Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:41]=[C:40]([C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])[CH:39]=[CH:38][C:7]=1[O:8][CH:9]([CH2:34][CH2:35][CH2:36][CH3:37])[C:10]([NH:12][C:13]1[C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)=[CH:21][C:16]2[NH:17]C(=O)[O:19][C:15]=2[CH:14]=1)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].C1(C)C(C)=CC=CC=1.[OH-].[Ca+2].[OH-]>C(O)CO>[NH2:17][C:16]1[CH:21]=[C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:28][CH:29]=2)[C:13]([NH:12][C:10](=[O:11])[CH:9]([O:8][C:7]2[CH:38]=[CH:39][C:40]([C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])=[CH:41][C:6]=2[C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:14][C:15]=1[OH:19]
Reactant: CCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc2oc(=O)[nH]c2cc1Oc1ccc(C(C)(C)C)cc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: OCCO
Solvent: Cc1ccccc1C
Product: CCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(O)c(N)cc1Oc1ccc(C(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
In a 250-ml flask inert with nitrogen, place 11.3 g (0.018 m) of 6-{2-(2,4-di-t-pentylphenoxy)hexanoyl}amino-5-(4-t-butylphenoxy)-benzoxazol-2-one (Formula I), 120 ml of xylene, 12 ml of ethylene glycol, and 8.0 g of calcium hydroxide. Heat under reflux collecting approximately 7 ml of water-ethylene glycol and 20 ml of xylene in a Dean-Stark trap. Detach the trap and heat under reflux for 5 hrs. Cool to 80° C. and add 100 ml of toluene, 100 ml of hot water, 25 ml of acetic acid, and 2 g sodium hydrosulfite. Stir the mixture at 60°-65° C. for 15 min and filter through a Celite pad to remove interlayer insolubles. Separate toluene-xylene solution, wash with 100 ml of hot water+12 ml of acetic acid+2 g sodium hydrosulfite and 100 ml of hot water twice, and concentrate under a reduced pressure to a thick oil. Dissolve the oil in 200 ml of heptane, add seed crystals, and stand at room temperature over night. Cool in an ice-water bath for 1 hr, collect solid, wash with heptane, and dry in a vacuum oven to give 9.2 g (85%) of 2-amino-5-{2-(2,4-di-t-pentylphenoxy)hexanoyl}amino-4-(4-t-butylphenoxy)-phenol (7b; Y=4-t-butylphenoxy and R′=1-(2,4-di-t-pentylphenoxy)pentyl).
Reaction SMILES: [CH3:1][C:2]([O:14][Si](C)(C)C)([CH3:13])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[OH:14][C:2]([CH3:13])([CH3:1])[C:3]#[C:4][C:5]([C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CC(C)(C#CC(=O)c1ccncc1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(O)C#CC(=O)c1ccncc1
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a room temperature, stirred solution of 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (0.5 g, 1.915 mmol) in DCM (10 mL) was added PTSA (0.47 g, 2.49 mmol). The reaction mixture was stirred for 2 h and then diluted with DCM (50 mL). The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 4-hydroxy-4-methyl-1-(pyridin-4-yl) pent-2-yn-1-one (0.35 g, 97%) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=[O:11].[C:13]1([CH2:19][C:20]([NH2:22])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:19]1([C@H:9]2[C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=3)[C:10](=[O:11])[NH:12][C:10]2=[O:11])[C:13]2=[C:18]3[C:17](=[CH:16][CH:15]=[CH:14]2)[CH2:7][CH2:2][CH2:3][N:22]3[CH:20]=1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Reactant: NC(=O)Cc1ccccc1
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccccc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-phenyl-pyrrolidine-2,5-dione was prepared according to the Example 40 replacing 2-chloro-4-fluorophenylacetamide with phenylacetamide. 1HNMR (DMSO-d6) 400 MHz δ: 11.511(s, 1H), 7.24-7.36(m, 6H), 7.13(d, 1H, J=7.2), 6.8-6.88(m, 2H), 4.49(d, 1H, J=8.0 Hz), 4.3 (d, 1H, J=7.6 Hz), 4.08(m, 2H), 2.88 (m, 2H), 2.088(m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C@@H:5]([NH:7][C:8](=[O:15])[C@@H:9]([NH2:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6])[CH3:2].[CH3:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]1.C(OC(Cl)=O)C(C)C.CN1CCOCC1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C@@H:5]([NH:7][C:8](=[O:15])[C@@H:9]([NH:14][C:24]([CH:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)=[O:25])[C:10]([CH3:11])([CH3:13])[CH3:12])[CH3:6])[CH3:2]
Reactant: CCOC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)(C)C
Reactant: CN1CCC(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)C1CCN(C)CC1)C(C)(C)C

Procedure:
For compound (A48) (S)-2-((S)-2-Amino-3,3-dimethyl-butyrylamino)-propionic acid ethyl ester was coupled with 1-Methyl-piperidine-4-carboxylic acid using isobutylchloroformate and N-methylmorpholine in DMF to give (S)-2-{(S)-3,3-Dimethyl-2-[(1-methyl-piperidine-4-carbonyl)-amino]-butyrylamino}-propionic acid ethyl ester. This was then quaternised with Mel in DCM-acetone and subsequently hydrolysed using an hydroxide resin such as Ambersep 900-OH resin.
Reaction SMILES: O=C=[N:3]C1CC(C)(C)CC(C)(CN=C=O)C1.C(O)COCCOCCO.[C:27]([O:31][CH2:32][CH2:33]O)(=[O:30])[CH:28]=[CH2:29]>>[C:27]([OH:31])(=[O:30])[CH:28]=[CH2:29].[NH2:3][C:27]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: C=CC(=O)OCCO
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Solvent: OCCOCCOCCO
Product: C=CC(=O)O
Product: CCOC(N)=O

Procedure:
2 moles of isophorone diisocyanate, 1 mole of triethylene glycol, and 2 moles of 2-hydroxyethyl acrylate were reacted by a predetermined method so as to yield urethane acrylate as a monomer of a ultraviolet-curing resin. Subsequently, a monomeric composition was prepared by mixing 50 grams of the urethane acrylate, 25 grams of the acrylic ester compound obtained in Example 1, 25 grams of 1,6-hexanediol diacrylate as a monomer of the ultraviolet-curing resin, and 3 grams of benzylmethyl ketal as a photopolymerization initiator (produced by Ciba-Geigy and marketed under the trade name "Irgacure 651").
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)#[N:21].C(#N)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)NC1CCCc2ccc(O)cc21
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCCc2ccc(OCc3cccc(C#N)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.9 %

Procedure:
tert-Butyl (7-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (0.026 g, 0.10 mmol) was combined with m-cyanobenzyl bromide (Aldrich, Cat. #145610) (0.029 g, 0.15 mmol), acetonitrile (2.0 mL) and cesium carbonate (0.065 g, 0.20 mmol) and allowed to stir at r.t. overnight. This was diluted with ethyl acetate, filtered to remove the solids and concentrated under reduced pressure to give crude tert-butyl 7-(3-cyanobenzyloxy)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (0.045 g) as a semisolid. Analytical LCMS (M+Na)+: m/z=401.0.
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.[F:11][C:12]([F:16])([F:15])[CH2:13]I.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:11][C:12]([F:16])([F:15])[CH2:13][N:3]1[C:4](=[O:10])[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[N:1]=[CH:2]1
Reactant: O=c1[nH]cnc2sccc12
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccsc2ncn1CC(F)(F)F
Temperature: 100 °C
Yield: 70.3 %

Procedure:
A mixture of thieno[2,3-d]pyrimidin-4(3H)-one (25 g, 164 mmol), 1,1,1-trifluoro-2-iodoethane (32.4 ml, 329 mmol) and cesium carbonate (53.5 g, 164 mmol) in DMF (100 ml) was heated at 100° C. for 18 h in a round bottom flask. 1 L of water was added to the reaction mixture and was extracted with ethyl acetate (3×300 ml). The combined organic phase was washed with water (500 ml), followed by brine. The organic phase was dried over MgSO4, filtrated, then concentrated in vacuo. The residue was purified by flash chromatography (0-100% ethyl acetate/DCM) to obtain the title compound (27 g, 70%). LCMS RT=0.88 min, M+H+=235.1.
Reaction SMILES: Br/[C:2](=[CH:10]\[C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=2[Cl:20])[N:13]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:12]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])/[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)C.CCCCCC>C1(C)C=CC=CC=1>[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1/[C:2](=[CH:10]\[C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=2[Cl:20])[N:13]([S:22]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)(=[O:24])=[O:23])[C:12]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])/[C:3]([O:5][C:6]([CH3:8])([CH3:7])[CH3:9])=[O:4]
Reactant: CCOC(=O)c1c(/C=C(\Br)C(=O)OC(C)(C)C)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Reactant: OB(O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1c(/C=C(/C(=O)OC(C)(C)C)c2ccco2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
Combine (Z)-2-bromo-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoic acid, t-butyl ester (1.00 g, 1.6 mmol), furan-2-boronic acid (0.27 g, 2.4 mmol), and cesium carbonate (1.00 g, 3.2 mmol) in toluene (15 mL). Sparge with nitrogen for 15 minutes. Add tetrakis(triphenylphosphine)palladium(0) (50 mg). Heat to 90° C. After 3 days, partition the reaction mixture between ethyl acetate and water. Separate the layers. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a reside. Chromatograph the residue on silica gel eluting with 15% diethyl ether/hexane to give the title compound.
Reaction SMILES: P(I)(I)P(I)I.[C:7]([NH:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:63][O:64][CH3:65])[C:33]([NH:35][CH:36]2[C:43](=[O:44])[N:42]3[CH:37]2[CH2:38][S:39][CH:40]([S:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([N+:60]([O-:62])=[O:61])[CH:55]=2)[C:41]3(O)[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:34])[N:31]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:7]([NH:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:63][O:64][CH3:65])[C:33]([NH:35][CH:36]2[C:43](=[O:44])[N:42]3[CH:37]2[CH2:38][S:39][C:40]([S:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([N+:60]([O-:62])=[O:61])[CH:55]=2)=[C:41]3[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:34])[N:31]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C1CSC(Sc1cccc([N+](=O)[O-])c1)C2(O)C(=O)OC(C)(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: IP(I)P(I)I
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(Sc3cccc([N+](=O)[O-])c3)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.08 h
Yield: 45.6 %

Procedure:
A suspension of 677 mg of diphosphorus tetraiodide in 7 ml of pyridine was stirred under an inert atmosphere for 5 minutes and then 780 mg of the product of Step A were added. The mixture was stirred for 2 hours and then a further 363 mg of diphosphorus tetraiodide were added. The stirring was maintained for 1 hour and the reaction mixture was poured into 50 ml of ethyl acetate and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in methylene chloride. The organic phase was washed with 0.1N hydrochloric acid, then with water, dried and concentrated to dryness. The residue was chromatographed on silica and eluted with a mixture of chloroform and acetone (10-0.5) to obtain 348 mg of racemic 1,1-dimethylethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(3-nitrophenylthio)-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate which crystallized from ether.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH:31]1[C:35]([CH2:36][C:37](O)=[O:38])=[N:34][N:33]=[N:32]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=O)C>[NH:31]1[C:35]([CH2:36][C:37]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[N:17]=[C:18]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[O:19][C:20]=4[C:21]([F:22])([F:23])[F:24])=[O:15])=[CH:11][CH:12]=3)[CH2:3][CH2:2]2)=[O:38])=[N:34][N:33]=[N:32]1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(O)Cc1nnn[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C2CCN(C(=O)Cc3nnn[nH]3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Yield: 17.2 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (50.7 mg, 0.122 mmol), (1H-tetrazol-5-yl)-acetic acid (15.6 mg, 0.122 mmol), triethylamine (51 uL, 0.366 mmol) and BOP (54 mg, 0.128 mmol) in 1 mL DMF were reacted as above to give a clear oil. The crude product was crystallized from methanol/acetonitrile to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[1-(2-1H-tetrazol-5-yl-acetyl)-piperidin-4-yl]-phenyl}-amide as off-white crystals (11 mg, 17%). ES-MS calcd for C25H22F3N7O3 (m/e) 525.49, obsd 526 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([CH2:12]Br)[CH:3]=1.[CH3:14][NH2:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[N:15]([CH3:14])[CH2:12]2
Reactant: CN
Reactant: COC(=O)c1ccc(Br)cc1CBr
Product: CN1Cc2cc(Br)ccc2C1=O
Temperature: 90 °C
Yield: 99.7 %

Procedure:
Methyl 4-bromo-2-(bromomethyl)benzoate (0.153 g, 0.497 mmol) was suspended in methanamine (2M solution in MeOH, 2.484 mL, 4.97 mmol) and the mixture was heated to reflux (90° C.) for 24 hours. The reaction mixture was cooled, concentrated in vacuo, and dried under high vacuum to give the title compound (0.112 g). 1H NMR (500 MHz, CDCl3) δ ppm 3.19 (s, 3 H), 4.36 (s, 2 H), 7.57-7.62 (m, 2 H), 7.70 (d, J=8.30 Hz, 1 H); ESI-MS m/z [M+H]+ 226.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14](/[CH:18]=[CH:19]/[C:20]#[N:21])=[CH:13][C:12]=1[CH3:22].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14](/[CH:18]=[CH:19]/[C:20]#[N:21])=[CH:13][C:12]=2[CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1cc(/C=C/C#N)cc(C)c1N
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(/C=C/C#N)cc(C)c1Nc1ccnc(Cl)n1
Temperature: 145 °C
Yield: 78.5 %

Procedure:
To a mixture of 2,4-dichloropyrimidine (25 gm) and (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride (28 gm) was added N,N-diisopropylethylamine (250 ml) under stirring. The mixture was then heated to 140 to 150° C. and stirred for 55 to 60 hours. The solution was then cooled to room temperature and the solvent was distilled off under reduced pressure to provide a residual solid. To the residual solid was added ethyl acetate (1500 ml) and water (1000 ml). The reaction mass was stirred for 30 minutes at room temperature and then the layers were separated. The organic layer was dried with sodium sulfate and then concentrates to provide 30 gm of (E)-3-(4-(2-chloropyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.[C:30](=[O:32])=[O:31]>O1CCCC1>[Cl:19][C:20]1[C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc2ccccc2nc1Cl
Temperature: -65 °C
Yield: 62 %

Procedure:
To a solution of 21.3 ml (0.15 mole) of diisopropyl amine in 300 ml of dry tetrahydrofuran under a continuous nitrogen blanket, at -70° C., was added 61.6 ml of 2.7M n-butyllithium in hexane (0.165 mole) while maintaining the temperature at -60 to -70° C. Subsequent to this addition, the temperature was maintained at -65° C. for approximately 20 minutes. A solution of 20 g (0.12 mole) of 2-chloroquinoline in 60 ml of tetrahydrofuran was added dropwise while maintaining the temperature at -60° to -70° C. After holding the temperature at -65° C. for 20 minutes subsequent to this addition, the entire reaction mixture was poured onto a large excess of dry ice. Most of the solvent was evaporated in a stream of air; the residual solvent was removed by rotary evaporation. The residue was taken up in 300 ml water, made basic with dil aq. sodium hydroxide and washed with 3×50 ml of isopropyl ether. The aqueous layer was filtered and made acidic (4 to 5 pH) with dilute aqueous hydrochloric acid. The precipitate was collected, washed with water, isopropyl alcohol, and isopropyl ether, and dried, giving 15.4 g (62%) of white crystals, m.p. 190°-210° C. (decomp.). A sample was recrystallized from isopropyl alcohol giving an analytical sample, m.p. 190°-210° C.
Reaction SMILES: [CH:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:2]1[C:4]([O-])=[O:5].[CH:11]1([NH2:14])[CH2:13][CH2:12]1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C1C=CC=CN=1)C>[CH:11]1([NH:14][C:4]([CH:2]2[CH2:3][CH:1]2[C:7]([O:9][CH3:10])=[O:8])=[O:5])[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: COC(=O)C1CC1C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C1CC1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 9.3 g of monomethyl (1RS,2RS)-1,2-cyclopropanedicarboxylate, 4.0 ml of N-cyclopropylamine and 11.6 g of N(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in 210 ml of methylene chloride is treated at 0° C. with 0.7 g of dimethylaminopyridine and subsequently stirred at room temperature for 2 hrs. The reaction solution is worked-up with methylene chloride/10% potassium hydrogen sulphate solution. The organic phase is washed with saturated sodium bicarbonate solution, dried and concentrated to give 10.6 g of methyl (1RS,2RS)-2-cyclopropylcarbamoyl-cyclopropanecarboxylate.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][NH:3][C:2]1=[O:11].[C:12]1([O:22][CH2:23][CH:24]2[O:26][CH2:25]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.CO>C1(C)C=CC=CC=1>[C:12]1([O:22][CH2:23][CH:24]([OH:26])[CH2:25][N:8]2[CH2:7][CH2:6][C:5]3([O:1][C:2](=[O:11])[NH:3][CH2:4]3)[CH2:10][CH2:9]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Reactant: O=C1NCC2(CCNCC2)O1
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1NCC2(CCN(CC(O)COc3cccc4ccccc34)CC2)O1
Yield: 73.4 %

Procedure:
A mixture of 2 g 1-oxa-3,8-diazaspiro[4.5]-decan 2-one, 3.12 g 2,3-epoxypropyl 1-naphthyl ether, 5 ml methanol and 10 ml toluene is heated at reflux for 5 hours. The solvent is removed by evaporation in vacuum. The residue is filtered through 20 g silica gel with 5% methanol/methylene chloride. Evaporation of solvent and recrystalization from ethyl acetate affords 3.35 g 8-[3-(1-naphthyloxy)-2-hydroxypropyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 178°-179°.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[Na].Br[CH2:22][CH2:23][CH:24]=[CH2:25].[OH-].[Na+]>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:25][CH2:24][CH:23]=[CH2:22])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Reactant: C=CCCBr
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C=CCCn1cnc2c1c(=O)n(CCCC)c(=O)n2CCCC
Temperature: 70 °C
Reaction time: 46 h

Procedure:
38.9 g of 1,3-di-n-butyl-xanthine are added at 25° C. to a solution of 3.4 g of sodium in 200 ml of absolute ethanol. 20.5 g of 4-bromobut-1-ene are then added at 50° C. After stirring for 46 hours under a nitrogen atmosphere at 70° C. the reaction mixture is cooled to 20° C., precipitated sodium bromide is filtered off and the filtrate is then evaporated under reduced pressure. The residue obtained is treated with chloroform and 1 N sodium hydroxide solution to remove 1,3-di-n-butyl-xanthine. From the chloroform phase there is obtained a yellow oily residue which after column chromatography on silica gel with methylene chloride/acetone (8:2) as eluent and after distillation under reduced pressure yields 29.7 g (78.8% of theory relative to reacted 1,3-di-n-butyl-xanthine) of the title compound with a melting point of 41° to 42° C.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OP([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(OCC)=O)C.[H-].[Na+].Cl>CN(C)C=O>[C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2/[CH:12]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cnoc1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnoc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a mixture of 5-phenylisoxazole-4-carbaldehyde (7.18 g), ethyl diethylphosphonoacetate (9.35 g) and N,N-dimethylformamide (150 ml) was added sodium hydride (60%, oil, 1.65 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl (E)-3-(5-phenyl-4-isoxazolyl)propenoate (8.88 g, yield 88%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). NMR (CDCl3) δ: 1.33 (3H, t, J=7.2 Hz), 4.27 (2H, q, J=7.2 Hz), 6.34 (1H, d, J=15.4 Hz), 7.48–7.82 (6H, m), 8.52 (1H, s).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](SC)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].C(O)C.O>O1CCOCC1.[Ni]>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[CH:14][N:13]=2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: CSc1ncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2nc(-c3cncnc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Yield: 21.8 %

Procedure:
((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methylsulfanyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine (400 mg, 0.728 mmol) was dissolved in dioxane (10 ml), ethanol (2 ml) and water (2 ml) and treated with 2 g of Raney Nickel (2000). This was refluxed for 16 hours. The reaction was filtered, evaporated and purified by silica gel chromatography (5% methanol/methylene chloride to give ((S)-1-methanesulfonyl-piperidin-3-yl)-{5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine (˜80 mg). MS (ES+): 504.