Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:14][O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][CH:21]=1>O1CCCC1.C(OCC)(=O)C>[CH3:14][O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][O:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:24][CH:25]=1
Reactant: Clc1ncnc2ccccc12
Reactant: COC(=O)CCCc1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCc1ccc(CCOc2ncnc3ccccc23)cc1
Reaction time: 3.5 h
Yield: 42.6 %

Procedure:
A dry 50 mL flask was fitted with an addition funnel. To the flask were added 4-chloroquinazoline (592 mg, 3.6 mmol), anhydrous tetrahydrofuran (10 mL), and 60 wt % sodium hydride (187 mg, 4.7 mmol). A solution of Example 1B (800 mg, 3.6 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise using the addition funnel. The reaction was stirred for 3.5 hours. The reaction was diluted with ethyl acetate and quenched by the addition of aqueous 0.1 N hydrochloric acid. The mixture was transferred to a separatory funnel and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Column chromatography [silica gel; eluent hexanes-ethyl acetate (4:1)] provided the desired product (538 mg, 43%). 1H (CDCl3) δ ppm): 1.92-1.98 (m, 2H); 2.33 (t, 2H); 2.64 (t, 2H); 3.19 (t, 2H); 3.66 (s, 3H); 4.79 (t, 2H); 7.15 (d, 2H); 7.27 (d, 2H); 7.57 (t, 1H); 7.83 (t, 1H); 7.94 (d, 1H); 8.15 (d, 1H); 8.80 (s, 1H). 26.68, 33.59, 34.93, 35.03, 51.67, 67.89, 116.48, 123.72, 127.23, 127.82, 128.87, 129.24, 133.74, 135.76, 139.90, 151.08, 154.56, 166.89, 174.10.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:18])OCC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[N:19]#[C:20][NH2:21]>C(O)C>[C:20]([NH:21][C:14](=[NH:18])[CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)#[N:19]
Reactant: CCOC(=N)CCSCc1csc(NC(=N)N)n1
Reactant: N#CN
Solvent: CCO
Product: N#CNC(=N)CCSCc1csc(NC(=N)N)n1
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To 1.9 g of ethyl 3-[(2-guanidinothiazol-4-yl)methylthio]-propionimidate was added 10 ml of an ethanol solution of 0.28 g of cyanamide and the mixture was allowed to stand overnight at room temperature. Then, the solvent was distilled off from the reaction mixture under reduced pressure and the residue obtained was purified by a silica gel column chromatography using a solvent mixture of chloroform and methanol as a developing solvent to provide 1.35 g of N-cyano-3-[(2-guanidinothiazol-4-yl)methylthio]propionamidine. The product shows the following physicochemical properties:
Reaction SMILES: [C:1]1([C:7]2([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)[CH2:17][C:18](=[O:20])C.C1OC1>C(O)C>[OH:20][CH2:18][CH2:17][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]#[N:14])[CH2:12][CH2:11]1
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: CC(=O)CC(C)C
Solvent: CCO
Solvent: C1CO1
Product: N#CC1(c2ccccc2)CCN(CCO)CC1
Temperature: 60 °C

Procedure:
A mixture of 8.0 parts of 4-phenylisonipecotonitrile, 41.8 parts of 4-methyl-2-pentanone, 4.3 parts of ethylene oxide and 79.2 parts of ethanol is heated in a sealed citric bottle at about 60° C. for 7 days. The resulting solution is cooled, the solvent is evaporated under reduced pressure and the residual material is partitioned between diluted sodium hydroxide and ether. The ether layer is then separated and extracted with diluted HCl. The acid layer is then made alkaline with aqueous sodium hydroxide and the resulting mixture is extracted with ether. The ether layer is dried over sodium sulfate and potassium carbonate and evaporated in vacuum. The residue is crystallized from a mixture of ether and n-pentane to give 1-(2-hydroxyethyl)-4-phenylisonipecotonitrile.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:14]1([CH2:20][CH2:21][C:22](Cl)=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O=P(Cl)(Cl)Cl>>[CH2:21]([C:22]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1)[CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol), TEA (0.153 ml; 1.1 mmol), phenylpropionylchloride (185 mg, 0.163 ml, 1.1 mmol) and POCl3 (0.5 ml; 5.5 mmol) as described in method 1; yield: 0.031 mg (10.7%); MS m/z: 291.3 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.09 (t, 2H, 3J=7.7 Hz); 3.25 (t, 2H, 3J=7.5 Hz); 7.15-7.19 (m, 1H); 7.23-7.27 (m, 4H); 7.84 (d, 1H, 3J=8.7 Hz); 7.92 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.20 (br s, 1H); 8.87 (s, 1H); HPLC (METHOD [A]): rt 11.82 min (100%)
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: BrCc1cccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: BrCc1cccc2c1cnn2C1CCCCO1
Yield: 86.9 %

Procedure:
A solution of 4-bromomethyl-1H-indazole (2.0 g, 9.476 mmol), 3,4-dihyro-2H-pyran (4.0 mL, 43.84 mmol), p-toluenesulfonic acid monohydrate (2.0 g, 10.51 mmol) and anhydrous THF (20 mL) was heated at 60° C. for 1 h. The reaction mixture was cooled, added to aqueous saturated sodium carbonate solution (50 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (20% EtOAc in hexanes) to give 4-bromomethyl-1-(tetrahydro-pyran-2-yl)-1H-indazole (2.43 g, 86.9%) as an off white solid. MS m/e 296.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][CH:5]([OH:11])[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C(C1SC=CC=1)(=O)C.Cl.CNC.C=O.Cl>C(O)(C)C>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:12])=[O:11]
Reactant: CN(C)CCC(O)c1cccs1
Agent: C=O
Agent: CC(=O)c1cccs1
Agent: CNC
Solvent: CC(C)O
Product: CN(C)CCC(=O)c1cccs1

Procedure:
One example of a known method for producing N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine uses the reaction between 2-acetylthiophene and dimethylamine hydrochloride in isopropanol in the presence of paraformaldehyde and hydrochloric acid to obtain (2-thienyl)(2-dimethylaminoethyl)ketone, and the (2-thienyl)(2-dimethylaminoethyl)ketone is reduced using sodium borohydride in ethanol (JP 7-188065 A). If N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine is produced in the same method as described above except that a monoalkylamine hydrochloride is used instead of the dimethylamine hydrochloride, since the production intermediate, i.e., (2-thienyl)(2-monoalkylaminoethyl)ketone, is unstable, an N,N′,N″-alkyl-bis[1-[3-oxo-3-(2-thienyl)propane]]amine, which is a dimer, is produced, and therefore the yield of the N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine obtained after the reduction using sodium borohydride is low.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[CH2:31][C@@H:32](O)[CH2:33][CH2:34][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Br)(Br)(Br)[Br:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[CH2:31][CH:32]([Br:39])[CH2:33][CH2:34][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](O)CN2C[C@H]1Cc1c[nH]c2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CCC(Br)CN2C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a suspension of 3,5-bis(trifluoromethyl)phenyl-[(3R,7S,9aR)-7-hydroxy-3-(1H-indol-3-ylmethyl)-octahydropyrido[1,2-a]pyrazin-2-yl]-methanone (3.85 g) in acetonitrile was added carbon tetrabromide (11.6 g) and triphenylphosphine (9.18 g), the resulting mixture was stirred at room temperature overnight. The formed precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash-chromatography (SiO2, CH2Cl2/MeOH 98:2) to afford 3,5-bis(trifluoromethyl)phenyl-[(3R,9aR)-7-bromo-3-(1H-indol-3-ylmethyl)-octahydropyrido[1,2-a]pyrazin-2-yl]-methanone (3.5 g). MH+ 588, Rf 0.38 (CH2Cl2/MeOH 97:3) (intermediate 17).
Reaction SMILES: [CH:1]1([N:6]2[CH:12]([CH3:13])[CH2:11][C:10](=[O:14])[N:9]([CH3:15])[C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:65][CH:66]1[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH:12]([CH3:13])[CH2:11][C:10](=[O:14])[N:9]([CH3:15])[C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH:65][CH:66]5[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]5)=[O:27])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)C(C)CC(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)C(C)CC(=O)N2C
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
A mixture of 0.042 g (0.0001 mole) of (rac)-4-(9-cyclopentyl-5,8-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-3), 0.042 g (0.00011 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.026 mL (0.00015 mole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.017 g (0.00015 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.044 g of (rac)-4-(9-cyclopentyl-5,8-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-4) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:2]=1.O.NN>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccnc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCc1cccnc1
Yield: 82.5 %

Procedure:
A mixture of 11.3 g of 2-[3-(3-pyridyl)propyl]-1H-isoindole-1,3(2H)-dione and 10.1 g of hydrazine hydrate was refluxed in 200 ml of ethanol for 6 hours, allowed to cool, and was filtered. The filtrate was concentrated and the residue distilled to give 4.77 g (70%) of 3-pyridinepropanamine, bp 84°-86° C./0.35 mm.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[CH:14]([OH:17])[CH2:15][CH3:16].[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>CCCCC.C1COCC1>[F:13][C:9]1[C:8]([CH:14]([OH:17])[CH2:15][CH3:16])=[C:7]([B:18]([OH:23])[OH:19])[CH:12]=[CH:11][CH:10]=1
Reactant: CCC(O)c1c(F)cccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCC(O)c1c(F)cccc1B(O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of n-BuLi (2.15 mL, 4.3 mmol) in pentane (2 M) is added dropwise to a solution of 1-(2-bromo-6-fluoro-phenyl)-propan-1-ol (500 mg, 2.15 mmol) in THF at −78° C. The mixture is stirred for 2 hours at −78° C. (i-PrO)3B (41 mL, 4.3 mmol) is added in one portion and the mixture is warmed slowly to room temperature and stirred for 12 hours. 1N HCl (10 mL) is added and the mixture is stirred for 2 hours at room temperature. The organic layer is separated and the aqueous layer is extracted with DCM (3×30 mL). The combined organic layers are dried and solvents are removed in vacuo. The crude product is purified by PTLC eluting with 5% MeOH in DCM to give 3-fluoro-2-(1-hydroxypropyl)phenylboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)O)=[CH:7][CH:6]=[CH:5][N:4]=1.C([BH3-])#N.[Na+]>[I-].[Zn+2].[I-].ClCCCl>[CH3:1][O:2][C:3]1[C:8]([CH2:9][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1C(O)c1cccs1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ncccc1Cc1cccs1
Temperature: 25 °C
Yield: 53.8 %

Procedure:
A mixture of 1.47 g of 2-methoxy-3-[2-thienyl(hydroxy)methyl]pyridine, 3.2 g of zinc iodide, 3.4 g of sodium cyanoborohydride and 30 ml of 1,2-dichloroethane was stirred at room temperature for two nights. Insoluble matters were filtered off, and to the filtrate was added an aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with brine and the solvent was evaporated. Then, the residue was subjected to silica gel column chromatography and eluted with hexane and then with hexane/ethyl acetate (40:1), to give 734 mg of the target compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]#[CH:15].[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=1I>N1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=2[CH:15]=1
Reactant: C#CCc1nc(-c2ccccc2)oc1C
Reactant: O=Cc1ccc(O)c(I)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(C=O)ccc2o1

Procedure:
To a slurry of cuprous oxide (12 g, 84 mmol) in pyridine (150 ml) were added a solution of 5-methyl-2-phenyl-4-(2-propynyl)oxazole in pyridine (150 ml) followed by a solution of 4-hydroxy-3-iodobenzaldehyde (35 g, 0.14 mol) in pyridine (100 ml). Bis(triphenyl-phosphine)palladium (II) chloride (0.50 g, 0.7 mmol) was then added as a solid and the mixture was heated to reflux overnight. The mixture was cooled and concentrated. The residue was taken up in ethyl acetate (250 ml +3×50 ml). The ethyl acetate solution was concentrated and the residue was extracted with hot cyclohexane. The hot solution was filtered and cooled and the solid was collected (29 g).
Reaction SMILES: C([O:3][P:4]([CH:9]([C:36]#[N:37])[CH2:10][C:11]([CH2:34][CH3:35])=[CH:12][CH2:13][C:14]1[C:15]([O:27]CC[Si](C)(C)C)=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5]CC)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:36]([CH:9]([P:4](=[O:3])([OH:5])[OH:8])[CH2:10][C:11]([CH2:34][CH3:35])=[CH:12][CH2:13][C:14]1[C:15]([OH:27])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])#[N:37]
Reactant: CCOP(=O)(OCC)C(C#N)CC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=CCc1c(O)c2c(c(C)c1OC)COC2=O)CC(C#N)P(=O)(O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
{1-Cyano-3-ethyl-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-pent-3-enyl}-phosphonic acid diethyl ester (19.5 mg, 0.035 mmol) was dissolved in a solution of 10% TFA/CH2Cl2 (2 mL) and stirred at room temperature for 10 minutes. The reaction mixture was dried under reduced pressure and purified by RP-HPLC to provide 9.5 mg (61%) of the desired product. This material was dissolved in DMF (0.5 mL) and DCM (0.5 mL) and TMSBr (27 μL, 0.2 mmol) and 2,6-lutidine (23 μL, 0.2 mmol) were added. The reaction solution was allowed stir at room temperature overnight before quenching with MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 5.1 mg (65%) of the desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.10 (t,3H), 2.16 (s, 3H), 2.23-2.52 (m, 3H), 2.67 (m,1H), 3.05-3.20 (m, 1H), 3.48 (d, J=7.2, 2H), 3.81 (s, 3H), 5.26 (s, 2H), 5.43 (t, J=7.2 Hz, 1H) ppm; 31P (121.4 MHz, CD3OD) δ 14.18 ppm; MS (m/z) 394 [M−H]−, 396 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:4](=[O:7])[CH:5]=[CH2:6])[CH3:3].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[S:18])[S-:17].C([NH+](CC)CC)C>C(#N)C.C(Cl)Cl.C(Cl)(Cl)Cl.C(OCC)(=O)C>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[S:17])[S:18][CH2:6][CH2:5][C:4](=[O:7])[C:2]([CH3:8])([CH3:3])[CH3:1]
Reactant: C=CC(=O)C(C)(C)C
Reactant: S=C([S-])Nc1ccccn1
Agent: CC[NH+](CC)CC
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)CCSC(=S)Nc1ccccn1
Reaction time: 2 h
Yield: 63.8 %

Procedure:
A solution of 2,2-dimethylpent-4-en-3-one (22.5 g) in anhydrous acetonitrile (50 cc) is added, at a maximum temperature of 5° C., to a suspension of triethylammonium pyrid-2-yldithiocarbamate (54.2 g) in anhydrous acetonitrile (150 cc). The reaction is allowed to proceed for 2 hours at between 5° and 20° C. The acetonitrile is evaporated off under reduced pressure (20 mmHg) at 45° C. The residue obtained is dissolved in methylene chloride (600 cc). The organic solution is washed four times with distilled water (total 600 cc), dried over sodium sulphate and evaporated. The product obtained (58.0 g) is dissolved in a mixture of chloroform (360 cc) and ethyl acetate (40 cc). The solution is chromatographed on a column of diameter 6 cm, containing silica (0.063-0.2 mm; 600 g). Elution is carried out with a mixture of chloroform (720 cc) and ethyl acetate (80 cc), this eluate being discarded, and then with a mixture of chloroform (3,000 cc) and ethyl acetate (350 cc), this eluate being collected and evaporated to dryness under reduced pressure (20 mmHg) at 45° C. The product obtained (42.0 g) is purified by recrystallisation from diisopropyl ether (200 cc). 4,4-Dimethyl-3-oxopentyl pyrid-2-yldithiocarbamate (36.0 g) (structure determined by IR spectroscopy in petroleum jelly), which melts at 95° C., is obtained.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH:22]1[CH2:25][CH2:24][CH2:23]1>>[N:22]1([C:16]([C:15]2[CH:14]=[N:13][C:12]([O:11][CH2:10][C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:21])=[CH:20][CH:19]=2)=[O:18])[CH2:25][CH2:24][CH2:23]1
Reactant: C1CNC1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)N2CCC2)cn1
Yield: 39 %

Procedure:
As described for example 19b, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted, using azetidine instead of L-2,2,2-trifluoro-1-(methyl)ethylamine, to the title compound (45 mg, 39%) which was obtained as a light yellow oil after purification by chromatography (silica, heptane:ethyl acetate=1:0 to 2:1). MS: m/e=330.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:16]([N:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[CH:27]=[CH:26][C:25]([NH:28][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccn(Cc2ccccc2)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ccn(Cc4ccccc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-benzyl-1H-pyrazol-3-ylamine. The title compound was obtained as a yellow solid (Yield=74%). MS ISP (m/e): 355.2 (100) [(M+H)+].
Reaction SMILES: [CH2:1]([CH:3]([CH2:30][CH3:31])[CH2:4][NH:5][C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[C:15]2[CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][C:20]=2[O:28][CH3:29])=[CH:10][CH:9]=1)=[O:7])[CH3:2].Cl.CN(C)CCCN=C=NCC.[C:44]1([CH3:54])[C:45]([S:50]([NH2:53])(=[O:52])=[O:51])=[CH:46][CH:47]=[CH:48][CH:49]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([CH:3]([CH2:30][CH3:31])[CH2:4][NH:5][C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[C:15]2[CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:53][S:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[CH3:54])(=[O:51])=[O:52])=[O:25])=[CH:21][C:20]=2[O:28][CH3:29])=[CH:10][CH:9]=1)=[O:7])[CH3:2]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: CCC(CC)CNC(=O)c1ccc2cccc(Cc3ccc(C(=O)O)cc3OC)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCC(CC)CNC(=O)c1ccc2cccc(Cc3ccc(C(=O)NS(=O)(=O)c4ccccc4C)cc3OC)c2c1
Reaction time: 18 h
Yield: 69.4 %

Procedure:
A mixture of 4-[7-(2-ethylbutylcarbamoyl)naphth-1-ylmethyl]-3-methoxybenzoic acid (189 mg), 4-dimethylaminopyridine (110 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (172 mg), and o-toluenesulfonamide (96 mg) in methylene chloride (2 ml) was stirred for 18 h. Methylene chloride (25 ml) was added, and the solution was washed (1N hydrochloric acid, brine), dried (MgSO4) and evaporated. The residue was recrystallized from 21 ml of 1:0.5:1 methylene chloride:methanol:hexane, ground to a powder and vacuum dried at 100° C. to give the title compound (179 mg, 70%) as a colorless solid; mp 126.0°-128.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH3:27][Si:28](Cl)([CH3:30])[CH3:29]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc(-c2ccsc2-c2ccc(OC)cc2)cc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(-c2cc([Si](C)(C)C)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,3-Bis(4-methoxyphenyl)thiophene (5.92 g, 20 mmole) was dissolved in 100 ml toluene and the volume reduced by approximately 3/4 by distillation. The cooled solution was diluted with 130 ml diethyl ether, cooled to ~10° and treated with 1.55 M n-butyl lithium (15.5 ml, 1.2 equiv.). The reaction mixture was heated at reflux for 1.5 hours, cooled to 0° and treated dropwise with a solution of trimethylsilyl chloride (3.1 ml, 1.2 equiv.) in 5 ml diethyl ether. The reaction mixture was stirred overnight at room temperature and then quenched with water.