Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:12][CH3:13])=[CH:6][CH:5]=1.O[Li].O.CO.O>C(O)(=O)C>[O:26]1[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[O:23][CH2:22][C@@H:21]1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=2)[CH2:12][CH3:13])=[CH:16][CH:17]=1
Reactant: CCN(Cc1ccc(C(=O)OC)cc1)Cc1ccc([C@H]2COc3ccccc3O2)cc1
Agent: [Li]O
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCN(Cc1ccc(C(=O)O)cc1)Cc1ccc([C@H]2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-({[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-ethyl-amino}-methyl)-benzoic acid methyl ester (65 mg, 0.16 mmol), LiOH.H2O (23 mg, 0.55 mmol), MeOH (5 mL) and water (0.5 mL) is stirred at room temperature for 16 h. The reaction mixture is neutralized with acetic acid and concentrated. The residue is diluted with water and DCM, phases are separated, the organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[NH:15][CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16]1[CH2:18][CH:17]1[CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.C(Cl)Cl>CC(O)C.O>[CH2:1]([N:8]1[CH2:14][CH:13]2[N:15]([CH2:18][CH:17]([OH:16])[CH2:19][O:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CC3CCC(C2)N3)cc1
Reactant: N#Cc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(OCC(O)CN2C3CCC2CN(Cc2ccccc2)C3)cc1
Temperature: 60 °C
Reaction time: 22 h
Yield: 88.9 %

Procedure:
A mixture of 3-benzyl-3,8-diazabicyclo[3.2.1]octane (3.46 g, 17.1 mmol; from Preparation B, step (e) above) and 4-(2-oxiranylmethoxy)benzonitrile (3.00 g, 17.1 mmol; prepared as described in international patent application WO 99/31100) in 2-propanol (70 mL) and H2O (7 mL) was stirred at 60° C. for 22 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 (200 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried (NaSO4), filtered and concentrated in vacuo to give the crude product. Flash chromatography on silica gel eluting with CH2Cl2:CMA (8:1) gave 5.74 g (89%) of the sub-title compound as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH:17][C:18]4[CH:19]=[C:20]([C:23](OC)=[O:24])[S:21][CH:22]=4)=[O:16])[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1.O.[NH2:28][NH2:29]>C(O)C>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH:17][C:18]4[CH:19]=[C:20]([C:23]([NH:28][NH2:29])=[O:24])[S:21][CH:22]=4)=[O:16])[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)c1cc(NC(=O)c2cc(-n3cnc(C4CC4)c3)ccn2)cs1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc(NC(=O)c2cc(-n3cnc(C4CC4)c3)ccn2)cs1
Yield: 103.1 %

Procedure:
Methyl 4-(4-(4-cyclopropyl-1H-imidazol-1-yl)picolinamido)thiophene-2-carboxylate (380 mg, 1.0 mmol) was dissolved in ethanol, hydrazine hydrate (0.26 mL, 5.2 mmol) was added, and the reaction was refluxed overnight. The solvent was removed under reduced pressure, and the solids were suspended in acetonitrile and filtered to afford 380 mg of 4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(5-(hydrazinecarbonyl)thiophen-3-yl)picolinamide as a white solid. M+1=369.1
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1)[CH3:2].[Br:16]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:16][CH2:15][C:11]1[C:7]2[C:8](=[O:10])[O:9][C:4]([O:3][CH2:1][CH3:2])=[N:5][C:6]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CCOc1nc2cccc(C)c2c(=O)o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCOc1nc2cccc(CBr)c2c(=O)o1

Procedure:
A solution of 2-ethoxy-5-methyl-4H-3,1-benzoxazin-4-one (330 mg), N-bromosuccinimide (340 mg) and AIBN (10 mg, 2,2'-azobis-iso-butyronitrile) was refluxed for 21/2 hours. The solution was evaporated to dryness. The residue was purified by column chromatography (silica gel) 10% ethyl acetate:petroleum ether 30-60). This afforded the title compound, 5-bromomethyl-2-ethoxy-4H-3,1-benzoxazin-4-one, m.p. 112°-114° C.; IR: 1760, 1630, 1590 cm-1.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:24])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:24])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCC1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCC1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
A solution of 5 g (13.55 mmol) of 2-[1-(6-chloroquinolin-2-yl)piperidin-4-yl]ethyl methanesulfonate, prepared in step 6.1., and 1.76 g (27.11 mmol) of sodium azide in 30 mL of N,N-dimethylformamide is refluxed for 4 hours, under an inert atmosphere.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[C:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CC(=Cc1ccc(F)cc1)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC(Cc1ccc(F)cc1)C(=O)O

Procedure:
To p-fluoro-α-methylcinnamic acid (177.9 g., 0.987 mole) in 3.6 l. ethanol is added 11.0 g. of 5% Pd/C and the mixture is reduced at room temperature under a hydrogen pressure of 40 p.s.i. uptake is 31/32 lbs. (97% of theoretical). After the catalyst is filtered, the filtrate is concentrated in vacuo to give the product, p-fluoro-α-methylhydrocinnamic acid that is used without weighing in next step.
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[C:17]([O:26][CH3:27])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:20].C(O)(=O)C>O>[CH3:27][O:26][C:17]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[N:20]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=2[CH:1]=[C:2]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:25]
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Reactant: COC(=O)c1ccccc1N
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccccc1-n1c(-c2ccccc2)cc2c1CCCC2

Procedure:
A solution of 10.8 g. (0.05 mole) of 2-phenacylcyclohexanone, 7.55 g. (0.05 mole) of methyl anthranilate, and 30 ml. of glacial acetic acid was heated under reflux for 7 hours, cooled, and diluted with water. The layers were separated, and the aqueous phase was extracted with ether. The combined organic phase was washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to an oil. Chromatography on silica gel with toluene as the eluent gave 2.91 g. (18%) of a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:22][C:21]3([CH3:24])[CH2:23][CH:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]3)=[O:15])=[CH:10][CH:9]=1)(C)(C)C.[H-].[Na+].Br[CH2:31][CH2:32][O:33][CH3:34]>CN(C=O)C>[CH3:34][O:33][CH2:32][CH2:31][NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([N:16]2[CH2:26][C:19]3([CH3:25])[CH2:18][CH:17]2[CH2:23][C:21]([CH3:22])([CH3:24])[CH2:20]3)=[O:15])=[CH:12][CH:13]=1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)C1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCNc1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a solution of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester (0.5 g, 1.34 mmol) in dry DMF (25 ml) was added sodium hydride (75 mg, 1.88 mmol in 60% mineral oil) and the mixture was stirred for 30 min. 1-Bromo-2-methoxy-ethane (224 mg, 1.61 mmol) was added and the mixture was heated to reflux and allowed to cool to room temperature with stirring. The reaction was quenched by addition of water (20 ml) and extracted with diethyl ether (2×25 ml). The combined organic phases were washed with saturated aqueous ammonium chloride (25 ml), dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in DCM (15 ml) and TFA (10 ml) was added. The resulting mixture was stirred for 5 hrs. at room temperature and evaporated in vacuo. To the residue was added water (10 ml) and diethyl ether (20 ml) and the pH was adjusted to 9 by addition of 1 N sodium hydroxide. The organic phase was separated and dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (silica gel) using EtOAc/heptane (1:1) as eluent. Pure fractions were collected and evaporated to dryness affording 0.3 g (68%) of the title compound as an oil.
Reaction SMILES: C([O:5][C:6](=[O:44])[C@@H:7]([NH:9][C:10]([C:12]1[N:16]2[C@@:17]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)=[CH:33][CH:32]=3)([CH3:29])[C:18](=[O:28])[N:19]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:15]2=[N:14][CH:13]=1)=[O:11])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[Cl:27][C:22]1[CH:21]=[C:20]([N:19]2[C:15]3=[N:14][CH:13]=[C:12]([C:10]([NH:9][C@@H:7]([CH3:8])[C:6]([OH:44])=[O:5])=[O:11])[N:16]3[C@@:17]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)([CH3:29])[C:18]2=[O:28])[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3ccc(F)cc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3ccc(F)cc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
To a solution of (S)-2-{[(R)-7-(3,5-dichloro-phenyl)-5-(4′-fluoro-biphenyl-4-ylmethyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid tert-butyl ester (0.15 g, 0.24 mmol) in CH2Cl2 (10 mL) was added TFA (4 mL) and the mixture stirred at room temperature for 12 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water, brine and dried with MgSO4. The mixture was filtered and concentrated to give 120 mg of (S)-2-{[(R)-7-(3,5-dichloro-phenyl)-5-(4′-fluoro-biphenyl-4-ylmethyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid as a white solid, m/z 581.3 [M]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][S:21]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27])(=[O:23])=[O:22].CC1C=CC([N+]([O-])=O)=CC=1S(N)(=O)=O.FC(F)(F)C(O)=O>Cl.CC(O)C>[NH2:20][S:21]([C:24]1[CH:25]=[C:26]([NH:27][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)[CH:28]=[CH:29][C:30]=1[CH3:31])(=[O:22])=[O:23]
Reactant: C#CCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Agent: Cc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: Cl
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: C#CCOc1ccc(Nc2nc(Nc3ccc(C)c(S(N)(=O)=O)c3)ncc2F)cc1
Temperature: 100 °C

Procedure:
2-Chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine (0.514 g, 1.85 mmol), 3-(aminosulfonyl)-4-methylaniline (0.689 g, 3.70 mmol, made by reduction of commercially available 2-methyl-5-nitrobenzenesulfonamide or synthesized as described below), and trifluoroacetic acid (0.186 mL, 2.41 mmol) were combined with iPrOH (6.0 mL) in a sealed vial and heated at 100° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with 1N HCl (80 mL). N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine (I) was isolated as a white solid by suction filtration (0.703 g). 1H NMR (DMSO-d6): δ 10.08 (bs, 2H), 8.19 (d, J=4.5 Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J=2.4 and 8.4 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.32 (bs, 2H), 7.23 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 4.79 (d, J=2.1 Hz, 2H), 3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97%; MS (m/e): 428 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=O)=[O:17])[CH3:15])=[CH:10][CH:9]=1.C(C1NC=CN=1)([C:24]1[NH:25]C=CN=1)=O.C(=O)=O.CN>O1CCCC1>[CH3:24][NH:25][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Agent: CN
Agent: O=C=O
Solvent: C1CCOC1
Product: CNC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1
Reaction time: 0.33 h

Procedure:
3.06 gm (10 millimols) of [1-(2'-fluoro-4 -biphenylyl)-ethylsulfinyl]-acetic acid of m.p. 164-165° C, were suspended in 50 ml of tetrahydrofuran, and 1.95 gm (12 millimols) of carbonyl-diimidazole were added to the suspension. The acid dissolved, accompanied by carbon dioxide evolution. After 20 minutes, dry methylamine was introduced until the mixture was saturated. After another hour, the mixture was evaporated in vacuo, and the residue was taken up in a mixture of dilute hydrochloric acid and ether. 2.55 gm (80% of theory) of the title compound, m.p. 136-137° C, were obtained from the ether phase after washing, drying, evaporation and recrystallization from toleuen/cyclohexane = 1/1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[ClH:25].CO>>[ClH:25].[CH:1]1[C:10]2[C:5](=[C:6]([NH:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cnccc23)CC1
Agent: Cl
Solvent: CO
Product: c1cc(NC2CCNCC2)c2ccncc2c1
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 32 (327 mg) and 10% hydrogen chloride/methanol solution (5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (286 mg) as light yellow powdery solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[CH:14]1[C:19](O)=[CH:18][CH:17]=[C:16]([CH3:21])[CH:15]=1>>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]1[C:18]2[C:19](=[CH:14][CH:15]=[C:16]([CH3:21])[CH:17]=2)[O:8][C:7](=[O:9])[CH2:6]1
Reactant: Cc1ccc(O)cc1
Reactant: COc1ccccc1C=CC(=O)O
Product: COc1ccccc1C1CC(=O)Oc2ccc(C)cc21
Reaction time: 2 h

Procedure:
A mixture of 2-methoxycinnamic acid (178 g, 1.0 mol), p-cresol (108 g, 1.0 mol), and p-touenesulphonic acid monohydrate (47.5 g, 0.25 mol) was stirred on a boiling water-bath for about 2 h during which time the system was evacuated with a waterpump to remove formed water. The solid was then broken up and washed copiously with water. The granular material was then stirred with a large volume of saturated NaHCO3 solution containing some 10% acetone. The product was filtered off, washed dried and recrystallised from acetone affording 167 g (62,5%) white crystals of the desired lactone, m.p. 140°.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:7][C:6]=1[O:24][CH3:25])(=[O:3])[CH3:2].C(OC1C=CC(CCO)=CC=1OC)(=O)C.[I-:41].[Na+]>CC(C)=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][I:41])=[CH:7][C:6]=1[O:24][CH3:25])(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: COc1cc(CCOS(=O)(=O)c2ccc(C)cc2)ccc1OC(C)=O
Agent: COc1cc(CCO)ccc1OC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(CCI)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 6:4 mixture of 2-methoxy-4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)phenyl acetate and 4-(2-hydroxyethyl)-2-methoxyphenyl acetate (1.57 g, 4.31 mmol) and sodium iodide (0.706 mL, 17.2 mmol) in dry acetone (28 mL) was stirred at room temperature overnight with protection from light. The acetone was removed in vacuo and the residue was triturated with toluene and filtered through a plug of Celite to remove insoluble inorganic material. The filtrate was concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 50% EtOAc in hexanes over 4536 mL) to give 4-(2-iodoethyl)-2-methoxyphenyl acetate. Rf=0.58 (20% EtOAc/hexanes). LCMS calc.=321.0; found=320.7 (M+H)+.
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].[C:16]([O:25][CH2:26][CH3:27])(=[O:24])/[CH:17]=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:26]([O:25][C:16]([CH: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]([CH3:15])[CH3:14])[CH2:4][CH:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:24])[CH3:27]
Reactant: C=C(CC)CC/C=C(\C)CCC=C(C)C
Reactant: CCOC(=O)/C=C\C(=O)OCC
Product: CCOC(=O)C1CC=C(CCC=C(C)CCC=C(C)C)CC1C(=O)OCC
Temperature: 180 °C
Yield: 75 %

Procedure:
The (E)-β-farnesene-containing product of Example 1 (10 g) and diethyl maleate (5.0 g) are heated together at 180° C. for two hours. The mixture is then distilled under reduced pressure to give 1,2-bis-(ethoxycarbonyl)-4-(4,8 dimethyl-3,7-nonadienyl) cyclohex-4-ene as a pale yellow oil (8.5 g, 75%); b.p. 175°-180° C./0.3τ; nD20 1.4894; M+ (m/z as % of base peak): 376 (6.6); δ(CCl4) 1.24 (t, 6H), 1.70 (m, 9H), 2.08 (m, 8H), 2.36 (m, 4H), 2.80 (m, 2H), 4.14 (q, 4H), 5.20 (m, 2H), 5.40 (br, t, 1H).
Reaction SMILES: CO[C:3](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:16][NH:17][NH2:18]>C(O)C>[NH2:13][C:12]1[N:17]([CH3:16])[N:18]=[C:3]([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]=1[C:14]#[N:15]
Reactant: CNN
Reactant: COC(Cc1ccccc1)=C(C#N)C#N
Solvent: CCO
Product: Cn1nc(Cc2ccccc2)c(C#N)c1N

Procedure:
A mixture of (1-methoxy-2-phenylethylidene)malononitrile (prepared by the method of B. C. Kraybill et al., J. Am. Chem. Soc. 2002, 124, 12118-12128; 10 g, 50 mmol) and methylhydrazine (2.3 g, 50 mmol) in ethanol (120 mL) was heated to reflux for 10 minutes. The reaction was concentrated in vacuo, and the residue was diluted with water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford C10 as a yellow solid. Yield: 10 g, 47 mmol, 94%.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=O)=[C:10]([CH3:20])[N:9]=1.O=S(Cl)[Cl:23]>C1COCC1.C(Cl)Cl>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][Cl:23])=[C:10]([CH3:20])[N:9]=1
Reactant: Cc1nc(Cl)c2ccccc2c1C=O
Reactant: O=S(Cl)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nc(Cl)c2ccccc2c1CCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
LAH (3.6 ml of 1M in THF, 3.62 mmol) is added to a solution of 1-chloro-3-methyl-isoquinoline-4-carbaldehyde (744 mg, 3.62 mmol) in THF (10 ml) at 0° C. After stirring for 30 min at ambient temperature, the mixture is quenched with small amounts of saturated sodium sulfate and filtered through a pad of celite. The filtrate is concentrated in vacuo to give the crude alcohol. SOCl2 (13 ml of 2M in DCM, 25 mmol) is added to a solution of the crude alcohol in DCM (5 ml). After stirring for 1 h at room temperature, the mixture is concentrated in vacuo and the residue is chromatographed on silica gel to give 737 mg of 1-chloro-4-chloromethyl-3-methyl-isoquinoline. 1H NMR (CDCl3) 8.44 (d, 1H), 8.18 (d, 1H), 8.02 (t, 1H), 7.82 (t, 1H), 5.03 (s, 2H), 3.00 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([N:33]2[CH2:37][CH2:36][CH2:35][C@H:34]2[CH2:38][OH:39])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[OH:39][CH2:38][C@@H:34]1[CH2:35][CH2:36][CH2:37][N:33]1[S:30]([C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:15][CH2:16]4)=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:22])[CH:29]=[CH:28][CH:27]=1)(=[O:32])=[O:31]
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)N2CCC[C@H]2CO)c1
Product: O=C(Nc1cccc(S(=O)(=O)N2CCC[C@H]2CO)c1)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) and (S)-[1-(3-amino-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (example B.13) according to general procedure II. Pale-yellow solid. Mp 180-182° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24](O)=[O:25])=[CH:6]2)#[N:2].[OH:27][CH2:28][C:29]1([C:34]#[N:35])[CH2:33][CH2:32][CH2:31][CH2:30]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[OH:27][CH2:28][C:29]1([CH2:34][NH:35][C:24]([C:7]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:21])[F:22])[CH:14]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)=[O:25])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: N#CC1(CO)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc2c(c1)cc(C(=O)NCC1(CO)CCCC1)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
5-Cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (200 mg, 0.56 mmol), 1-hydroxymethyl-cyclopentanecarbonitrile (145 mg, 1.12 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (117 mg, 0.61 mmol) and 1-hydroxybenzotriazole hydrate (83 mg, 0.61 mmol) were stirred in DCM (20 ml) for 66 h at room temperature. The reaction was poured into water (25 ml) and diluted with DCM (25 ml). The organic layer was isolated using a hydrophobic filter tube and the DCM removed under reduced pressure and purified by semi-preparative HPLC followed by purification on neutral alumina giving the title compound (75 mg, 28%) as a glassy solid.
Reaction SMILES: OC1C=CC(S[CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])=CC=1.OO.CSC>C(O)(=O)C>[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])[CH3:9]
Reactant: O=C(CSc1ccc(O)cc1)Nc1ccccc1
Agent: OO
Solvent: CSC
Solvent: CC(=O)O
Product: CC(=O)Nc1ccccc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 185 %

Procedure:
6.0 g (23.2 mmol) of 2-(4-hydroxyphenylthio)acetoanilide and 50 mL of acetic acid were added under a room temperature into a 100 mL flask with four inlets and attached with a stirrer and a thermometer. To the resultant solution, 5.6 g (49.4 mmol) of 30% aqueous solution of hydrogen peroxide was added, and the solution was stirred for 4 hours at a room temperature and consequently for 5 hours at 100° C. Following to the completion of the reaction, 0.5 g of dimethyl sulfide was added into the solution, and then, the solution was extracted with MIBK. The MIBK layer was washed several times with water, and followed by washing with sodium hydrogencarbonate. The MIBK in the solution was distilled out under reduced pressure, and the resultant residue was subjected to recrystallization with MIBK to obtain 5.8 g of 2-(4-hydroxphenylsulfonyl) acetoanilide. The yield was 86% and the melting point of the compound was in a range of 188 to 189° C.