.2 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (405 mg, 1.72 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethanol (178 mg, 1.38 mmol), PPh3 (451 mg, 1.72 mmol), THF (8 ml) and DIAD (348 mg, 1.72 mmol) were reacted together according to general procedure C. The crude product was subjected to chromatography on alumina eluting with ethyl acetate:heptane (50:50) to provide the title compound (130 mg, 27%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.87 (d, 2H), 4.09-3.95 (m, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.09 (m, 1H), 2.40 (s, 2H), 2.35 (s, 3H), 2.30-1.99 (m, 6H), 1.96 (s, 6H), 1.93-1.63 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4](=[CH2:10])[CH2:5][C:6](OC)=[O:7].[NH3:12]>CO>[O:7]=[C:6]1[NH:12][CH2:10][CH:4]([C:3]([O:2][CH3:1])=[O:11])[CH2:5]1
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: N
Solvent: CO
Product: COC(=O)C1CNC(=O)C1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a solution of 2-methylene-succinic acid dimethyl ester (158 g, 1 mol, 1 eq) in MeOH (150-160 mL) was added dropwise anhydrous liquid ammonia (17 g, 1 mol, 1 eq). The mixture was stirred at room temperature for 1.5-2 h, keeping the outlet of the flask connected with a small mercury trap (1-2 cm Hg), and left to stand overnight. Most part of MeOH was evaporated on a water bath and then residual MeOH was evaporated in vacuo until the mixture transformed into a semisolid mass. This mass was distilled in vacuo. Starting compound was distilled (bp 60-70° C. at 1 mm Hg) followed by distillation of title compound (bp 140-150° C. at 1 mm Hg) as colorless liquid, which crystallized very fast (72 g, 0.5 mol, 50%).
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[CH:8])(C)(=O)=O.Cl.[Cl:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:8][CH2:7][C:6]#[CH:5])[CH2:20][CH2:21]2)=[CH:22][CH:23]=1
Reactant: Clc1ccc(CC2CCNCC2)cc1
Reactant: C#CCCS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCCN1CCC(Cc2ccc(Cl)cc2)CC1
Yield: 85 %

Procedure:
A mixture of 1-mesylbut-3-yne (2.22 g, 15.0 mmol), 4-(4-chlorobenzyl)piperidine hydrochloride (2.95 g, 12.0 mmol), K2CO3 (4.97 g, 36.0 mmol) in 50 mL of CH3CN is allowed to reflux for 12 hr. The inorganic salt is removed through a short column of silica gel and washed with EtOAc (3×30 mL). Evaporation of solvents gives a residue, which is purified by flash chromatography giving the product as pale yellow oil (2.67 g, 85%): 1H NMR (CDCl3) 1.31 (m, 2 H), 1.50 (m, 1 H), 1.59 (m, 2 H), 1.96 (m, 3 H), 2.38 (m, 2 H), 2.48 (m, 2 H), 2.55 (m, 2 H), 2.88 (d, J=11.1 Hz, 2 H), 7.04 (d, J=8.1 Hz, 2 H), 7.26 (d, J=8.1 Hz, 2 H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1.C(N(CC)CC)C.[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1.O>C(#N)C>[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:15][C@H:14]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)=[O:47])=[CH:44][CH:43]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2ccc(Cl)cc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99 %

Procedure:
To a solution of the compound (0.55 g) obtained in step 4 and triethylamine (439 μL) in acetonitrile (5 mL) was added 4-chlorobenzoyl chloride (177 μL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 25→50% ethyl acetate/hexane) to give the title compound (0.51 g, 99%) as a white powder.