Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17](O)=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH2:16][CH2:15][C:10]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]1[C:46](=[O:58])[N:47]([CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[N:48]([CH3:51])[C:49]=1[CH3:50].C(N(CC)CC)C>CN1C(=O)CCC1.CS(C)=O>[CH:52]1([N:47]2[C:46](=[O:58])[C:45]([NH:44][C:17]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]4[CH2:16][CH2:15][C:10]5([CH2:11][CH2:12][CH2:13][CH2:14]5)[CH2:9][CH:8]=4)[O:5][N:4]=3)=[O:18])=[C:49]([CH3:50])[N:48]2[CH3:51])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: Cc1c(C(=O)O)noc1C1=CCC2(CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1=CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-methyl-5-(spiro[4.5]dec-7-en-8-yl)isoxazole-3-carboxylic acid (95 mg, 0.364 mmol) in dry NMP (3 ml), HATU (152 mg, 0.400 mmol) was added followed by 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (84 mg, 0.400 mmol) and triethylamine (0.111 mL, 0.800 mmol) and this was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc (30 mL) and 1M NaOH (aq) (30 mL) and the organic phase was washed with water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give an orange oil. The crude material was dissolved in DMSO and purified using UV-directed automated reverse phase chromatography over a 9.5 minute gradient of 50-98% MeCN in water (0.1% formic acid). The product fraction was added to EtOAc (50 mL) and washed with a saturated aqueous NaHCO3 solution (50 mL). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:17][C:18]([O:20]C(C)(C)C)=O)=[C:6]([NH:9][C:10](OC(C)(C)C)=[O:11])[S:7][CH:8]=2)[CH2:3][CH2:2]1.C(OCC)(=O)C(OCC)=O>C(O)(=O)C>[CH:1]1([C:4]2[C:5]3[NH:17][C:18](=[O:20])[C:10](=[O:11])[NH:9][C:6]=3[S:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1scc(C2CC2)c1NC(=O)OC(C)(C)C
Solvent: CCOC(=O)C(=O)OCC
Solvent: CC(=O)O
Product: O=c1[nH]c2scc(C3CC3)c2[nH]c1=O
Yield: 47 %

Procedure:
A mixture of di-t-butyl 4-cyclopropylthiophene-2,3-dicarbamate (1.66 g, 4.7 mmol), diethyl oxalate (20 ml, 146 mmol) and glacial acetic acid (20 ml) was refluxed for 12 h. The mixture was concentrated in vacuo and the residue recrystallized from glacial acetic acid to afford 460 mg (72%) of the title compound. M.p.>250° C. 1H-NMR (DMSO-d6, δ): 0.6 (m, 2H), 0.85 (m, 2H), 2.0 (m, 1H), 6.55 (s, 1H), 12.0 (s, 1H), 12.2 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]([NH:8][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([O:16][C:17]2[CH:22]=[C:21]([I:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=2[CH:26]([CH3:28])[CH3:27])=[CH:11][N:10]=1)=[O:7].[OH-].[Li+]>C1COCC1.O>[NH2:15][C:13]1[C:12]([O:16][C:17]2[CH:22]=[C:21]([I:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=2[CH:26]([CH3:27])[CH3:28])=[CH:11][N:10]=[C:9]([NH:8][C:6](=[O:7])[CH2:5][CH2:4][C:3]([OH:29])=[O:2])[N:14]=1
Reactant: COC(=O)CCC(=O)Nc1ncc(Oc2cc(I)c(OC)cc2C(C)C)c(N)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(NC(=O)CCC(=O)O)nc2N)cc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 7.6 %

Procedure:
To a solution of N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-succinamic acid methyl ester (0.54 g, 1.05 mmoles) in THF (20 ml) was added a solution of Lithium hydroxide (0.33 g, 13.8 mmoles) in water (10 ml). The mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure. The aqueous residue was pH adjusted to pH=8, washed with EtOAc, and lyophilized for 36 hours. The resulting solid was washed with 30% methanol in ethyl acetate, and filtered. The filtrate was evaporated and the residue was washed twice with dichloromethane, dissolved in water and pH adjusted pH=7 by addition of 0.5 N HCl aqueous solution. The resulting precipitate was recrystallized from water, and the crystals were washed with dichloromethane/ether to give 40 mg of N-[4-Amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-succinamic acid as a light yellow solid. MS (M+H)=501.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5](I)=[CH:4][N:3]=1.[C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1)#[CH:14].C(OCC)(=O)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C.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.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:14]#[C:13][C@@H:15]2[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16]2)=[CH:4][N:3]=1
Reactant: C#C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CCCNc1nc(Cl)ncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCNc1nc(Cl)ncc1C#C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a solution of 2-chloro-5-iodo-N-propylpyrimidin-4-amine (F1, 78 mg), bis(triphenylphosphine)palladium(II) dichloride (18 mg) and copper(I) iodide (10 mg) in N,N-dimethylformamide (2 mL), triethylamine (181 μL) and tert-butyl ((1S,3R)-3-ethynylcyclohexyl)carbamate (P0, 70 mg) were added at room temperature, and the mixture was stirred at the same temperature for 8 hours. To the reaction mixture, ethyl acetate and saturated aqueous ammonium chloride were added. The organic layer was separated, washed successively with saturated aqueous ammonium chloride, water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 94 to 60% hexane in ethyl acetate) to obtain tert-butyl ((1S,3R)-3-((2-chloro-4-(propylamino)pyrimidin-5-yl)ethynyl)cyclohexyl)carbamate (P1, 83 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](=[O:20])[NH:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.[CH:21](I)([CH3:23])[CH3:22]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](=[O:20])[N:17]([CH:21]([CH3:23])[CH3:22])[C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: CC(C)I
Reactant: COc1cc2c(cc1OC)-c1cc(=O)[nH]c(=O)n1CC2
Product: COc1cc2c(cc1OC)-c1cc(=O)n(C(C)C)c(=O)n1CC2
Yield: 50 %

Procedure:
In a manner analogous to that of Example 3, 9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido(6,1-a)isoquinolin-2,4-dione is reacted with isopropyl iodide. Yield 50%; melting point 190°-192° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1.ClCCl>[CH2:27]([O:26][C:24]([NH:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:25])[CH3:28]
Reactant: COC(=O)c1sc2cc(OC)ccc2c1N
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)Nc1c(C(=O)OC)sc2cc(OC)ccc12
Yield: 87.7 %

Procedure:
A mixture of 27.4 g (0.115 mol) of methyl 3-amino-6-methoxybenzo[b]thiophene-2-carboxylate, 38 g (0.275 mol) of potassium carbonate and 13.2 ml (0.138 mol) of ethyl chloroformate in 330 ml of toluene is heated at reflux for three hours. 7 ml (0.069 mol) of ethyl chloroformate are then added and the mixture is left heating at reflux for a further seven hours, with stirring. The mixture is then diluted with dichloromethane and washed with water. The organic phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure. Recrystallization is carried out from a mixture of isopropanol and diisopropyl ether. 31.2 g of product are obtained.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7].Cl[C:17]1[CH:22]=[C:21]([Cl:23])[N:20]=[CH:19][C:18]=1[C:24]#[N:25]>C1COCC1.CCOC(C)=O>[Cl:23][C:21]1[CH:22]=[C:17]([NH:3][C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=2[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])[C:18]([C:24]#[N:25])=[CH:19][N:20]=1
Reactant: N#Cc1cnc(Cl)cc1Cl
Reactant: CON(C)C(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccccc1Nc1cc(Cl)ncc1C#N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 34.2 %

Procedure:
Sodium hydride (0.888 g, 22.20 mmol) was added portionwise to a mixture of 2-amino-N-methoxy-N-methylbenzamide (1.00 g, 5.55 mmol), in THF (30 mL) cooled to 0° C. under an atmosphere of nitrogen. The resulting suspension was stirred at room temperature for 20 minutes and then 4,6-dichloropyridine-3-carbonitrile (0.960 g, 5.55 mmol) was added portionwise and the mixture heated overnight at 60° C. The mixture was allowed to cool to room temperature and then diluted with EtOAc (50 mL). The mixture was washed sequentially with water (50 mL), a saturated solution of NaHCO3 (50 mL), water (25 mL) and finally with a saturated solution of NaCl (20 mL). The organic layer was dried over Na2SO4 and then evaporated. The residue was crystallised from Et2O/MeOH to afford 2-[(2-chloro-5-cyanopyridin-4-yl)amino]-N-methoxy-N-methylbenzamide (0.602 g, 34% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.15 (3H, s), 3.47 (3H, s), 6.56 (1H, s), 7.39-7.44 (2H, m), 7.52-7.56 (2H, m), 8.45 (1H, s), 9.33 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=317.28 and 319.30.
Reaction SMILES: [CH2:1]([N:3]([C@H:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([O:10]C(C)(C)C)=[O:9])[C:4](=[O:6])[CH3:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:3]([C@H:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])[C:4](=[O:6])[CH3:5])[CH3:2]
Reactant: CCN(C(C)=O)[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(C)=O)[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of product from example 122B (81 mg, 0.293 mmol) in CH2Cl2 (3 mL) was added 2,2,2-trifluoroacetic acid (1.5 mL, 0.293 mmol), and the resulting mixture was stirred at rt for 1 hr. The mixture was concentrated in vacuo to give the title compound (50 mg, 77%).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1)#[N:2].[F:18][C:19]1[CH:20]=[C:21]([SH:28])[C:22](=[CH:26][CH:27]=1)[C:23](O)=[O:24]>N1C=CC=CC=1>[F:18][C:19]1[CH:27]=[CH:26][C:22]2[C:23](=[O:24])[N:2]=[C:1]([C:3]3[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=3)[S:28][C:21]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Reactant: O=C(O)c1ccc(F)cc1S
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccc(F)cc3s2)n1
Yield: 54.1 %

Procedure:
tert-Butyl 3-(6-cyano-2-pyridyl)propanoate (1.5 g, 6.5 mmol) and 4-fluorothiosalicylic acid (1.7 g, 9.7 mmol) were dissolved in pyridine (10 ml), and the mixture was refluxed for 15 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (1.36 g, 54%) as white crystals.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH:10]=2)O1.[CH2:21]([N:23]1[CH:27]=[C:26](I)[C:25]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[N:24]1)[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH2:21]([N:23]1[CH:27]=[C:26]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH:10]=2)[C:25]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[N:24]1)[CH3:22]
Reactant: CCn1cc(I)c(-c2cccs2)n1
Reactant: CCC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(=O)Nc1cc(-c2cn(CC)nc2-c2cccs2)ccn1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]propanamide (0.60 mmol) and bis(tricyclohexylphosphine)palladium(II) chloride (0.05 mmol) were weighed into a microwave vial (reaction volume 2-5 mL). A solution of 1-ethyl-4-iodo-3-(2-thienyl)-1H-pyrazole (0.50 mmol) in 3.3 mL degassed dioxane and 1.1 mL of a degassed 2 M aqueous sodium carbonate solution were added. The reaction mixture was purged with argon, the microwave vial was capped with a septum and transferred to a laboratory microwave oven. The reaction mixture was irradiated to a reaction temperature of 120° C. for 15 min. After cooling to room temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane:ethyl acetate 95:5 to 0:100) to afford 152 mg N-{4-[1-ethyl-3-(2-thienyl)-1H-pyrazol-4-yl]pyridin-2-yl}propanamide (93% yield).
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].[CH3:28][C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>O1CCOCC1.[Cu](I)I.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>[OH:33][C:29]([CH3:30])([CH3:28])[C:31]#[C:32][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: C#CC(C)(C)O
Reactant: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: CCC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
50 mg (0.26 mmol) of copper iodide, 69 mg (0.68 mmol) of triethylamine and 37 mg (0.05 mmol) of dichlorobis(triphenylphosphine)-palladium (II) are added to a suspension of 200 mg (0.52 mmol) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 5 ml of anhydrous dioxan, then this mixture is degassed under argon. After 15 minutes, 66 mg (0.78 mmol) of 2-methyl-but-3-yn-2-ol are added, then the mixture is heated at 100° C. for 1 hour. The raw reaction product is then filtered on celite, the filtrate is evaporated to dryness and the residue is purified by chromatography on silica (ethyl acetate), then the product is triturated in methanol to give 135 mg (76%) of 8-(3-hydroxy-3-methyl-but-1-ynyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:16][C@H:17]([C:22]([O:24]C)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])=[O:11].[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])[C:10]([NH:12][CH:13]([CH3:14])[CH3:15])=[O:11]
Reactant: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)NC(C)C)c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](N[C@@H](C(=O)NC(C)C)c1ccc(F)cc1F)C(=O)O
Reaction time: 1.5 h
Yield: 79.6 %

Procedure:
To a solution of methyl N-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucinate (1.32 g) in methanol (15 ml) was added a solution of lithium hydroxide (294 mg) in water (15 ml). The reaction was rapidly stirred for 1.5 hours and then evaporated in vacuo. The residue was dissolved in water and neutralised using 2N hydrochloric acid. The resulting solid was collected by filtration and dried in vacuo. The filtrate was applied to 4 Oasis cartridges (6 g), which were eluted with water (x2) and methanol (x2). The required fractions were combined and concentrated in vacuo to afford N-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucine (1.01 g). HPLC Rt=2.51 minutes; m/z [M+H]+=343.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([O-:15])=[O:14].[Na+].O>CCCCCC.C1COCC1.CS(C)=O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: O=C([O-])CCl
Reactant: Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(OCC(=O)O)cc1
Temperature: -15 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
Sodium hydride (0.86 g of 60% NaH in oil=0.516 g, 21.5 mmol) in oil dispersion was washed twice with 10 ml of hexane. THF was added (5 ml) and the mixture was cooled to -15° C. A solution of p-methylphenol (1.95 g, 18 mmol) in THF was then added, and the mixture was warmed to 25° C. for 1 hour. The THF was removed by distillation under vacuum and a solution of sodium chloroacetate (2.5 g, 22 mmol) in DMSO (50 ml) was added. The mixture was stirred at room temperature for 20 hours, then diluted with 300 ml. of water. The mixture was extracted twice with 50 ml. of hexane. The aqueous phase was acidified with 4N hydrochloric acid and the product was extracted twice with 100 ml. of ethyl acetate. The combined ethyl acetate layers were washed twice with 100 ml. water, dried over MgSO4, filtered, and the solvent was removed by distillation under reduced pressure to give 2.9 g of product as a white solid. Yield of product=97.6%.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:13]I.[H-].[Na+]>>[CH3:13][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH:11]=[O:12])=[C:2]1[Cl:1]
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: Cn1c(Cl)c(C=O)c2ccccc21
Yield: 93.8 %

Procedure:
Prepared from (1) (18 g), methyl iodide (17.1 g) and NaH (2.88 g) yielding (3) (18.2 g), m.p. 88°-90° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH:15]=[CH2:16])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1.C(OC(C)C)(C)C>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH2:15][CH2:16][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC1=NC=C(OCc2ccccc2)C(=O)C1
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: O=C1CC(CCN2CCCC2)=NC=C1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 5-benzyloxy-2-vinyl-4-pyridone (2.90 g) and pyrrolidine (5.33 ml) was heated and refluxed for an hour. The mixture was cooled and diluted with tetrahydrofuran (20 ml) and diisopropyl ether (80 ml). After being stirred for an hour at ambient temperature, the resulting precipitate was collected by filtration, washed with diisopropyl ether and air-dried at ambient temperature to give 5-benzyloxy-2-[2-(1-pyrrolidinyl)ethyl]-4-pyridone (3.79 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17]CC2C=CC=CC=2)=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:7]=1>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:7]=1
Reactant: CC1(C)OB(c2cc(Cl)ccc2OCc2ccccc2)OC1(C)C
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OB(c2cc(Cl)ccc2O)OC1(C)C
Reaction time: 0.5 h

Procedure:
The product from step d) was dissolved in ethanol (100 ml) and treated with palladium on activated carbon (5%), the suspension was stirred for 30 min under hydrogen (1 bar). The mixture was then filtered, and the filtrate was concentrated in vacuo to give the subtitle compound (4.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]3[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([C:21]#[N:22])[CH:15]=3)=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:21]([C:16]1[CH:15]=[C:14]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:3][CH:4]=3)[N:8]([CH:11]([CH3:12])[CH3:13])[CH:7]=2)[N:18]([CH2:19][CH3:20])[N:17]=1)#[N:22]
Reactant: CCn1nc(C#N)cc1-c1cn(C(C)C)c2cc(N)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCn1nc(C#N)cc1-c1cn(C(C)C)c2cc(NS(C)(=O)=O)ccc12
Yield: 90.4 %

Procedure:
Stir a solution of 5-(6-Amino-1-isopropyl-1H-indol-3-yl)-1-ethyl-1H-pyrazole-3-carbonitrile (0.126 g, 0.393 mmol), pyridine (0.062 g, 0.786 mmol) and methanesulfonyl chloride (0.068 g, 0.590 mmol) in methylene chloride (3 mL) at room temperature for 2.5 h. After this time, Purify the reaction directly by chromatography (silica, methylene chloride to 1:9 ethyl acetate/methylene chloride) then freeze-dried from acetonitrile/water to afford N-[3-(5-Cyano-2-ethyl-2H-pyrazol-3-yl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide (0.132 g, 90%) as alight purple solid: mp 144-145° C.; 1H NMR (500 MHz, DMSO-d0.6 δ0.60 (s, 1H), 7.84 (s, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.11 (s, 1H), 7.04 (dd, J=8.5, 1.5 Hz, 1H), 4.73 (m, 1H), 4.27 (q, J=7.0 Hz, 21H), 2.96 (s, 3H), 1.52 (d, J=6.5 Hz, 6H), 1.35 (t, J=7.0 Hz, 3H) LCMS (Method 4)>99%, 6.96 min, m/z 372 [M+H]+.
Reaction SMILES: NCCC[O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[N:23]([CH3:24])[CH2:22][CH2:21][C@:17]45[C:18]=2[C:19]=1[O:20][C@H:16]4[C@@H:15]([OH:25])[CH:14]=[CH:13][C@@H:12]35.C1(N=C=NCCN2CCOCC2)CCCCC1.CC1C=CC(S(O)(=O)=O)=CC=1>>[CH:8]1[C:9]2[CH2:10][C@H:11]3[N:23]([CH2:22][CH2:21][C@@:17]45[C@H:12]3[CH:13]=[CH:14][C@H:15]([OH:25])[C@@H:16]4[O:20][C:19]([C:18]=25)=[C:6]([OH:5])[CH:7]=1)[CH3:24]
Reactant: CN1CC[C@]23c4c5ccc(OCCCN)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: C(=NCCN1CCOCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reaction time: 16 h

Procedure:
3-O-Aminopropylmorphine is reacted with a latex suspension in the presence of 1-cyclohexyl-3-(2-morpholino-ethyl)carbodiimide metho p-toluenesulfonate. The resultant complex is washed by repeated sedimentation of the solid latex particles by centrifugation and resuspension in an appropriate buffer until no free aminopropylmorphine is left in the aqueous phase of the suspension. The aminopropylmorphine is used at a concentration of 1 mg per ml in distilled water. The solution is adjusted to pH 5.0. The latex suspension is a carboxylated styrene butadiene copolymer (Dow Chemical Corp. No. 816), which has been washed and then diluted in water to contain approximately 5% latex solids. The concentration of the carbodiimide used is 1% weight/volume in distilled water. The reaction mixture is comprised of the following ratio of reactants: 1 volume of 1% carbodiimide, one volume of aminopropylmorphine and 6 volumes of latex polymer suspension. The reaction is allowed to proceed at room temperature overnight for 16 hrs. under continuous agitation. The solid polymer complex is then sedimented by centrifugation, washed with water and resuspended in 0.1 M tris saline buffer, pH 7.3 to a final concentration of 80 mg solids/ml.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[I:18])[C:11](OC)=[O:12])[CH2:4][CH2:5][CH3:6].Cl>O1CCCC1>[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH2:11][OH:12])[CH:15]=[CH:16][C:17]=1[I:18])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1cc(C(=O)OC)ccc1I
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCOc1cc(CO)ccc1I
Temperature: 60 °C
Yield: 100.1 %

Procedure:
8.17 g (0.375 mol, 3 eq) of lithium borohydride are added to a solution of 41.78 g (0.125 mol, 1 eq) of methyl 3-butoxy-4-iodobenzoate in 210 ml of tetrahydrofuran. The reaction medium is heated at 60° C. for 2 hours and then hydrolyzed cautiously with ice-cold saturated ammonium chloride solution. The reaction medium is neutralized with concentrated hydrochloric acid and then extracted with ethyl acetate. The organic phases are washed with water and dried over magnesium sulfate. The solvent is evaporated off to give 38.31 g of (3-butoxy-4-iodophenyl)methanol in the form of a whitish oil. Yield=100%.