Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]#[N:13])[CH2:3][CH2:2]1.[C:14](OC(=O)C)(=[O:16])[CH3:15].C([O-])(=O)C.[Na+]>[Ni]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:3][CH2:2]1
Reactant: N#CCC1CCOc2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)NCCC1CCOc2ccccc21
Temperature: 50 °C

Procedure:
The saturated cyano compound obtained in Step B is solubilised in the reactor of a Parr apparatus with acetic anhydride. Sodium acetate (1.5 eq.) and also Raney nickel (6 mg per 50 mg of product) are then introduced into the reaction medium. The whole is heated at 50° C. under hydrogen pressure of 40 psi for 12 hours. Once the solvent has been removed after returning to normal temperature and pressure conditions, extraction is carried out with ethyl acetate. Purification of the concentrated organic phase by flash chromatography (CHCl3/AcOEt 7/3) results in the desired amide. Colourless gum.
Reaction SMILES: O=[C:2]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6]CC)=O.[CH3:15][C:16]1[C:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:23]=2[CH3:32])=[C:19]([NH2:33])[NH:18][N:17]=1>C(O)(=O)C>[CH3:15][C:16]1[C:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[C:23]=2[CH3:32])=[C:19]2[NH:33][C:2]([CH:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:3][C:4](=[O:6])[N:18]2[N:17]=1
Reactant: Cc1n[nH]c(N)c1Cc1cccc(C(F)(F)F)c1C
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Solvent: CC(=O)O
Product: Cc1nn2c(=O)cc(C3CCOCC3)[nH]c2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 140 °C
Reaction time: 8 h

Procedure:
To a suspension of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.78 mg, 3.90 mmol) in acetic acid was added 3-methyl-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-5-amine (1.0 g, 3.71 mmol) in microwave reaction vessel. It was sealed and heated with microwave reactor at 140° C. for 40 minutes. The reaction mixture was cooled, diluted with acetic acid (5 mL) and stood for overnight. Precipitate was observed, filtered. Solid was washed with acetic acid (2 mL) and cooled methanol (2 mL). Solid was dried. The titled compound was obtained and used in next step. (1.02 g, 68%) LC/MS: MS (ES+) m/e 406 (MH+).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][C:13]2[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:23])[N:3]=1.[CH3:34][C:35]([OH:39])([C:37]#[CH:38])[CH3:36].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][C:13]3[C:14]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:31])([F:32])[F:33])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:3]=[C:2]([C:38]#[C:37][C:35]([CH3:36])([OH:39])[CH3:34])[C:10]=12
Reactant: Cc1cccc2cc(Cn3nc(I)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc2cc(Cn3nc(C#CC(C)(C)O)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 3-iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.0569 g, 0.102 mmol) and copper(i) iodide (0.00387 g, 0.0203 mmol, 0.2 eq) in DMF (2 mL) was treated with 2-methyl-3-butyn-2-ol (0.0984 mL, 1.02 mmol, 10 eq), triethylamine (0.0282 mL, 0.203 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium(0) (0.0117 g, 0.0102 mmol, 10 mol %) under Ar. The mixture was stirred under Ar at rt for 45 min. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 over 14 min as eluent to provide 4-(4-amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methylbut-3-yn-2-ol [PI3Kδ IC50=116 nM] as a tan solid. 1H NMR (DMSO-d6) δ ppm 8.21 (1 H, s), 8.02 (1H, s), 7.87 (1 H, d, J=7.8 Hz), 7.77-7.82 (1 H, m), 7.65 (1 H, d, J=6.7 Hz), 7.57-7.62 (2 H, m), 7.51-7.57 (1 H, m), 7.26-7.32 (1 H, m), 5.76 (1 H, s), 5.44 (2 H, s), 2.60 (3 H, s), 1.46 (6 H, s). Mass Spectrum (ESI) m/e=517.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH2:13])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][C:21]=2[N+:23]([O-:25])=[O:24])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)C[C@@H]1CO
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])C[C@@H]1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
Reflux a mixture of (2R,4R)-4-amino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (198 g, 0.92 mol), 5-bromo-fluoronitrobenzene (224 g, 0.98 mol), triethylamine (273 mL, 1.96 mol) in ethyl acetate (2 L) for 16 h under nitrogen with vigorous stirring. Cool to room temperature and wash with brine. Back-extract the brine layer with ethyl acetate (1 L), combine the organic layers, dry over sodium sulfate, filter and concentrate. Dissolve the resulting solid in warm ethyl acetate (2 L), concentrate to approximately 500 mL and allow crystals to start forming Treat the solution slowly with hexanes (2 L) and allow the mixture to stand at room temperature for 2 h. Collect the yellow solid by filtration, wash with hexanes and dry at 40° C./20 mm Hg to obtain 227 g of desired product. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel column chromatography (2:3:5 ethyl acetate/dichloromethane/heptane gradually increasing to 2:3 ethyl acetate/heptane) to obtain an additional 54 g of desired product. Overall yield: 281 g (70%). [α]D20−81 (c=1.0 in methanol). 1H NMR (400 MHz, DMSO-d6) δ 1.40 (s, 9H), 1.90 (m, 1H), 2.48 (br s, 1H), 3.14 (m, 1H), 3.45 (m, 1H), 3.63 (m, 1H), 3.81 (m, 2H), 4.29 (m, 1H), 5.12 (m, 1H), 7.08 (d, 1H), 7.65 (dd, 1H), 8.15 (d, 1H), 8.57 (br d, 1H, NH).
Reaction SMILES: [C:1]([C@H:5]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH2:7][C:8]([OH:10])=[O:9])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]1)[N:16]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:15]3)([O:3]C)=[O:2].O.O[Li].O.OS([O-])(=O)=O.[Na+]>O1CCOCC1>[C:1]([C@H:5]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH2:7][C:8]([OH:10])=[O:9])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]1)[N:16]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:15]3)([OH:3])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12CC(=O)O
Agent: O=S(=O)([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)N1C[C@H]2[C@@H]3CC[C@H](C(=O)O)[C@@]3(CC(=O)O)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 17β-carbomethoxy-6-t-butylcarboxy-6-azaandrost-4-en-3-one (15.4 g, 36 mmol), from part E, in dioxane (150 mL) and water (100 mL) is treated with LiOH·H2O (3.31 g, 79 mmol) and stirred overnight on a water bath. The reaction is poured into saturated aqueous NaHSO4 (150 mL), extracted with methylene chloride (3×100 mL), extracts washed with saturated aqueous NaCl, dried over MgSO4 and concentrated to a volume of 100 mL. At this point crystals begin to form and 2:1 hexanes/ethyl acetate (50 mL) is added, the mixture triturated, cooled to room temperature and 17β-carboxy-6-t-butylcarboxy-6-azaandrost-4-en-3-one collected as a fluffy white powder; yield: 9.44 g (63%); m.p. 215°-216° C. Anal. Calcd. for C24H35NO5 ·1/4H2O; C, 68.30; H, 8.48; N, 3.32. Found: C, 68.45; H, 8.41; N, 3.28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[Cl-].[NH4+:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH2:28])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Agent: [Cl-]
Product: NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to ammonium chloride via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 386 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:3]=1.[S:27](N)([NH2:30])(=[O:29])=[O:28]>O1CCOCC1.O.C(=O)(O)[O-].[Na+]>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([NH2:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: NS(N)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(N)(=O)=O)CC2)nc1N

Procedure:
[4-Amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (308 mg, 0.848 mmol, Example 107) in dioxane (3 mL) and sulfamide (814 mg, 8.48 mmol, Aldrich) refluxed overnight. The mixture was diluted with water and sodium bicarbonate and extracted with dichloromethane. The organic solution was washed with water, dried (MgSO4), filtered and evaporated. Chromatography on silica gel (methanol/triethylamine/ethyl acetate 5:2:95) gave, after crystallization from ethanol/ethyl ether, 255 mg of colorless solid, MP 217-218° C. MS(ES) MH+443
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C1COCC1.CC([O-])(C)C.[K+].CS([C:31]1[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][N:32]=1)(=O)=O>O>[CH3:40][S:37]([C:34]1[CH:35]=[CH:36][C:31]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:15])=[CH:6][CH:7]=2)=[N:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(C(=O)c3ccccc3)cc2)nc1

Procedure:
To 5.5 g of p-hydroxybenzophenone in a 25 ml THF/25 ml DMSO mixture was added 3.6 g of t-BuOK and then 6.51 g of 2,5-bis(methylsulfonyl)pyridine, and the resulting mixture was heated at 62° C. for 11/2 hrs. The reaction mixture was cooled and added to approximately 3 to 4 volumes of water and stirred. The crude product which formed was filtered and dried. Recrystallization from ethanol gave purified (4-((5-(methylsulfonyl)-2-pyridinyl)oxy)phenyl)phenylmethanone, m.p. 130°-131.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[NH:16]([C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=1)[NH2:17].CC(O)=O>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[N:16]([C:18]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=3)[N:17]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: N#Cc1ccnc(NN)c1
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1ccnc(-n2nc(-c3ccc(Cl)cc3)cc2O)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a mixture of ethyl 3-(4-chlorophenyl)-3-oxopropanoate (500 mg, 2.2 mmol) and 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2, 296 mg, 2.2 mmol) in EtOH (15 mL) was added AcOH (2 mL) at r.t. The reaction mixture was stirred at 90° C. overnight. After the reaction was completed, the mixture was concentrated, washed with PE/EA (10 mL, V/V=1/1) to give the title compound (500 mg, 76%) as a brown solid and used as crude for next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]([O:34]CC)=[O:33].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]([OH:34])=[O:33]
Reactant: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCC(Oc1ccc(OCC(=O)O)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of ethyl {[2-methyl-4-({1-[4′-(trifluoromethyl)-4-biphenylyl]pentyl}oxy)phenyl]oxy}acetate (310 mg, 0.62 mmol) in dioxan (6 mL) and water (3 mL), was added aqueous NaOH (2M, 2.43 mL, 1.22 mmol), and the mixture stirred at rt for 1 hour. The dioxan was removed under vacuum and brine (5 mL) added to the residue. The precipitate was collected by filtration and dried under vacuum to give the title compound as a white solid (250 mg).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:9][F:10])([CH3:8])[C:4](OC)=[O:5].[H-].[Na+].[CH3:13][C:14]#[N:15]>C1COCC1>[F:1][CH2:2][C:3]([CH2:9][F:10])([CH3:8])[C:4](=[O:5])[CH2:13][C:14]#[N:15]
Reactant: CC#N
Reactant: COC(=O)C(C)(CF)CF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CF)(CF)C(=O)CC#N
Temperature: 70 °C
Yield: 80.1 %

Procedure:
According to the procedure described in Example 161B Step 1, methyl 3-fluoro-2-(fluoromethyl)-2-methylpropanoate (5.21 g, 34.2 mmol), NaH (1.248 g, 52 mmol), and MeCN (2.791 g, 68 mmol) in THF (40 mL) were heated at 70° C. overnight, to afford 5-fluoro-4-(fluoromethyl)-4-methyl-3-oxopentanenitrile as oil (4.412 g, 80%). 1H NMR (300 MHz, CDCl3) δ 4.67 (m, 2H), 4.52 (m, 2H), 3.80 (s, 2H), 1.27 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Na].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
32 g (0.20 mol) 2-chloro-5-nitropyridine in 120 mL toluene were combined with 200 mL (0.20 mmol) of a 1M sodium benzylate solution in benzylalcohol and stirred overnight at RT. The organic phase was washed with water and saturated sodium chloride solution, dried on sodium sulphate and the toluene was eliminated by distillation. The residue was cooled with ice, the precipitate formed was suction filtered and washed several times with tert.-butylmethylether.
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:38])[C:19]([C:35](=[O:37])[CH3:36])=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:22]=1)[CH3:16].[NH4+].[Cl-]>C1COCC1.O>[CH2:15]([O:17][C:18](=[O:38])[CH:19]([C:35](=[O:37])[CH3:36])[CH:20]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:22]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: Br[Mg]Cc1ccccc1
Reactant: CCOC(=O)C(=Cc1ccc(OC)c(OC2CCCC2)c1)C(C)=O
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C(C)=O)C(Cc1ccccc1)c1ccc(OC)c(OC2CCCC2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
Cuprous iodide (1.15 g, 6.05 mmol) in dry THF (10 ml) was treated at 0° C. with benzylmagnesium bromide (2M in THF, 6.05 ml, 12.1 mmol) over a 3 minute period. The cuprate was stirred at 0° C. for 30 minutes and then cooled to -78° C. and then TMSCl (3.28 g, 30.2 mmol) in THF (5 ml) was added dropwise keeping the reaction temperature below -60° C. The mixture was stirred at below -60° C. for a further 10 minutes and then ethyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-acetyl-prop-2-enoate (1 g, 3.01 mmol) in THF (5 ml) was added dropwise over 3 minutes. The mixture was stirred at below -60° C. for 45 minutes and then saturated NH4Cl (30 ml) and water (20 ml) were added. The mixture was allowed to warm to room temperature, the resultant precipitate was removed by filtration and the filtrate evaporated, the residue was dissolved in methylene chloride (200 ml), washed with water (30 ml), In HCl (50 ml) and water (30 ml), dried over Na2SO, and the volatiles removed in vacuo. Flash chromatography (SiO2 ; EtOAc:hexane (1.9)) afforded ethyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-acetyl-4-phenyl-butanoate (1.19 g), 92%) as a yellow oil.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:40][C@H:41]([C:51]1[NH:52][C:53]([I:56])=[CH:54][N:55]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:49][CH3:50])=[O:48]>CN(C=O)C>[I:56][C:53]1[NH:52][C:51]([C@@H:41]([NH:40][C:6]([C:5]2[S:1][CH:2]=[N:3][CH:4]=2)=[O:8])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:49][CH3:50])=[O:48])=[N:55][CH:54]=1
Reactant: O=C(O)c1cncs1
Reactant: CNC(=O)CCCCC[C@H](N)c1ncc(I)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CCCCC[C@H](NC(=O)c1cncs1)c1ncc(I)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of thiazole-5-carboxylic acid (1.5 eq.) in DMF (1 M) was treated with EDC.HCl (1.5 eq.), HOBt (1.5 eq.) and DIPEA (1.5 eq.), Reaction mixture was stirred at room temperature for 10 min and then added to a solution of D7 in DMF (0.33 M). The reaction mixture was stirred at room temperature for 1 h and subsequently partitioned between DCM and sat. aq. NaHCO3. The organic phase was separated and the aqueous phase extracted with DCM. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a crude that was purified by flash chromatography (Biotage; 25M; DCM/MeOH) to afford the title compound as a white powder. 1H-NMR (400 MHz, 300K, DMSO-d6) δ 12.25 (br s, 1H), 9.23 (s, 1H), 9.02 (d, 1H, J 8.0 Hz), 8.58 (s, 1H), 7.65 (br s, 1H), 7.23 (s, 1H), 5.05 (m, 1H), 2.55 (d, 3H, J 5.2 Hz), 2.02 (t, 2H, J 7.6 Hz), 1.97 (m, 1H), 1.82 (m, 1H), 1.47 (m, 2H), 1.25 (m, 4H); MS (ES+) C15H20IN5O2S: 462 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([SH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.Cl[CH2:22][C:23]([O:25][CH:26]1[CH:30]([O:31][C:32](=[O:34])[CH3:33])[CH2:29][O:28][CH2:27]1)=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:32]([O:31][CH:30]1[CH2:29][O:28][CH2:27][CH:26]1[O:25][C:23]([CH2:22][S:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:20])=[C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][C:12]=3[C:13]2=[O:14])[CH:6]=1)=[O:24])(=[O:34])[CH3:33]
Reactant: CC(=O)OC1COCC1OC(=O)CCl
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(S)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OC1COCC1OC(=O)CSc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reaction time: 5 h
Yield: 64.8 %

Procedure:
A mixture of 14.0 g of N-(4-chloro-2-fluoro-5-mercaptophenyl)-3,4,5,6-tetrahydrophthalimide, 11.0 g of 4-acetoxytetrahydrofuran-3-yl chloroacetate, 7.46 g of potassium carbonate, 1.5 g of potassium iodide and 150 ml of acetone was refluxed under stirring for 5 hours. After cooling, the salt was filtered off, and the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/hexane=2/3), to obtain 14.5 g of a compound described in Table 1 (No. 6) (65 %).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]3[CH2:15][CH:16]([CH2:17]O)[CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br-:19].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:17][CH:16]1[CH:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=3[CH:13]([C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:15]1
Reactant: OCC1CC2c3ccccc3C1c1ccccc12
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCC1CC2c3ccccc3C1c1ccccc12

Procedure:
9,10-Dihydro-9,10-ethanoanthracene-11-methanol (2 gm) was combined with triphenylphosphine dibromide (5.3 gm) in carbon tetrachloride (60 ml). The mixture was heated to reflux 1 hour, filtered, and the filtrate was concentrated on a rotary evaporator. The residue was boiled in n-heptane (75 ml), filtered hot, and the filtrate cooled. The white precipitate was filtered and air dried to provide the product (mp=103°-106° C.).
Reaction SMILES: C[Mg]Br.O1CCC[CH2:5]1.[CH:9]([N:12]1[C:17](=[O:18])[CH2:16][O:15][CH:14]([C:19]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[CH2:27][CH2:26][CH2:25]3)=[O:20])[CH2:13]1)([CH3:11])[CH3:10]>O.C(OCC)(=O)C>[OH:20][C:19]([O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][CH2:26][CH2:25]2)([CH:14]1[O:15][CH2:16][C:17](=[O:18])[N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13]1)[CH3:5]
Reactant: C1CCOC1
Reactant: CC(C)N1CC(C(=O)Oc2ccc3c(c2)CCC3)OCC1=O
Agent: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)N1CC(C(C)(O)Oc2ccc3c(c2)CCC3)OCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
After adding dropwise a solution of 5 g. of methyl magnesium bromide in 27 ml. of tetrahydrofuran to a mixture of 4.0 g. of 4-isopropyl-5-oxo-2-(1-oxo-5-indanyloxymethyl)morpholine and 100 ml. of tetrahydrofuran with stirring at room temperature, the mixture was stirred for 3 hours at room temperature. Then, after adding a small amount of water to the reaction mixture, the solvent was distilled off under reduced pressure. To the residue formed were added 50 ml. of ethyl acetate and 50 ml. of water to dissolve the residue and they were filtered. The ethyl acetate filtrate (100 ml.) was recovered, washed twice each with 50 ml. of saturated sodium chloride aqueous solution, and condensed under reduced pressure, the obtained residue was adsorbed on a silica gel column prepared from 100 ml. of silica gel in chloroform, and then eluted using ethyl acetate as the eluting solution. After removing the first 30 ml. of the ethyl acetate eluting solution emerging from the column, 300 ml. of the subsequent ethyl acetate eluting solution was collected and dried to provide 2.5 g. (yield 59.3%) of oily 2-(1-hydroxy-1-methyl-5-indanyloxymethyl)-4-isopropyl-5-oxomorpholine.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:9]=[C:10]([C:12](OC(C)C)=[O:13])[CH:11]=1.[CH2:28]([CH2:30][NH2:31])[OH:29].N12CCCN=C1CCCCC2>CO>[CH3:21][C:19]1[N:20]=[C:7]2[C:6]([NH:5][CH2:4][C:3]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:2]=3[CH3:1])=[CH:11][C:10]([C:12]([NH:31][CH2:30][CH2:28][OH:29])=[O:13])=[CH:9][N:8]2[C:18]=1[CH3:22]
Reactant: NCCO
Reactant: Cc1cccc(C)c1CNc1cc(C(=O)OC(C)C)cn2c(C)c(C)nc12
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccc(C)c1CNc1cc(C(=O)NCCO)cn2c(C)c(C)nc12
Temperature: 5 °C
Yield: 81.9 %

Procedure:
Isopropyl 8-[(2,6-dimethylbenzyl)amino]-2.3-dimethylimidazo[1,2-a]pyridine-6-carboxylate (obtained as described in WO2/20523) (5 g, 14 mmol), ethanolamine (2.0 g 33 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) 1.5 g, 10 mmol) were dissolved in methanol (25 ml). The mixture was refluxed over night. The reaction mixture was cooled to 5° C. The solid product was filtered off and washed with methanol (15 ml). 4.2 g (84%) of the title compound was obtained as a white solid. The structure of the compound was confirmed with 1H-NMR spectrum.