Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[O:27]1[CH2:31][CH2:30][CH:29]([N:32]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:34]=[N:33]2)[CH2:28]1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:16]2[CH:17]=[C:12]([N:8]3[CH:7]([CH3:26])[CH2:6][C:5]4[C:10](=[CH:11][C:2]([C:35]5[CH:34]=[N:33][N:32]([CH:29]6[CH2:30][CH2:31][O:27][CH2:28]6)[CH:36]=5)=[CH:3][CH:4]=4)[CH2:9]3)[N:13]=[C:14]([NH2:25])[N:15]=2)[CH2:23][CH2:22]1
Reactant: CC1(C)OB(c2cnn(C3CCOC3)c2)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(C4CCOC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.0 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. It was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (4.7 mg). LCMS (M+H)+: m/z=475.2.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([Cl:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:13]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1>C1C=CC=CC=1>[ClH:10].[N:13]1([CH2:18][CH2:19][NH:20][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][CH3:12])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NCCN1CCCC1
Reactant: CCC(C(=O)Cl)c1ccccc1
Solvent: c1ccccc1
Product: CCC(C(=O)NCCN1CCCC1)c1ccccc1
Product: Cl

Procedure:
To a solution of 1 mol of α-phenyl-α-ethyl acetyl chloride in 2 liters of benzene add, with agitation, a benzene solution of 1 mol of 2-pyrrolidino -ethyl amine. The hydrochloric acid formed during condensation attaches itself to the pyrrolidine group and the expected derivative crystallizes out in the reaction medium.
Reaction SMILES: [CH3:1][C@:2]12[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][C@H:15]([OH:22])[C:13](=[O:14])[C@@H:12]1[C@:11]1([CH3:23])[C@H:5]([C:6]([O:8][C@H:9]([C:24]3[CH:25]=[CH:26][O:27][CH:28]=3)[CH2:10]1)=[O:7])[CH2:4][CH2:3]2.C1(=O)O[C:32](=[O:33])[CH2:31]C1.C1CCN2C(=NCCC2)CC1>ClCCl>[CH3:31][C:32]([O:22][C@@H:15]1[C:13](=[O:14])[C@H:12]2[C@@:2]([CH3:1])([CH2:3][CH2:4][C@@H:5]3[C@:11]2([CH3:23])[CH2:10][C@@H:9]([C:24]2[CH:25]=[CH:26][O:27][CH:28]=2)[O:8][C:6]3=[O:7])[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16]1)=[O:33]
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Reactant: O=C1CCC(=O)O1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OC(C)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To Salvinorin B (190 mg, 0.487 mmol) and succinic anhydride (112 mg, 2.5 eq) suspended in dichloromethane (5 ml) at 0° C. was added DBU (218 pl, 3 eq) dropwise. The mixture was stirred at 0° C. for 15 mins, washed with 3% citric acid (5 ml), saturated NaHCO3 solution (5 ml) and brine (5 ml). The mixture was dried over sodium sulfate, filtered and evaporated to dryness. The crude residue was purified by column chromatography (silica gel: CH2Cl2 to 5% MeOH in CH2Cl2) to give salvinorin hemisuccinate (130 mg, 54%).
Reaction SMILES: O=C(C)C[N:4]1[C:8]([NH:9][C:10]([C:23]2C=CC=CC=2)([C:17]2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=[N:5]1.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[CH3:23][C:10]1[NH:9][C:8]2[N:4]([CH:17]=1)[N:5]=[CH:6][CH:7]=2
Reactant: CC(=O)Cn1nccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cn2nccc2[nH]1
Reaction time: 2 h

Procedure:
To a solution of 1-(2-oxopropyl)-5-triphenylmethylaminopyrazole (0.75 g) in methanol was added conc. hydrochloric acid (0.75 ml). The mixture was stirred for 2 hours. The reaction mixture was added to a mixture of ethyl acetate, tetrahydrofuran and ice-cold water, and the mixture was adjusted to pH 8 with sodium bicarbonate. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was pulverized with diisopropyl ether to give 2-methyl-1H-imidazo[1,2-b]pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24](O)=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10]1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][NH2:34].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24]([NH:34][O:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10]1
Reactant: NOC1CCCCO1
Reactant: Cc1cccc(CN2CC[C@@H](Nc3ncc(/C=C/C(=O)O)cc3Cl)C2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(CN2CC[C@@H](Nc3ncc(/C=C/C(=O)NOC4CCCCO4)cc3Cl)C2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77 %

Procedure:
A mixture of A mixture of (2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (410 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (142 mg), HOBt (156 mg) and EDCI (180 mg) in DMF (15 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (400 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:12][CH2:11]2)[C:5]([C:37]#[N:38])=[C:4]([S:39][CH2:40][C:41]2[N:42]=[C:43]([C:46]3[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=3)[S:44][CH:45]=2)[N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C@H:10]2[CH2:15][CH2:14][C@H:13]([O:16][CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]2)[C:5]([C:37]#[N:38])=[C:4]([S:39][CH2:40][C:41]2[N:42]=[C:43]([C:46]3[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][CH:51]=3)[S:44][CH:45]=2)[N:3]=1
Reactant: CC(C)(C)[Si](OCCOC1CCC(c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)CC1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1[C@H]1CC[C@H](OCCO)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
35 mg (0.05 mmol) of the compound from Example 7A (trans isomer) are dissolved in 5 ml of dry THF, 18 mg (0.07 mmol) of tetra-n-butylammonium fluoride are added and the mixture is stirred at RT for 20 h. 15 ml of ethyl acetate are then added to the mixture. The mixture is washed twice with in each case 3 ml of saturated aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate. After removal of the solvent on a rotary evaporator the crude product is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[N:22]=[C:21]2[C:33]1[CH:38]=[N:37][CH:36]=[C:35](Cl)[N:34]=1>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[N:22]=[C:21]2[C:33]1[N:34]=[C:35]([O:3][C@@H:4]2[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:36]=[N:37][CH:38]=1
Reactant: Clc1cncc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
NaH (60% in mineral oil, 0.081 g, 2.032 mmol) was added to a solution of (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (0.245 g, 1.219 mmol, Astatech, Inc.) in DMF (2.50 mL) at 0° C. The mixture was stirred for 15 min then 5-bromo-3-(6-chloropyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 1c (0.400 g, 1.016 mmol, Pharmacore) was added and the heterogenous mixture was warmed to RT. After 60 min at RT, ice was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide tert-butyl (3R)-3-((6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-pyrazinyl)oxy)-1-piperidinecarboxylate (0.562 g, 1.006 mmol, 99% yield) as a light-yellow foam. MS (ESI, pos. ion) m/z: 558.0, 560.0 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])=[O:25])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:7].[OH-].[Na+]>C(O)C>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6](=[S:7])[NH:5][C@H:4]([C:3]([OH:34])=[O:2])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]([C:26]2[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=2[Cl:32])=[O:25])=[CH:21][CH:22]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=S)c1c(C)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cl)c1C(=S)N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Temperature: 52.5 °C
Reaction time: 3.5 h
Yield: 96.1 %

Procedure:
To a suspension of N-[(2-chloro-6-methylphenyl)thioxomethyl]-4-[[(2,6 -dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester (2.89 mmol, 1.55 g) in ethanol (8 mL) was added aqueous 1.0N sodium hydroxide (5 mL) at room temperature. The mixture was heated to 50-55° C. and the resulting clear solution was stirred for 3-4 h. TLC analysis of the mixture indicated the absence of starting material. The mixture was concentrated to remove ethanol, then was diluted with 15 mL of water and extracted with 25 mL of diethyl ether to remove any neutral impurities. The aqueous layer was acidified with 1N HCl and the precipitated colorless solid was extracted into ethyl acetate (2×30 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to afford 1.45 g (96%) of N-[(2-chloro-6-methylphenyl)thioxomethyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine as an amorphous colorless solid. HRMS: Obs. mass, 521.0241. Calcd. mass, 521.0260 (M+H).
Reaction SMILES: [OH-].[Na+].[CH:3]1([NH:9][C:10]2[C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][N:13]=[C:12]3[N:21]([CH2:24][CH3:25])[N:22]=[CH:23][C:11]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.O>C(O)C>[CH:3]1([NH:9][C:10]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=[C:12]3[N:21]([CH2:24][CH3:25])[N:22]=[CH:23][C:11]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1ncc2c(NC3CCCCC3)c(C(=O)O)cnc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Sodium hydroxide solution (4.09 gm in 20 ml water) was added to a solution of ethyl 4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (9.32 gm, 0.0294 mole) (example 4) in ethanol. The reaction mixture was stirred for about 14 h at room temperature and then warmed for about 1 h at 60° C. Water was added and the reaction mixture was extracted with ethyl acetate. Aqueous layer was acidified by using hydrochloric acid (2N) to pH of about 4-5. White solid, which was obtained, was filtered and dried in vacuo.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[OH:16][CH2:17][CH2:18][NH:19][NH2:20]>O>[NH2:11][C:10]1[N:19]([CH2:18][CH2:17][OH:16])[N:20]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: NNCCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(-c2ccccc2)nn1CCO
Yield: 78.7 %

Procedure:
Benzoylacetonitrile (25 g, 0.17 mol) was suspended in a mixture of 125 mL reagent grade anhydrous alcohol and 20 mL glacial acetic acid. 2-Hydroxyethylhydrazine (14.4 g, 1.1 equiv) dissolved in 35 mL alcohol was added all at once. The mixture was heated at reflux for 4 h, cooled, water was added to make 500 mL total volume and the solution was chilled in a refrigerator overnight. Crystals were filtered cold on a Buchner funnel, washed with cold water and dried on high vacuum to give the desired product (27.2 g, 79%).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.II.[CH2:17]([O:19][C:20](=[O:23])[CH2:21]Br)[CH3:18].Cl>C1C=CC=CC=1.[Zn]>[OH:14][C:12]([C:9]1[CH:8]=[CH:7][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1)([CH3:13])[CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:23]
Reactant: CC(=O)c1ccc(C2CCCC2)cc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC(C)(O)c1ccc(C2CCCC2)cc1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To a refluxing mixture of 4′-cyclopentylacetophenone (17 g), I2 (5 mg) and Zn dust (12 g) in benzene (150 ml) was added ethylbromoacetate (11 ml) dropwise over 30 minutes. The mixture was refluxed for next 45 min and then cooled to room temperature. It was acidified with 10% aqueous HCl solution (150 ml) and organic layer was separated out. The organic layer was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel to furnish 22 g (88.1% yield) of ethyl 3-hydroxy-3-(4′-cyclopentylphenyl)-butanoate (2a) as oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(N)ccc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(F)c(OC)c3)n2)cc1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 4-fluoro-3-methoxyaniline (Combi-Blocks Inc.) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine, and isolated as a brown solid (100%). 1H NMR (400 MHz, d6-DMSO) δ 11.91 (br. s., 1H); 8.80 (br. s., 1H); 8.35 (br. s., 1H); 7.55 (br. s., 1H); 7.24 (br. s., 4H); 7.11 (d, J=1.2 Hz, 1H); 6.77-6.94 (m, 6H); 4.79 (br. s., 4H); 3.77 (br. s., 3H); 3.72 (d, J=10.6 Hz, 6H); 2.56 (br. s., 3H). m/z (ESI, +ve ion) 567.0 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[O:6])[CH2:2][CH3:3].[C:8](CC(OCC)=O)#[N:9].[O-:16][CH2:17][CH3:18].[Na+]>>[NH2:9][C:8]1[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:6])[NH:7][C:17](=[O:16])[CH:18]=1
Reactant: CCCNC(N)=O
Reactant: CCOC(=O)CC#N
Reactant: CC[O-]
Agent: [Na+]
Product: CCCn1c(N)cc(=O)[nH]c1=O

Procedure:
This method was utilized to prepare the N-3 propylpurines. The starting material used was n-propyl urea condensed with ethyl cyanoacetate in the presence of sodium ethoxide to yield the 6-amino-1-propylpyrimidinedione in moderate yield. Commercially available 3-n-propylxanthine could also be used as the starting material.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]1[S:8][C:9]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]#[N:21])[CH:16]=3)[C:10]=2[N:11]=1)([CH3:5])[CH3:4].CCCCCC.[C:28](OCC)(=[O:30])C>>[CH3:4][C:3]1([CH3:5])[CH2:2][O:1][C:28](=[O:30])[N:6]1[C:7]1[S:8][C:9]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]#[N:21])[CH:16]=3)[C:10]=2[N:11]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(CO)Nc1nc2c(s1)CCc1cc(C#N)ccc1-2
Solvent: CCCCCC
Product: CC1(C)COC(=O)N1c1nc2c(s1)CCc1cc(C#N)ccc1-2
Yield: 93 %

Procedure:
In the same manner as described in step 4 of Example 81, replacing 2-fluoro-4-{2-[(2-hydroxy-1,1-dimethyl-ethyl)amino]-1,3-thiazol-4-yl}benzonitrile with 2-[(2-hydroxy-1,1-dimethylethyl)amino]-4,5-dihydronaphtho[1,2-d][1,3]thiazole-7-carbonitrile, prepared in the previous step, and purification of the crude product on silica using a stepwise gradient of 6:1 to 1:1 hexane:ethyl acetate as the eluent gave the title compound (2.7 g, 93%), mp>230° C. (dec.).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)Cl.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(N(CC)CC)C>[CH3:23][S:24]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\CCCCCCCCOS(C)(=O)=O
Yield: 96.4 %

Procedure:
Preparation A was repeated using 410 g oleyl alcohol, 2 liters DCM, 322 ml triethylamine, 194 g methane sulphonylchloride to yield 510 g (96%) oleyl methanesulphonate product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[NH2+]C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:34][N:35]1[CH2:38][CH:37]([CH2:39][NH2:40])[CH2:36]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10](=[O:12])[NH:40][CH2:39][CH:37]1[CH2:38][N:35]([CH2:34][C:33]2[CH:41]=[CH:42][C:43]([Cl:44])=[C:31]([Cl:30])[CH:32]=2)[CH2:36]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Agent: C[NH2+]C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Reaction time: 0.08 h

Procedure:
A solution of tert-Butoxycarbonylamino-acetic acid (1.88 g, 10.7 mmol) in dichloromethane (15 ml) is treated with triethylamine (1.5 ml, 10.7 mmol) and [Dimethylamino-[1,2,3]-triazolo-[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (4.06 g, 10.7 mmol) and stirred for 5 minutes. To the reaction mixture is added a solution of C-[1-(3,4-Dichloro-benzyl)-azetidin-3-yl]-methylamine (2.64 g, 10.7 mmol) in dichloromethane (15 ml) with stirring for a further 3 hours. The reaction mixture is partitioned between dichloromethane and saturated sodium bicarbonate solution, the organic phase is washed with brine, dried over magnesium sulphate and evaporated. The crude product is purified by chromatography over flash silica eluting with 7% methanol in dichloromethane to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].C(O[CH:17]=[C:18]([C:24]#[N:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.O>C(O)(=O)C>[NH2:25][C:24]1[N:10]([C:4]2[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=2[C:2]([F:1])([F:12])[F:13])[N:11]=[CH:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1ccc(Cl)cc1C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2C(F)(F)F)c1N
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A solution of 31.58 g of 2-(trifluoromethyl)-4-chlorophenylhydrazine and 27.92 g of ethyl (ethoxymethylene)cyanoacetate dissolved in 225 ml of acetic acid and 75 ml of water was heated on a steam bath for approximately 16 hours. The reaction mixture was cooled to room temperature and placed in the refrigerator. The precipitated solid was collected by filtrate to provide 43 g of 5-amino-1-[2-(trifluoromethyl)-4-chlorophenyl]-1H-pyrazole-4-carboxylic acid, ethyl ester. mp=114°-116° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C@@:18]([CH3:28])([S:24]([CH3:27])(=[O:26])=[O:25])[C:19]([O:21]CC)=[O:20])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Li+].Cl>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C@@:18]([CH3:28])([S:24]([CH3:27])(=[O:25])=[O:26])[C:19]([OH:21])=[O:20])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)[C@@](C)(CCn1cc(C#Cc2cccc(C#N)c2)cn1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@](CCn1cc(C#Cc2cccc(C#N)c2)cn1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of ethyl (2R)-4-{4-[(3-cyanophenyl)ethynyl]-1H-pyrazol-1-yl}-2-methyl-2-(methylsulfonyl)butanoate (0.415 g, 1.04 mmol) in THF-H2O (20 mL:10 mL) was added lithium hydroxide (0.249 g, 10.4 mmol, 10 eq). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was then acidified with 1M HCl and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to give (2R)-4-{4-[(3-cyanophenyl)ethynyl]-1H-pyrazol-1-yl}-2-methyl-2-(methylsulfonyl)butanoic acid (0.360 g, 93% yield) as a white solid. LC-MS M+H+372.1.
Reaction SMILES: [C:1]([N:4]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([Cl:47])[CH:45]=2)[C:6]2([CH:11]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[O:19][C:20]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[O:22])[CH2:10][C:9](=O)[NH:8][CH:7]2[C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[CH3:40])[C:5]1=[O:48])(=[O:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:58])=CC=1>C1(C)C=CC=CC=1>[C:1]([N:4]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([Cl:47])[CH:45]=2)[C:6]2([CH:11]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[O:19][C:20]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[O:22])[CH2:10][C:9](=[S:58])[NH:8][CH:7]2[C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[CH3:40])[C:5]1=[O:48])(=[O:3])[CH3:2]
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)N(C(C)=O)c1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)N(C(C)=O)c1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Temperature: 125 °C
Yield: 29.2 %

Procedure:
A mixture of chiral (2′S, 3S, 4′R)-1-acetyl-6-chloro-4′-[5-chloro-2-(2-methanesulfonylamino-1,1-diethyl-2-oxo-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.07 mmol) and Lawesson's Reagent (56 mg, 0.126 mmol) in toluene (5 mL) was heated at 125° C. for 1.5 h. The mixture was purified by flash column chromatography to give the title compound as white solid (15 mg).