Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.C(N(CC)CC)C.ClC(OCC)=O.[Cl:27][C:28]1[CH:40]=[CH:39][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:30][CH:29]=1>C(#N)C.C(O)(C)(C)C>[Cl:27][C:28]1[CH:40]=[CH:39][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([C:6](=[O:8])[CH:5]=[CH:4][C:3]3[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=3[Cl:1])[CH2:35][CH2:34]2)=[CH:30][CH:29]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1Cl
Reactant: Clc1ccc(CN2CCNCC2)cc1
Agent: CCOC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: O=C(C=Cc1ccc(Cl)cc1Cl)N1CCN(Cc2ccc(Cl)cc2)CC1
Reaction time: 0.08 h
Yield: 65.3 %

Procedure:
In a mixture of acetonitrile and tert-butanol (5: 1, v/v, 20 ml) are dissolved 2,4-dichlorocinnamic acid (4.3 g, 19.8 mmole) and triethylamine (3 ml, 21.5 mmole), and the mixture is cooled with an ice water bath. To the mixture is added dropwise a solution of ethyl chloroformate (2 ml, 21.0 mmole) in a mixture of acetonitrile and tert-butanol (5:1, v/v, 5 ml) over a period of 3 minutes. After the addition, the mixture is stirred for 5 minutes, and then to the mixture is added an aqueous solution (15 ml) of N-(4-chlorobenzyl)piperazine (4.2 g, 20 mmole) (which is prepared by the process as disclosed in Yoshiaki Ikeda et al., Yakugaku Zasshi, Vol. 89, 669-676, 1969), and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure until about half volume, and thereto is added water (20 ml), and then extracted with benzene (30 ml) twice. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated to dryness. The resulting residue is recrystallized from methanol to give 1-(4-chlorobenzyl)-4-(2,4-dichlorocinnamoyl)piperazine (5.3 g, 65 %) as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][C:8]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:7][C:6]=1[CH3:25])[CH3:2].[F-].[K+].[Br-].[K+].[CH:31]1(B(O)O)C[CH2:32]1.[C:37]1(C)C=CC=CC=1>>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[C:10]([CH3:37])=[CH:9][C:8]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:7][C:6]=1[CH:25]1[CH2:32][CH2:31]1)[CH3:2]
Reactant: OB(O)C1CC1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)c1c(C)cc(N2CCOCC2)cc1OS(=O)(=O)C(F)(F)F
Agent: [Br-]
Agent: [F-]
Agent: [K+]
Product: CCOC(=O)c1c(C)cc(N2CCOCC2)cc1C1CC1
Yield: 85 %

Procedure:
A solution of 2-methyl-4-morpholin-4-yl-6-(trifluoromethylsulfonyl)oxy-benzoic acid ethyl ester (0.7 g, 1.76 mmol), potassium fluoride (0.43 g, 7.41 mmol), potassium bromide (0.25 g, 2.12 mmol) and cyclopropylboronic acid (0.30 g, 3.53 mmol) in dry toluene (16 ml) is degassed and flushed with argon for 20 min. To the reaction mixture is added tetrakis(triphenylphosphin)palladium(0) (0.20 g, 0.18 mmol) and subjected to microwave irradiation at 120° C. for 1 h. The reaction mixture is poured onto ice and extracted with ethyl acetate (3×30 ml). The combined organic layers are washed with water (20 ml), brine (20 ml) and dried over sodium sulfate. The solvent is evaporated to get the crude product, which is purified by column chromatography (silica gel, 8% acetone/hexane) to afford 2-cyclopropyl-6-methyl-4-morpholin-4-yl-benzoic acid ethyl ester (0.46 g, 1.59 mmol, 85%).
Reaction SMILES: [CH:1]1([C:4]2([F:25])[CH2:7][N:6]([C:8]3[N:13]=[C:12]([S:14]([CH3:17])(=O)=O)[N:11]=[C:10]([NH:18][C:19]4[NH:23][N:22]=[C:21]([CH3:24])[CH:20]=4)[CH:9]=3)[CH2:5]2)[CH2:3][CH2:2]1.[NH2:26][C:27]1[N:32]=[CH:31]C(S)=[CH:29][CH:28]=1>CN(C=O)C.C(OC(=O)C)C.C([O-])(O)=O.[Na+]>[NH2:26][C:27]1[N:32]=[CH:31][C:17]([S:14][C:12]2[N:11]=[C:10]([NH:18][C:19]3[NH:23][N:22]=[C:21]([CH3:24])[CH:20]=3)[CH:9]=[C:8]([N:6]3[CH2:7][C:4]([CH:1]4[CH2:3][CH2:2]4)([F:25])[CH2:5]3)[N:13]=2)=[CH:29][CH:28]=1
Reactant: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)nc(S(C)(=O)=O)n2)[nH]n1
Reactant: Nc1ccc(S)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)nc(Sc3ccc(N)nc3)n2)[nH]n1
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (880 mg, 2.4 mmol) and 6-aminopyridine-3-thiol) (300 mg, 2.4 mmol) in DMF (10 ml) was heated to 80° C. and stirred for 2 hrs. The reaction was diluted with ethylacetate (150 ml) and Sat. NaHCO3 (50 ml) and the organic layer washed with brine (50 ml), dried (MgSO4) and concentrated to give an oil. The residue was purified by flash column chromatography eluting with Pentane/EtOAc (5% MeOH) 0 to 100%. The resulting compound was triturated in 10:1 DCM:MeOH and filtered to give the title compound as a white solid (300 mg, 30%). 1H NMR (DMSO, 400 MHz) 0.42-0.44 (2H, m), 0.55-0.60 (2H, m), 1.35-1.45 (1H, m), 2.11 (3H, s), 3.81-3.90 (4H, m), 5.55-5.80 (2H, m), 6.35 (2H, s), 6.49-6.52 (1H, d), 7.46-7.49 (1H, d), 7.97 (1H, s), 9.30-9.35 (1H, s). ES+ 413
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>O>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
4-bromo-4′-fluorobenzophenone was synthesized by the Friedel-Crafts acylation of fluorobenzene with 4-bromobenzoyl chloride. More specifically, fluorobenzene (117 grams, 1.2 mol) and 4-bromobenzoyl chloride (39.8 grams, 0.18 mol) was charged to a 250 milliliter flask equipped with a mechanical stirrer, N2 inlet, and reflux condenser. The mixture was then cooled to 0° C. and anhydrous AlCl3 (27 grams, 0.20 mol) was added. The mixture was stirred for 15 minutes at 23° C. for 16 hours. The resulting slurry was poured into 2 liters of water acidified with HCl. The organics were extracted with methylene chloride and subsequently dried over MgSO4. The slurry was filtered and the methylene chloride was removed under reduced pressure. Recrystallization from ethanol gave 43.4 grams (86 percent yield) of the desired crystalline product.
Reaction SMILES: C(Cl)(=O)[O:2][CH2:3][CH3:4].F[CH2:8][C:9]([O-])=O.[Na+].[F:13][C:14]1[CH:38]=[CH:37][C:17]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][NH2:36])[CH:33]=4)[CH:28]=[CH:27]3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][N:36]5[CH2:9][CH2:8][CH2:4][C:3]5=[O:2])[CH:33]=4)[CH:28]=[CH:27]3)[CH2:24][CH2:25]2)=[CH:37][CH:38]=1
Reactant: CCOC(=O)Cl
Reactant: NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Reactant: O=C([O-])CF
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Yield: 57 %

Procedure:
Under ice cooling, ethyl chlorocarbonate (96 μl) was added to a suspension of sodium fluoroacetate (100 mg) in dimethylformamide (5 ml) and the resultant mixture was stirred for 20 min. Next, a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg) obtainedinExample 322-3) indimethylformamide (5 ml) was added thereto and the resultant mixture was stirred at room temperature for 2 hr. Then a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction mixtures. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (100 mg) as a white powder (yield: 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[C:5]([NH:7][CH:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH:9]1[OH:18])=O.C(N(CC)CC)C.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:18][C:9]3[CH2:10][C:11]4([O:12][CH2:13][CH2:14][O:15]4)[CH2:16][CH2:17][C:8]=3[N:7]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH:24]1[CH2:25][CH2:26]1
Reactant: O=C(NC1CCC2(CC1O)OCCO2)c1ccc(OCC2CC2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Clc1cc(-c2nc3c(o2)CC2(CC3)OCCO2)ccc1OCC1CC1
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of 3-chloro-4-(cyclopropylmethoxy)-N-(7-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)benzamide (20.8 g) in dimethyl sulfoxide (80 mL) were added triethylamine (22.8 mL) and sulfur trioxide-pyridine complex (26.0 g), and the mixture was stirred for 1 hr under a nitrogen stream. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in THF (80 mL) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (21.4 g), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (10.0 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31](/[CH:34]=[CH:35]/[C:36]3[CH:41]=[CH:40][C:39](Br)=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2].[C:43]([OH:48])(=[O:47])[CH2:44][CH:45]=[CH2:46].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31](/[CH:34]=[CH:35]/[C:36]3[CH:41]=[CH:40][C:39](/[CH:46]=[CH:45]/[CH2:44][C:43]([OH:48])=[O:47])=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(/C=C/c4ccc(Br)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=CCC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(/C=C/c4ccc(/C=C/CC(=O)O)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
A mixture of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[(E)-2-(4-bromophenyl)vinyl]benzofuran (0.2 g), 3-butenoic acid (0.053 mL), triethylamine (0.22 mL), palladium (II) acetate (7 mg) and tris(2-methylphenyl)phosphine (19 mg) in acetonitrile (4 mL) was heated for reflux under an argon atmosphere for 8 hours. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. The filtrate was diluted with ethyl acetate. The solution was washed with 0.5 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-dichloromethane/methanol=20/1) to give the title compound (0.17 g).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:12][CH2:13]Cl)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[C:15](#[N:25])[CH2:16][C:17]1[C:18](=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:19]#[N:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O>[C:15]([C:16]1([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])[CH2:13][CH2:12][N:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][CH2:2]1)#[N:25]
Reactant: N#CCc1ccccc1C#N
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2C#N)CC1
Temperature: 25 °C

Procedure:
A solution of bis(2-chloroethyl)-N-(1,1-dimethylethoxy)carbonyl amine (19 g, 78 mmol) and homophthalonitrile (8.6 g, 60 mmol) and cesium carbonate (79 g, 241 mmol) was stirred at 60° C. for 12 hours. The solution cooled to room temperature and diluted with 500 ml EtOAc and washed with saturated aqueous NaHSO4 and saturated aqueous NaCl. The solution was dried over Na2SO4, concentrated in vacuo, and purified by PCTLC (30% EtOAc in Hexane) to afforded 4-cyano-N-(1,1-dimethylethoxy)carbonyl-4-(2-cyanophenyl)piperidine as a yellow/orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:13][C:14]([C@@H:16]([NH2:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4].C(O)(=O)C.[CH3:26][C:27]([CH3:32])([CH3:31])[CH2:28][CH:29]=O>CO>[CH3:26][C:27]([CH2:28][CH2:29][NH:21][C@H:16]([C:14]([NH:13][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])[CH2:17][C:18]([OH:20])=[O:19])([CH3:32])[CH3:31]
Reactant: CC(C)(C)CC=O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.6 %

Procedure:
Aspartame (5.88 g), acetic acid (1.20 g) and methanol (100 ml) were charged to a hydrogenation vessel, followed by 3,3-dimethylbutyraldehyde (2.00 g). The vessel was pressure purged with nitrogen (4×), and 0.24 g of 4% palladium on carbon (containing 50% water) was added. After pressure purging the reactor with nitrogen (4×), followed by hydrogen (4×), the mixture was hydrogenated at 50 psig for 12 hours at room temperature. After completion of the reaction, the vessel was purged with nitrogen (4×). The catalyst was removed from the reaction mixture by filtration through powdered cellulose. Methanol (20 ml) was used to rinse the reaction vessel and the filter cake. The combined filtrate and wash was evaporated to dryness. The residue was stirred with 50 ml of deionized water and 50 ml of heptane for 4 hours at room temperature. The crystallized solid was isolated by filtration and washed with 20 ml heptane. The wet product was dried under vacuum at 40° C. to give 7.15 g of neotame (>97% by HPLC).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH:4]([C:12]([OH:14])=[O:13])[CH2:3]1.[C:15]1([NH:21]N)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:23][CH2:24]O>OS(O)(=O)=O>[CH2:23]([O:14][C:12]([CH:4]1[C:3]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:21][C:2]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:5]1)=[O:13])[CH3:24]
Reactant: NNc1ccccc1
Reactant: O=C1CC(C(=O)O)Sc2ccccc21
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of 4-oxo-thiochroman-2-carboxylic acid (3 g, 14 mmol) and phenyl hydrazine (1.4 ml, 14 mmol) in EtOH (14 ml), H2SO4 (1.8 ml) was added, and the mixture was heated at reflux for 5 hr. The reaction was cooled to room temperature and the solid, which formed overnight, was filtered, washed with cold EtOH and cold Et2O to give 2.26 g (51%) of 6,11-dihydro-5-thia-11-aza-benzo[α]fluorene-6-carboxylic acid ethyl ester as a crème solid. 1H NMR (CDCl3) δ 8.47 (1H, br s), 7.53-7.58 (1H, m), 7.10-7.40 (7H, m), 5.00 (1H, s), 4.09 (2H, q), 1.15 (3H, t).
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[C:6]1[C:11]([F:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[N:19][CH:20]=3)[NH:15][N:14]=2)[N:9]=[C:8](F)[C:7]=1[F:23])([CH3:4])([CH3:3])[CH3:2].[CH3:26][CH:27]([CH3:37])[C@:28]([C@@H:31]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32]1)([OH:30])[CH3:29].N1([Si:43]([CH3:46])([CH3:45])[CH3:44])C=CN=C1>C1COCC1.CCOC(C)=O>[Si:5]([C:6]1[C:7]([F:23])=[C:8]([N:35]2[CH2:34][CH2:33][NH:32][C@H:31]([C@:28]([O:30][Si:43]([CH3:46])([CH3:45])[CH3:44])([CH:27]([CH3:37])[CH3:26])[CH3:29])[CH2:36]2)[N:9]=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[N:19][CH:20]=3)[NH:15][N:14]=2)[C:11]=1[F:12])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:25])[CH3:24]
Reactant: C[Si](C)(C)n1ccnc1
Reactant: CC(C)[C@@](C)(O)[C@@H]1CNCCN1
Reactant: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(-c2n[nH]c3ncncc23)c1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[C@@](C)(O[Si](C)(C)C)[C@@H]1CN(c2nc(-c3n[nH]c4ncncc34)c(F)c([Si](C)(C)C(C)(C)C)c2F)CCN1
Temperature: 90 °C
Yield: 54.1 %

Procedure:
tert-butyl-dimethyl-[2,3,5-trifluoro-6-(1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-pyridyl]silane (170 mg, 0.42 mmol), (2R)-3-methyl-2-[(2S)-piperazin-2-yl]butan-2-ol (109.8 mg, 0.64 mmol), imidazol-1-yl-trimethyl-silane (297.9 mg, 310.3 μL, 2.12 mmol) were dissolved in THF (420 μL). The reaction mixture was heated at 90° C. for 2 days under sealed tube conditions. After this time, the reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc, washed with saturated aqueous NaHCO3, water, brine, dried (MgSO4), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (ISCO Companion™, 24 g column, eluting with 1-5% NH4OH:MeOH (1:9)/DCM) to give the sub title compound as cream solid 134 mg, 53.5% Yield). H1 NMR (400 MHz, DMSO) δ 14.26 (H, d), 9.66 (H, s), 8.97 (H, s), 3.82 (H, d), 3.60 (H, d), 3.06 (H, dd), 3.72 (4H, m), 1.75 (2H, m), 1.10 (3H, d), 0.80 (15H, m), 0.35 (6H, s) and 0.00 (9H, s).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][C:17]([OH:19])=O)([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:32][CH:33]1[CH2:37][NH:36][C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:34]1>C(#N)C.C(OCC)(=O)C>[OH:32][CH:33]1[CH2:37][N:36]([C:17](=[O:19])[CH2:16][P:4]([O:3][CH2:1][CH3:2])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:5])[C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:34]1
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)O
Reactant: COC(=O)[C@@H]1CC(O)CN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC(O)C[C@H]1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A mixture of [ethoxy(4-phenylbutyl)phosphinyl]acetic acid (1.71 g), acetonitrile and carbonyldiimidazole (0.97 g) is stirred under argon at 0° C. for 1 hour. (S)-4-hydroxyproline, methyl ester (0.006 mole) is suspended in acetonitrile, added to the mixture and stirred at room temperature 90 minutes. Solvent is stripped off, and the resulting oil is taken up in ethyl acetate, washed with 5% potassium bisulfate, washed with saturated sodium bicarbonate, washed with brine, dried over magnesium sulfate, and the solvent stripped to leave 2.23 g of the title compound as an oil.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([C:9]([NH2:11])=[O:10])[C:6]([NH2:8])=[NH:7].Cl.Br[CH:14]([CH3:24])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=O>C(O)C>[NH2:7][C:6]1[NH:8][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[C:14]([CH3:24])[C:5]=1[C:9]([NH2:11])=[O:10]
Reactant: CC(Br)C(=O)c1ccc(Br)cc1
Reactant: N=C(N)CC(N)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1c(-c2ccc(Br)cc2)[nH]c(N)c1C(N)=O
Reaction time: 0.5 h
Yield: 4.1 %

Procedure:
Under ice-cooling, sodium ethoxide (1.4 g, 20 mmol) was added to a suspension of malonamamidine hydrochloride (2.8 g, 20 mmol) in dehydrated ethanol (80 mL), and the mixture was stirred for 30 minutes. Moreover, 2,4′-dibromopropiophenone (2.9 g, 10 mmol) was added thereto, and the whole was stirred overnight at room temperature. After the reaction mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography to give the title reference compound (0.12 g) as a white solid (Yield 4%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1.O>CC(N(C)C)=O>[NH2:19][C:20]1[N:25]=[C:24]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Nc1nccc(Cl)n1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nccc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Temperature: 25 °C

Procedure:
252 mg (1.15 mmol) 2,2,2-trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide is dissolved in 2 mL dry dimethylacetamide under argon atmosphere, and 56 mg (2.31 mmol) NaH is added. 100 mg (0.77 mmol) 2-amino-4-chloro-pyrimidine (2) is added and the solution stirred at room temperature over night. 1 mL water is added carefully to quench all excess NaH and the mixture poured into 50 ml of 0.5 N HCl. The crude product is extracted with ethyl acetate, the combined organic phases washed with brine and dried over MgSO4. After evaporation of the solvent, the product is purified by flash column chromatography (ethyl acetate:cyclohexane 1:1). Yield: 160 mg (63%). ESI-MS m/z 327.4 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7](OC2CCC(=O)C=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[H-].[Na+].[CH3:25][NH:26][C:27]1[CH2:31][N:30]([CH3:32])[C:29](=[O:33])[CH:28]=1>CS(C)=O>[OH:1][C@H:2]1[C@H:7]([N:26]([CH3:25])[C:27]2[CH2:31][N:30]([CH3:32])[C:29](=[O:33])[CH:28]=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:21])[CH3:22]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](OC2=CC(=O)CC2)[C@@H]1O
Reactant: CNC1=CC(=O)N(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CC(N(C)[C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)=CC1=O

Procedure:
402 mg of the epoxide of example 1 in 4 ml of dimethylsulfoxide are reacted analogously to example 5 with 60 mg of sodium hydride and 25.2 mg of the amide obtained above. Usual work up yields the title compound having a m.p. of 266°-69° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([OH:12])=[O:11])(=O)[CH3:2].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O1CCOCC1>[CH3:2][C:1]1[O:12][C:10](=[O:11])[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[N:4]=1
Reactant: CC(=O)Nc1ccsc1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: Cc1nc2ccsc2c(=O)o1
Temperature: 25 °C
Yield: 119.4 %

Procedure:
To a mixture of 3-acetamidothiophene-2-carboxylic acid (15.1 g, 75.67 mmol) and sodium acetate (6.45 g, 78.6 mmol) in dioxane (200 mL) was added acetic anhydride (71 mL, 75.7 mmol). The reaction was refluxed 2 hours, cooled to ambient temperature and partitioned between chloroform and water. Phases were separated and the aqueous layer was extracted with chloroform. The combined organic phase was washed with water and brine, dried over magnesiuym sulfate and concentrated to leave 15.1 g of 2-methyl-thieno[3,2-d][1,3]oxazin-4-one as a brown oil which slowly solidified.