Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].[Si:11]([C:18]#[C:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Si:11]([CH:18]1[C:19](=[CH:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[O:10]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)C#CCO[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(I)c(O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC([Si](C)(C)C(C)(C)C)C2=CO[Si](C)(C)C(C)(C)C
Reaction time: 4 h
Yield: 60.8 %

Procedure:
A suspension of 2-iodo-5-methoxyphenol (1.1 g, 4.41 mmol), 1-(tert-butyldimethylsilyl)-3-(tert-butyldimethylsilyloxy)propyne (1.5 g, 5.28 mmol), lithium chloride (189 mg, 4.45 mmol) and sodium carbonate (2.34 g, 22.08 mmol) in dry dimethylformamide (5 mL) at 100° C. was deoxygenated 4 times by evacuation and backfilling with nitrogen. Palladium acetate (135 mg, 0.60 mmol) was added and the reaction vessel was degassed twice with nitrogen. The reaction mixture was then stirred at this temperature for 4 hours (monitored by tlc) and the solvent was removed by distillation under vacuum. The residue was dissolved in ethyl acetate (75 mL), stirred well, filtered and treated with triethylamine (5 mL). The solution was concentrated onto silica gel (10 g) and purified by flash chromatography (silica gel, eluent=hexane/diethyl ether/triethylamine; 95:5:1%) to give the title compound as a yellow oil (1.09 g, 87%); 1H NMR (300 MHz, CDCl3) δ 7.52 (d, 1H, J=8.57 Hz), 6.97 (d, 1H, J=2.15 Hz), 6.83 (dd, 1H, J=8.54, 2.18 Hz), 4.81 (s, 2H, CH2), 3.83 (s, 3H, OMe), 0.93 (s, 9H), 0.91 (s, 9H), 0.34 (s, 6H), 0.11 (s, 6H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][C:14]1[C:23]2[C:18](=[C:19]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[N:1]1([CH2:13][C:14]2[C:23]3[C:18](=[C:19]([NH:24][C:25](=[O:34])[C:26]4[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:33])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(Nc1cccc2c(CBr)ccnc12)c1c(Cl)cccc1Cl
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2c(Cn3cnc4ccccc43)ccnc12)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a stirred solution of benzimidazole (26.5 mg) in N,N-dimethylformamide (1 ml) was added sodium hydride (60% in oil, 8.6 mg) in an ice bath, and the mixture was stirred at the same temperature for half an hour. To this mixture was added 4-bromomethyl-8-(2,6-dichlorobenzoylamino)quinoline (80 mg) one portion, and the reaction mixture was stirred at the same temperature for half an hour and then at ambient temperature for one hour. Water was added thereto, and the resulting precipitate was collected by filtration. The solid was washed with hot 95% aqueous ethanol (1 ml) and allowed to cool to ambient temperature. The solid was collected by filtration and air-dried to give 4-(1H-benzimidazol-1-ylmethyl)-8-(2,6-dichlorobenzoylamino)quinoline (65 mg) as an off-white solid.
Reaction SMILES: Br[CH:2]([CH3:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:7]=1[OH:13])=[O:4].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:12][C:8]1[C:7]2[O:13][CH:2]([CH3:14])[C:3](=[O:4])[NH:5][C:6]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CC(Br)C(=O)Nc1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1Oc2c(Br)cccc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A mixture of 2-bromo-N-(3-bromo-2-hydroxyphenyl)propanamide (4.72 g, 14.61 mmol) and potassium carbonate (2.020 g, 14.61 mmol) in DMF (50 mL) was stirred at room temperature overnight. At the conclusion of this period, the reaction mixture was diluted with water and extracted with ether. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (100:0:0 to 0:90:10 hexanes:ethyl acetate:methanol) to afford the title compound (3.35 g, 95% yield) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 8.17 (br. S, 1H), 7.22 (dd, J=8.0, 1.4 Hz, 1H), 6.85 (t, J=7.9 Hz, 1H), 6.76 (dd, J=7.8, 1.4 Hz, 1H), 4.78 (q, J=6.8 Hz, 1H), 1.64 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[F:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([N:15]=[C:16]=[O:17])=[O:14].C([O-])(=O)CCC([O-])=O>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:16]([NH:15][C:13](=[O:14])[C:12]1[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=1[F:10])=[O:17])[CH2:3]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C=NC(=O)c1ccccc1F
Agent: O=C([O-])CCC(=O)[O-]
Product: O=C(NC(=O)c1ccccc1F)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine (0.63 g, 5 mmol) and crude 2-fluorobenzoyl isocyanate (1.3 g, ca 7 mmol). The product (1.35 g) was converted to the 1:1 succinate, mp 187°-188° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH2:5]O)[CH3:2].[BrH:14]>>[CH2:1]([C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH2:5][Br:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1CO
Reactant: Br
Product: CCc1cc(C)cc(CC)c1CBr
Yield: 89 %

Procedure:
14.7 g (82.5 mmol) of 2,6-diethyl-4-methylbenzyl alcohol in 150 ml of hydrobromic acid are stirred at 100° C. for 4 h. After cooling, the mixture is extracted with dichloromethane and the extract is washed with water, dried (magnesium sulphate) and concentrated using a rotary evaporator. Distillation (110° C. bath temperature, 0.3 mbar) gives 17.82 g (89%) of 2,6-diethyl-4-methylbenzyl bromide as a colourless oil. 1H-NMR (400 MHz, CDCl3): δ=1.28 (t, 6H), 2.30 (s, 3H), 2.73 (q, 4H), 4.61 (s, 2H), 6.90 (s,
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([Cl:14])[CH:9]=[C:8](Cl)[N:7]=1)(=[O:3])[CH3:2].[C:16]1([C@H:22]([NH:24][C:25]([NH2:27])=[O:26])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(N(CC)CC)C>C1COCC1>[C:1]([O:4][CH2:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([Cl:14])[CH:9]=[C:8]([NH:27][C:25]([NH:24][C@@H:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:23])=[O:26])[N:7]=1)(=[O:3])[CH3:2]
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: CC(=O)OCc1nc(Cl)cc(Cl)c1C#N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc(Cl)c1C#N
Temperature: 50 °C

Procedure:
A mixture of (4,6-dichloro-3-cyanopyridin-2-yl)methyl acetate (366.3 mg, 1.495 mmol), (R)-1-(1-phenylethyl)urea (443 mg, 2.70 mmol) and Xantphos G2 precatalyst (130 mg, 0.146 mmol) in THF (2 ml) was sealed, sparged with argon, charged with triethylamine (0.73 ml, 5.24 mmol) and heated to 50° C. for 17 hr. The mixture was filtered through celite, eluted with EtOAc, concentrated in vacuo and purified via flash chromatography (25-100% Et2O/Hex) to provide (R)-(4-chloro-3-cyano-6-(3-(1-phenylethyl)ureido)pyridin-2-yl)methyl acetate. MS ESI calc'd. For C18H18ClN4O3 [M+H]+ 373. found 373.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=3)[CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (0.22 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.124 g, 54%). MS (ISP) 461.1 [(M+H)+]; mp 205° C.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl[CH2:15][CH:16]([OH:27])[CH2:17][N:18]([CH2:24][CH2:25][OH:26])[CH2:19][CH:20]([OH:23])[CH2:21]Cl>C1(C)C(C)=CC=CC=1>[OH:27][CH:16]([CH2:17][N:18]([CH2:24][CH2:25][OH:26])[CH2:19][CH:20]([OH:23])[CH2:21][NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: OCCN(CC(O)CCl)CC(O)CCl
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCNCC(O)CN(CCO)CC(O)CNCCCCCCCCCCCC
Temperature: 70 °C
Yield: 77.2 %

Procedure:
A reactor was charged with 280 g (1.51 moles) of dodecylamine and 100 g of xylene, and the contents were heated to 70° C. To the contents, a solution with 38.5 g (0.18 mole) of N,N-bis(3-chloro-2-hydroxypropyl)hydroxyethylamine dissolved in 20 g of xylene was added dropwise over 30 minutes. The resultant mixture was aged further for 4 hours. Thereafter, xylene was distilled off under reduced pressure, and unreacted dodecylamine was then distilled off at 100° C. and 0.5 mmHg. The residue was subjected to extraction and washing with a mixture of 500 ml of hexane and 500 ml of 5% aqueous sodium hydroxide. Thereafter, a hexane layer was taken out and concentrated, thereby obtaining 75.6 g (yield: 77%) of 15,19-dihydroxy-17-hydroxyethyl-13,17,21-triazatritriacontane represented by the following formula. ##STR12##
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][N:17]=2)[CH2:11][CH2:10]1
Reactant: COC(=O)c1ccc(CN2CCC(NC(=O)OC(C)(C)C)CC2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CN2CCC(N)CC2)nc1

Procedure:
The product of example 30 is heated for 3 hours at 40° C. in a solution of CH2Cl2 containing 11 ml of CF3COOH. The solvent is evaporated off and the substance crystallised in acetone. The named product is obtained: M. P. 173-175° C.
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17])[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1>CO.O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:18]1[C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1
Reactant: O=CC(CO)OC(C=O)n1ccc(=O)[nH]c1=O
Reactant: Cc1cc(N)no1
Solvent: O
Solvent: CO
Product: Cc1cc(N2C(O)[C@H](n3ccc(=O)[nH]c3=O)O[C@H](CO)C2O)no1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.7 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)pyrimidineacetaldehyde, (uridinedialdehyde), (4.0 g) was dissolved in a mixture of methanol (30 ml) and water (30 ml). To the solution was added 3-amino-5-methylisoxazole (1.62 g). The mixture was stirred at ambient temperature for five hours and evaporated in vacuo. The residue was triturated with acetone to give 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(5-methylisoxazol-3-yl)morpholin-2-yl]uracil (4.2 g).
Reaction SMILES: [K].[O-]CCCC.[C:7]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])(OC)=[O:8].C(O)(=O)C>CS(C)=O.O>[O:8]=[C:7]1[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH:20]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)COc1ccccc1OCC(=O)OC
Agent: CCCC[O-]
Agent: [K]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C1Oc2ccccc2OCC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium t.-butoxide (15.8 g.) dissolved in DMSO (130 ml.) is added dropwise over a 45 minute period to 1,2-bis-carbomethoxymethoxybenzene (18.3 g.) in DMSO (30 ml.) under an atmosphere of nitrogen. The mixture then is stirred 3 hours at ambient temperature and a mixture of acetic acid (16 ml.) and water (200 ml.) is added. The reaction mixture is extracted with benzene, the powdery material removed by filtration and the benzene then dried over magnesium sulfate and the benzene then evaporated leaving 3-oxo-4-carbomethoxy-3,4-dihydro-2H-1,5-benzodioxepin that is used in the following step without purification.
Reaction SMILES: [CH2:1]([C@@H:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[N:14][C:6]=2[NH:5]1)[C:2]#[CH:3].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.CCOC(C)=O>N1C=CC=CC=1>[CH2:1]([C@@H:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[N:14][C:6]=2[N:5]1[S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])[C:2]#[CH:3]
Reactant: C#CC[C@H]1Nc2ncccc2NC1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C#CC[C@@H]1C(=O)Nc2cccnc2N1S(=O)(=O)c1ccc(C)cc1
Reaction time: 7 h
Yield: 67.9 %

Procedure:
To (R)-3-(prop-2-ynyl)-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one (0.42 g, 2244 μmol) in pyridine was added p-toluenesulfonyl chloride (642 mg, 3365 μmol). The reaction mixture was stirred for 7 h and then EtOAc was added. The organic layer was separated, washed with brine, brine/5mL 10% HCl, dried, evaporated to give 0.52 g of solid. Purification by column chromatograph (DCM to 20% EtOAc/DCM) gave the title compound. MS 342 (M+1).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:6]=2/[CH:7]=[N:8]/[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:2]1.CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:1]1([S:4][C:5]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:6]=2[CH:7]2[CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:9][NH:8]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCC/N=C/c1cc([N+](=O)[O-])ccc1SC1CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCNC1c1cc([N+](=O)[O-])ccc1SC1CC1
Reaction time: 3 h
Yield: 36.2 %

Procedure:
To 76B (ca 31 mmol) in CH2Cl2 (150 mL) at −15° C. was added Et3N (5.94 mL, 43 mmol) followed by TiCl4 (1.0 M in CH2Cl2, 37.2 mL, 37.2 mmol). The mixture was stirred from −15° C. to rt over 3.0 h before it was quenched with sat. K2CO3 (200 mL) at 0° C. and stirred at rt for 1.0 h. CH2Cl2 was removed under vacuo and EtOAc was added to the crude (for better filtration). The mixture was filtered through a pad of wet Celite®, extracted with EtOAc (3×100 mL). The organic layer was washed with water, dried over Na2SO4. The cude was purified by silica gel flash column chromatography using gradient CH2Cl2 in hexanes to give 76C (3.77 g, 56% yield) and retrieved 76A (2.8 g). LC-MS indicated a mixture of cis and trans isomer in ca. 1:1 ratio. LC-MS 337 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2SC(NC3C=CC(O)=CC=3)=N[CH:7]=2)=[CH:2]1.S1C=CC(C2C=C(CC=O)C=CC=2)=C1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH2:44])=[S:43])=[C:37]([CH3:45])[CH:36]=1>>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]2[S:43][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:7][N:44]=2)=[C:37]([CH3:45])[CH:36]=1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Reactant: COc1ccc(NC(N)=S)c(C)c1
Agent: O=CCc1cccc(-c2ccsc2)c1
Product: COc1ccc(Nc2ncc(-c3ccsc3)s2)c(C)c1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol but starting from (3-thiophen-3-yl-phenyl)-acetaldehyde (Example 25) and (4-methoxy-2-methyl-phenyl)-thiourea. The title compound: ES-MS: 303.0 [M+H]+; single peak at tR=3.96 min (System 2).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C@H:3]1[C:15]([NH2:17])=O.B.CSC>C1COCC1>[NH2:17][CH2:15][C@H:3]1[C@@H:2]([OH:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4]1
Reactant: NC(=O)[C@@H]1CN(Cc2ccccc2)CC[C@@H]1O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: NC[C@@H]1CN(Cc2ccccc2)CC[C@@H]1O
Temperature: 80 °C

Procedure:
A solution of (cis)-4-hydroxy-1-(phenylmethyl)-3-piperidinecarboxamide (0.7 g, 3 mmol) in THF (6 ml) was treated with a borane-methyl sulphide complex (2M solution in THF, 3.3 ml). The reaction mixture was heated at 80° C. for 1300 s under microwave irradiation conditions. This was repeated twelve times and then the reaction mixtures were combined and the solvent was removed under reduced pressure and the residue was subjected to column chromatography on silica gel using a dichloromethane, methanol and aqueous ammonia gradient (20% methanol/dichloromethane-20% 2M ammonia in methanol/dichloromethane) to provide 4.6 g of the desired pure compound and 1.1 g of less pure material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[C:5]([N:7]1[CH2:12][CH2:11][C:10]([CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)([F:13])[CH2:9][CH2:8]1)=[O:6].C(CN)O>>[NH2:15][CH2:14][C:10]1([F:13])[CH2:11][CH2:12][N:7]([C:5]([C:4]2[CH:26]=[CH:27][C:28]([F:29])=[C:2]([Cl:1])[CH:3]=2)=[O:6])[CH2:8][CH2:9]1
Reactant: O=C(c1ccc(F)c(Cl)c1)N1CCC(F)(CN2C(=O)c3ccccc3C2=O)CC1
Solvent: NCCO
Product: NCC1(F)CCN(C(=O)c2ccc(F)c(Cl)c2)CC1
Temperature: 55 °C
Yield: 87.3 %

Procedure:
0.10 g of 2-[l-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4-yl-methyl]isoindole-1,3-dione (0.238 mmol) and 0.50 ml of ethanolamine (8.28 mmol) are mixed and the solution obtained is heated at 55° C. under a nitrogen atmosphere for 2 hours. The mixture is poured into ice-cold water and then extracted with chloroform. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and the solvent evaporated off. 0.06 g of the title product is obtained in the form of a colorless oil which is used in the next stage without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@@:5]12[O:12][C@@H:9]([CH2:10][CH2:11]1)[C:8](=[O:13])[CH2:7][C:6]2=[O:14])[CH3:2].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([Pb+3])=[C:34]([CH2:39][CH3:40])[CH:33]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([CH:7]2[C:8](=[O:13])[C@H:9]3[O:12][C@:5]([CH2:4][O:3][CH2:1][CH3:2])([CH2:11][CH2:10]3)[C:6]2=[O:14])=[C:34]([CH2:39][CH3:40])[CH:33]=1
Reactant: CCc1cc(Br)ccc1[Pb+3]
Reactant: CCOC[C@]12CC[C@H](O1)C(=O)CC2=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC[C@]12CC[C@H](O1)C(=O)C(c1ccc(Br)cc1CC)C2=O
Temperature: 80 °C
Yield: 29.2 %

Procedure:
(1S*,5S*)-1-Ethoxymethyl-8-oxabicyclo[3.2.1]octane-2,4-dione (0.8 g, 4.04 mmol) and 4-dimethylaminopyridine (2.4 g, 19.67 mmol) are added to a mixture of chloroform (16 ml) and toluene (4 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2-ethylphenyllead triacetate (2.49 g, 4.38 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×25 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1S*,5S*)-3-(4-bromo-2-ethylphenyl)-1-ethoxymethyl-8-oxabicyclo[3.2.1]octane-2,4-dione as white solid (0.45 g).
Reaction SMILES: [CH3:1][CH2:2][C:3]([CH2:5][CH2:6]/[CH:7]=[C:8](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])\[CH3:9])=[CH2:4].[N:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CCOCC>[CH2:21]([O:20][C:18]([N:17]1[CH2:1][CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])[CH2:4][N:16]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:19])[CH3:22]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: C=C(CC)CC/C=C(\C)CCC=C(C)C
Solvent: CCOCC
Product: CCOC(=O)N1CC=C(CCC=C(C)CCC=C(C)C)CN1C(=O)OCC
Temperature: -20 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A solution of the (E)-β-farnesene-containing product of Example 1 (14.5 g) in ether (20 ml) is cooled to -20° C. and diethyl azodicarboxylate (8.7 g) is slowly added with stirring. The mixture is stored at -20° C. overnight and then at 4° C., the reaction being shown by n.m.r. to be complete after 8 hours at 4° C. The mixture is then subjected to fractional distillation to give the adduct, 1,2-bis(ethoxycarbonyl)-4-(4,8-dimethyl-3,7-nonadienyl)-1,2,3,6-tetrahydropyridazine (I) as a yellow oil (8 g, 43%) 180°-185° C./0.3τ; nD20 1.4938; M+ (m/z as % of base peak): 378(2.9); δ(CCl4) 1.30 (t, 6H), 1.70 (m, 9H), 2.08 (m, 8H), 3.60-4.40 (m, 4H), 4.26 (q, 4H), 5.20 (m, 2H), 5.60 (br, t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[NH2:12].[SH:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([N:18]([CH3:20])[CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([S:13][C:14]2[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH:4]=1
Reactant: CN(C)C(=O)c1ccccc1S
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccccc1Sc1cc(N)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 74.5 %

Procedure:
A solution of 2.5-dichloro-4-nitro-phenylamine (17) (3.0 g, 14.5 mmol) and 2-mercapto-N,N-dimethyl-benzamide (3.0 g, 16.6 mmol) in DMF (50 mL) was heated to reflux with potassium carbonate (10 g) for 24 h. The mixture was poured into ice water and the precipitate was collected by a filtration. A dark colored solid was recrystalized from petroleum ether/methylene chloride yielded 3.8 g of (18) as a pale yellow powder (75%): IR (cm−1, KBr) 3461, 3376, 3153, 3154, 1627, 1575, 1492, 1135; 1H NMR (200 MHz CDCl3) δ 8.23 (s, 1H), 7.3–7.6 (m, 4H), 6.16 (s, 1H), 4.8 (br s, 2H), 3.37 (s, 3H), 2.86 (s, 3H). Anal. (C15H14ClN3O3S) C, H, N.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]([C@@H:8]1[CH2:10][C@H:9]1[C:11]([O:13]CC)=[O:12])=[O:7])[CH3:4].O>C(O)C.CC(C)=O>[CH2:3]([O:5][C:6]([C@@H:8]1[CH2:10][C@H:9]1[C:11]([OH:13])=[O:12])=[O:7])[CH3:4]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.7 %

Procedure:
Add a solution of 0.709 g (17.72 mmol) sodium hydroxide in 7.38 mL ethanol to a solution of (+/−)-trans-cyclopropane-1,2-dicarboxylic acid diethyl ester (3.00 g, 16.11 mmol) in 36.9 mL acetone. Stir at room temperature for 24 hours. Pour reaction mixture into 100 mL water and extract with ethyl acetate (1×70 mL). Acidify the aqueous layer with 5N HCl and concentrate under reduced pressure. Add ethyl acetate and filter the resulting slurry. Concentrate the filtrate under reduced pressure to provide the desired compound (2.26 g, 88.7%).