Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:21]3[CH2:22][CH:20]3[CH2:19][C:8]=2[N:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[N:10]=1)=[O:5])C.COC(C1C2C3CC3CC=2N(C2C=CC(F)=CC=2F)N=1)=O.[OH-].[Na+]>CO.C1COCC1>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[N:9]1[C:8]2[CH2:19][CH:20]3[CH2:22][CH:21]3[C:7]=2[C:6]([C:4]([OH:5])=[O:3])=[N:10]1
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2F)c2c1C1CC1C2
Agent: COC(=O)c1nn(-c2ccc(F)cc2F)c2c1C1CC1C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C1CC1C2
Temperature: 20 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of 1-(2,4-difluoro-phenyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylic acid ethyl ester (0.66 g, 2.169 mmol) and 1-(2,4-difluoro-phenyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylic acid methyl ester (0.08 g, 0.276 mmol) in methanol (6 mL) and THF (6.00 mL) was added a 2.0 M aqueous solution of sodium hydroxide (3.25 mL, 6.51 mmol). The resulting yellow solution was stirred at 20° C. for 16 h. The organic solvents were removed under reduced pressure. The remaining aqueous solution was diluted with water (25 mL) then acidified to pH 2 by addition of 6 M HCl. The resulting precipitate was collected by filtration, rinsed with water, and then dried under reduced pressure to give the title compound as a tan solid (0.575 g). LCMS m/z=277.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.28 (td, J=4.4, 3.8 Hz, 1H), 1.12 (td, J=7.6, 4.7 Hz, 1H), 2.10-2.15 (m, 1H), 2.19-2.23 (m, 1H), 2.79 (d, J=17.0 Hz, 1H), 2.98 (dd, J=17.0, 6.6 Hz, 1H), 7.25-7.29 (m, 1H), 7.56-7.60 (m, 1H), 7.72 (td, J=8.8, 6.2 Hz, 1H), 12.83 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:12][CH2:13][CH2:14][OH:15].Cl.N1C=CC=CC=1>C(C(C)=O)C>[C:1]([O:15][CH2:14][CH2:13][Br:12])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCBr
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Solvent: CCC(C)=O
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)OCCBr
Temperature: 25 °C
Yield: 86.9 %

Procedure:
35.3 g (0.212 mol) of cinnamic acid chloride and 100 mL of methyl ethyl ketone were placed in a reaction vessel and stirred at room temperature under a nitrogen atmosphere. Then 28.2 g (0.225 mol) of 2-bromoethanol and 21 g of pylidine were dissolved in 100 mL of methyl ethyl ketone. The resulting solution was added dropwise in the aforementioned reaction vessel at room temperature, and then refluxed with stirring for 2 hours. After cooling the solution, pyridine hydrochloride was precipitated and then separated from the solution by filtration. The filtrate was concentrated and then dissolved in methylene chloride. The solution of methylene chloride was poured into a separating funnel and washed with water. Then the solution was dried with sodium sulfuric anhydride and concentrated. Thus 47 g (86.9% yield) of 2-bromoethyl cinnamate was obtained.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.N[C:19]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=C[NH:21][N:20]=1>C(O)(=O)C>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:5]2[N:21]3[N:20]=[CH:19][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:17]3[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: COc1ccc(C(=O)C=CN(C)C)cc1OC
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccc(OC)c(OC)c3)ccnc12

Procedure:
A mixture of 2.35 g. of 3-dimethylamino-3',4'-dimethoxyacrylophenone and ethyl 3-aminopyrazole-4-carboxylate in 25 ml. of glacial acetic acid is refluxed for 20 hours and worked up to give the product, m.p. 148°-149° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH3:7])[CH2:5][OH:6].C(Cl)Cl.C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl>>[CH3:21][O:22][CH2:23][O:6][CH2:5][C@@H:4]([CH3:7])[C:3]([O:2][CH3:1])=[O:8]
Reactant: COC(=O)[C@H](C)CO
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC[C@@H](C)C(=O)OC
Temperature: -78 °C
Yield: 87.2 %

Procedure:
(R)-3-Hydroxy-2-methyl-propionic acid methyl ester (8.60 g, 0.0728 mol) was dissolved in methylene chloride (200 mL, 3 mol), followed by N,N-diisopropylethylamine (25.4 mL, 0.146 mol). The reaction mixture was then cooled to −78° C., and chloromethyl methyl ether (9.48 mL, 0.0874 mol) was added dropwise. The reaction mixture was then allowed to warm up gradually over for 5 hours to 23° C., and quenched with Na2CO3 (sat). Organic layer was separated, and washed with water, brine, and then dried over Na2SO4. The to crude mixture was purified via chromatography (SiO2, 120 g, 0-30% ethyl acetate/hexanes) to give 10.3 g clear liquid product (87%). 1H NMR (CHLOROFORM-d) δ: 4.61 (s, 2H), 3.71 (m, 4H), 3.58 (dd, J=9.5, 5.5 Hz, 1H), 3.35 (s, 3H), 2.77 (m, 1H), 1.19 (d, J=7.0 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2[C:17]([C:38](=[O:40])[NH2:39])=[C:18]([NH:20][C:21](=[O:37])[NH:22][C:23]3[CH:28]=[CH:27][C:26](C(=O)C4C=CC=CC=4)=[CH:25][CH:24]=3)[S:19][C:13]=2[CH2:12]1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:50]>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2[C:17]([C:38]([NH2:39])=[O:40])=[C:18]([NH:20][C:21](=[O:37])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:50])=[CH:25][CH:24]=3)[S:19][C:13]=2[CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCc2c(sc(NC(=O)Nc3ccc(C(=O)c4ccccc4)cc3)c2C(N)=O)C1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCN1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1

Procedure:
A stirred suspension of tert-butyl-N-[3-(2-{[(4-benzoylphenyl)carbamoyl]amino}-3-carbamoyl-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-yl)propyl]carbamate (70 mg, 0.14 mmol) in 4 mL of DCM at rt was treated with 2 mL of TFA. The resultant solution was stirred at rt for 40 min whereupon it was concentrated in a rotary evaporator. The product was taken up in MeOH and the solution concentrated in vacuo (×2) to afford the title compound as a light tan solid in quantitative yield. LRMS [M+H]408.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[CH3:8][O:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11].CI>C1COCC1>[CH3:8][O:9][C:10]([C:12]1([CH3:1])[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1)=[O:11]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
137 mL Diisopropylamine in 3390 mL THF was cooled to 0° C. and 360 mL n-buthyllithium was added dropwise under nitrogen. The reaction was cooled to −78° C. and a solution of 180 mL piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester in 1800 mL THF was added dropwise over 1 h. The reaction was stirred at −78° C. for 2 h and then 168 mL methyliodide in 300 mL THF was added in one portion. The mixture was stirred 2 h at −78° C. and then allowed to warm to RT. The reaction was quenched with saturated aqueous sodium sulfate solution, the organig phase was separated, dried and evaporated. The residue was purified by chromatography on silica gel to give 155 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([OH:14])=[O:13])=[CH:7]2.S(Cl)(Cl)=O.[CH3:19]O>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([O:14][CH3:19])=[O:13])=[CH:7]2
Reactant: CO
Reactant: O=C(O)c1ccc2c(Br)cccc2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(Br)cccc2c1
Yield: 69 %

Procedure:
5-Bromo-2-naphthoic acid (17.33 g, 69 mmol) and 250 mL of MeOH were combined in a flask under N2 atmosphere. Thionyl chloride (5.84 mL, 80 mmol) was added dropwise over 15 minutes at a temperature of 25-30° C. resulting in a pale yellow mixture. The mixture was heated at reflux for 3¼ hours. The resulting yellow solution was concentrated in vacuo to 137.4 g of solution then placed in the freezer overnight. The resulting thick mixture was filtered and the solid was washed with 100 mL of cold MeOH. The solid was dried in vacuo at 50° C. to give 11.39 g of intermediate title compound as white crystals. A second crop was filtered and washed with 100 mL of cold MeOH. The solid was dried to 1.31 g of white crystals. Yield: 69%, 2 crops.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[C:12]([S:15]([CH3:17])=[O:16])[S:13][CH3:14].[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[CH2:25]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[C:12]([S:15]([CH3:17])=[O:16])[S:13][CH3:14])[C:3]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:2]=1[Cl:1])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CSC(=Cc1ccccc1Nc1c(Cl)cccc1Cl)S(C)=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSC(=Cc1ccccc1N(Cc1ccccc1)c1c(Cl)cccc1Cl)S(C)=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
In 25 ml of DMF, 3.8 g (0.010 mole) of 1-[o-(2,6-dichloroanilino)phenyl]-2-methylsulfinyl-2-methylthioethylene was dissolved and 0.98 g (0.022 mole) of sodium hydride (55%; oil dispersion) was added at 20° to 30° C. and the mixture was stirred at 80° C. for 1 hour and cooled to 20° C. and 44 g (0.026 mole) of benzyl bromide was further added and the mixture was stirred at room temperature (20° to 30° C.) for 12 hours and the reaction mixture was poured into a large amount of water to precipitate yellow crystals and the resulting crystals were filtered and dried under a reduced pressure and further recrystallized from benzene to obtain 4.5 g of 1-[N-benzyl-o-(2,6-dichloroanilino)phenyl]-2-methylsulfinyl-2-methylthioethylene as pale yellow crystals. Yield: 98%
Reaction SMILES: [OH:1][C:2]1[CH2:10][CH2:9][N:8]2[C:4](=[N:5][C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=32)[C:3]=1[C:15]([O:17]CC)=O.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[N:24]1[CH:25]=[CH:26][C:21]([NH:20][C:15]([C:3]2[C:4]3=[N:5][C:6]4[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=4[N:8]3[CH2:9][CH2:10][C:2]=2[OH:1])=[O:17])=[CH:22][CH:23]=1
Reactant: Nc1ccncc1
Reactant: CCOC(=O)C1=C(O)CCn2c1nc1ccccc12
Product: O=C(Nc1ccncc1)C1=C(O)CCn2c1nc1ccccc12

Procedure:
The pyridobenzimidazo derivative VII (4.0 g, 15.5 mmol) and 4-aminopyridine (2.82 g, 30.0 mmol) were combined in xylenes (200 mL) and heated at reflux for 6 h in a flask fitted with a Dean Stark trap. The resulting solid was isolated from the cooled reaction mixture and recrystallized from a mixture of methylene chloride and EtOH to give the title compound as a crystalline solid: mp 274°-276° C.; MS: 307 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=1[CH:29]([CH3:31])[CH3:30].[CH2:33](O)[CH2:34][CH2:35][OH:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:32][C:2]1([CH3:1])[P:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=2[CH:29]([CH3:31])[CH3:30])[C:4]([CH3:9])([CH3:10])[CH2:5][C:6]2([O:36][CH2:35][CH2:34][CH2:33][O:8]2)[CH2:7]1
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(=O)CC2(C)C)c(C(C)C)c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC3(CC2(C)C)OCCCO3)c(C(C)C)c1
Temperature: 125 °C
Yield: 66.3 %

Procedure:
A flask was charged with 0.40 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-one (0.89 mmol, 1.0 equiv), 10 mL of argon-sparged toluene, 0.65 mL of 1,3-propanediol (8.9 mmol, 10 equiv) and 0.015 g of p-toluenesulfonic acid monohydrate (0.09 mmol, 0.1 equiv). The atmosphere was purged with argon and the reaction flask was equipped with a Dean-Stark trap and warmed in an oil bath at 125° C. for 20 h under argon atmosphere. The distilled toluene was collected in the Dean-Stark trap. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate and partitioned between toluene and water. The aqueous solution was back extracted once with toluene, the combined organic solution was washed once with water, dried over potassium carbonate and concentrated in vacuo. The unpurified material was purified by flash chromatography over silica gel with gradient elution using acetone/heptane mixtures. After concentration. 0.3 g (66% yield) of 8,8,10,10-tetramethyl-9-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,5-dioxa-9-phosphaspiro[5.5]undecane was isolated as a solid. 1H NMR (C6D6, 500 MHz) δ ppm 1.02 (d, 6H, J=10 Hz), 1.12 (d, 6H, J=7 Hz), 1.24 (d, 6H, J=7 Hz), 1.31-1.28 (pent, 2H, J=5.5 Hz), 1.42 (d, 6H, J=20 Hz), 1.45 (d, 6H, J=7 Hz), 2.13 (d, 2H, J=14.5 Hz), 2.25 (dd, 2H, J=14.5, 6 Hz), 2.80 (sept, 2H, J=7 Hz), 2.86 (sept, 1H, J=7 Hz), 3.48 (t, 2H, J=5.5 Hz), 3.72 (t, 2H, J=5.5 Hz), 7.01 (td, 1H, J=7.5, 1.5 Hz), 7.08 (br t, 1H, J=7.5 Hz), 7.24 (s, 2H), 7.26-7.24 (m, 1H), 7.89 (br d, 1H, J=8 Hz); 31P NMR (C6D6, 200 MHz) δ ppm −2.7 (br singlet).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH2:5]([C:7]1[CH:15]=[C:14]([S:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:13]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:12][C:8]=1[C:9](Cl)=[O:10])[CH3:6].C(C1C=C(Cl)C(S(C)(=O)=O)=CC=1C(O)=O)C.SC1C=CN=CC=1.O(C)[Na].O=S(Cl)Cl>>[NH2:3][C:2]([NH2:4])=[N:1][C:9](=[O:10])[C:8]1[CH:12]=[C:13]([S:23]([CH3:26])(=[O:25])=[O:24])[C:14]([S:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[CH:15][C:7]=1[CH2:5][CH3:6]
Reactant: N=C(N)N
Reactant: CCc1cc(Sc2ccncc2)c(S(C)(=O)=O)cc1C(=O)Cl
Agent: CCc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Agent: CO[Na]
Agent: Sc1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1cc(Sc2ccncc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
In analogy to Example 1, the reaction of guanidine with 2-ethyl-4-(4-pyridylthio)-5-methylsulfonylbenzoyl chloride [obtainable by reacting 2-ethyl-4-chloro-5-methylsulfonylbenzoic acid with 4-mercaptopyridine in the presence of NaOCH3 at 180° followed by chlorination with SOCl2 ] gives N-diaminomethylene-2-ethyl-4-(4-pyridylthio)-5-methylsulfonylbenzamide.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH:5]([O:7][P:8]([OH:38])([CH2:10][CH2:11][NH:12][CH2:13][C:14]([CH3:37])=[CH:15][CH2:16][C:17]1[C:18]([O:30]CC[Si](C)(C)C)=[C:19]2[C:23](=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[CH2:22][O:21][C:20]2=[O:29])=[O:9])[CH3:6])C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:38][P:8]([CH2:10][CH2:11][NH:12][CH2:13][C:14]([CH3:37])=[CH:15][CH2:16][C:17]1[C:18]([OH:30])=[C:19]2[C:23](=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[CH2:22][O:21][C:20]2=[O:29])([O:7][CH:5]([CH3:6])[C:4]([OH:39])=[O:3])=[O:9]
Reactant: CCOC(=O)C(C)OP(=O)(O)CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C)c2c(c(O)c1CC=C(C)CNCCP(=O)(O)OC(C)C(=O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.2 %

Procedure:
A solution of 2-[hydroxy-(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphinoyloxy]-propionic acid ethyl ester (15 mg, 0.026 mmol) in 10% TFA-CH2Cl2 (1 mL) was stirred at ambient temperature for 10 minutes. The reaction was worked up by removal of the solvent. The residue was dissolved in THF (0.5 mL) and water (0.4 mL) and 1N aqueous NaOH solution (0.1 mL) was added. The solution was stirred at room temperature for 20 minutes when it was acidified with 1N aqueous HCl solution. The resulting solution was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 6.8 mg of the product as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.38 (d, 3H, J=7 Hz), 1.91 (s, 3H), 2.13 (s, 3H), 2.12-2.28 (m, 2H), 3.12-3.33 (m, 2H), 3.41 (d, 2H, J=6 Hz), 3.56 (br s, 2H), 3.75 (s, 3H), 4.71-4.88 (m, 1H), 5.16 (s, 2H), 5.58-5.71 (m, 1H), 7.88 (br s, 3H), 8.60 (br s, 1H), 8.78 (br s, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 22.0 ppm; MS (m/z) 458.3 [M+H]+, 480.3 [M+Na]+.
Reaction SMILES: C([C:3]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:5]=[CH:6][N:7](C)[CH3:8])#N.[ClH:16].O.[OH-].[Na+]>C(O)(C)C>[Cl:16][N:7]1[CH:6]=[CH:5][CH:4]=[C:3]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH2:8]1
Reactant: CC(C)S(=O)(=O)C(C#N)=CC=CN(C)C
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)S(=O)(=O)C1=CC=CN(Cl)C1
Reaction time: 20 h
Yield: 51.5 %

Procedure:
The 1-cyano-1-isopropylsulphonyl-4-dimethylamino-1,3-butadiene (34 g, 0.15 mol) obtained in (a) above was dissolved in isopropanol (350 ml). The solution was then heated to reflux and saturated with dry hydrogen chloride. After about 20 hours, the solution was cooled and poured into water and crushed ice. This solution was then neutralised with sodium hydroxide solution and extracted with toluene (5×100 ml). The combined extracts were then evaporated and the remaining brown syrup purified over silica using 1:1 toluene:ethyl acetate as eluant to leave an oil which yielded 7 g 1-chloro-3-isopropylsulphonylpyridine as yellow crystals, m.pt. 82°-84° C., after stirring with petroleum ether. Yield: 51.5% of the theoretical.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[CH:20]=[C:21]([CH2:23][CH2:24][CH:25]=[C:26]([CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])[CH3:27])[CH3:22].Cl>C(OCC)(=O)C.CN(C=O)C>[CH3:22]/[C:21](/[CH2:23][CH2:24]/[CH:25]=[C:26](\[CH3:27])/[CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])=[CH:20]\[CH2:19][O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCl
Reactant: COC(=O)c1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC/C=C(\C)CC/C=C(\C)CCC=C(C)C)cc1O
Temperature: 60 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
In 10 m of DMF were poured 1.28 g (7.6 mmol) of methyl 2,4-dihydroxybenzoate and 1.05 g (7.6 mmol) of potassium carbonate, and 1.84 g (7.6 mmol) of farnesyl chloride was added thereto dropwise at room temperature. After the addition, the mixture was stirred at 60° C. for 3 hours and then poured into a 12% hydrochloric acid aqueous solution. Ethyl acetate was poured thereinto to conduct extraction. The resulting extract was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The resulting crude product was purified by column chromatography on silica gel to obtain 2.0 g (yield: 71%) of methyl 4-{(2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrienyloxy}-2-hydroxybenzoate represeted by the following structural formula (hereinafter referred to as compound 37) as a colorless, clear and oily substance. The analytical results are shown below. ##STR58##
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].O[C:13]1[C:18]2[S:19][CH:20]=[CH:21][C:17]=2[CH:16]=[CH:15][CH:14]=1>C1COCC1>[Cl:1][CH2:2][CH2:3][C@@H:4]([O:5][C:13]1[C:18]2[S:19][CH:20]=[CH:21][C:17]=2[CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: Oc1cccc2ccsc12
Solvent: C1CCOC1
Product: ClCC[C@@H](Oc1cccc2ccsc12)c1ccccc1
Reaction time: 18 h
Yield: 42.6 %

Procedure:
4,4-(Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenyl phosphonium (1.15 g, 2.80 mmol) was added in one portion to a stirred solution of (S)-(−)-3-chloro-1-phenyl-1-propanol (317 mg, 1.86 mmol) and 7-hydroxybenzo[b]thiophene (280 mg, 1.86 mmol) in dry THF (5 mL) under an inert atmosphere on nitrogen. The resulting suspension was allowed to stir for a further 18 hrs before the solvent was removed in vacuo. The residue was triturated with hexane (ca. 15 mL) and the solid filtered, the filtrate was concentrated in vacuo and the resulting pale yellow oil was purified by flash chromatography eluting silica gel with hexane:ether [95:5] to yield the title compound as a colourless oil (240 mg, 43%); Rf=0.78 in hexane:ether [10:1]; δH (300 MHz, CDCl3) 7.66–7.00 (9H, m, Ar); 6.55 (1H, d, Ar), 5.80–5.72 (1H, m, CHO), 3.91–3.60 (2H, m, CH2), 2.62–2.50 (1H, m, CHH), 2.38–2.22 (1H, m, CHH).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][O:7][CH2:8][CH:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[OH:10])[CH3:4].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>N1C=CC=CC=1>[C:21]([O:10][CH:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH2:8][O:7][CH2:6][CH2:5][N:3]([CH3:2])[CH3:4])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCOCC(O)c1cccc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)OC(COCCN(C)C)c1cccc2ccccc12

Procedure:
2-[2-(N,N-dimethylamino)ethoxy]-1-(1-naphthyl)ethanol hydrochloride was reacted with acetic anhydride in pyridine in the presence of triethylamine to obtain oily 1-acetoxy-2-[2-(N,N-dimethylamino)ethoxy]-1-(1-naphthyl)ethane (compound No. 300).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([Li])CCC.CCCCCC.[CH:26](N1CCOCC1)=[O:27]>CCOCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][C:12]([CH:26]=[O:27])=[CH:13][N:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(-c2nccs2)cc1
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1cnc(-c2ccc([N+](=O)[O-])cc2)s1
Reaction time: 0.5 h

Procedure:
As depicted in Scheme 25 below, 2-(4-nitrophenyl)thiazole (19.9 mmol) dissolved in ether (20 ml) is added dropwise over 1 hour to a stirred and cooled (−78° C.) solution of butyl lithium (1.5 M) in n-hexane (20 ml, 29.9 mmol), diluted with ether (50 ml). The mixture is stirred at −78° C. for 30 minutes and then a solution of N-formylmorpholine (29.9 mmol) in ether (30 ml) is added dropwise over a time period of 15 minutes. After 30 minutes at −78° C., the mixture is washed with saturated aqueous NaHCO3 (30 ml) and extracted with ether (2×20 ml). The organic phase is dried over Na2SO4 and the solvent is removed under reduced pressure to give the crude 2-(4-Nitro-phenyl)-thiazole-5-carbaldehyde.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1C(OC(C)(C)C)=O)=O.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH2:1][C@@H:3]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][NH:4]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C=O
Reactant: C1CCNC1
Product: c1ccc2c(c1)CN[C@H](CN1CCCC1)C2

Procedure:
Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (57 mg, 0.22 mmol) and pyrrolidine (16 mg, 0.22 mmol) provided a crude oil which was used without purification in preparation of Example 111. MS(ESI+) m/z 217.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH2:11][C:12]#[N:13])[C:7]=2[CH:14]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH2:11][C:12](=[N:16][OH:17])[NH2:13])[C:7]=2[CH:14]=1
Reactant: NO
Reactant: COc1ccc2onc(CC#N)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2onc(CC(N)=NO)c2c1
Yield: 76.6 %

Procedure:
In ethanol (20 ml) was dissolved 5-methoxy-1,2-benzisoxazole-3-acetonitrile (2.0 g) and thereto was added a solution of hydroxylamine hydrochloride (0.88 g) and sodium carbonate (1.34 g) in water (10 ml). After heating the mixture on water bath at 70° to 80°C for 3 hours, ethanol was distilled off under a reduced pressure. To the residue was added water and the precipitated crystallines were separated by filtration, washed with water and dried to give the desired compound (1.8 g), which was recrystallized from ethanol. m.p. 180° to 183°C.