Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([C:20]([OH:22])=O)=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:26](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([C:20](=[O:22])[NH2:26])=[CH:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(C(=O)O)cn(CC(=O)OC(C)(C)C)c2c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(C(N)=O)cn(CC(=O)OC(C)(C)C)c2c1
Reaction time: 16 h

Procedure:
To a mixture of 1-tert-butoxycarbonylmethyl-6-methoxy-1H-indole-3-carboxylic acid (500 mg, 1.28 mmol) in DMF (6 mL) were added successively NH4Cl (137 mg, 2.55 mmol), HBTU (1.21 g, 3.19 mmol) and DIPEA (0.90 mL, 5.11 mmol), and stirring was continued at RT for 16 h. Additional aliquots of NH4Cl (2 equiv) and DIPEA (4 equiv) were added to the reaction mixture. After stirring for 16 h, water was added and the aqueous layer was extracted repeatedly with EtOAc. The combined organics were washed with saturated aqueous NaHCO3 solution and brine, dried (phase separator) and concentrated in vacuo. Purification by preparative HPLC (Macherey Nagel, VP250/40, C18 nucleosil 100-10, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) and lyophilization of the purified fractions afforded the title compound as a beige solid. MS: 305 [M+H]+, 609 [2M+H]+; tR (HPLC conditions c): 4.26 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1.Cl.[CH3:32][N:33]([CH3:39])[CH2:34][CH2:35][C:36](O)=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)[C:36](=[O:37])[CH2:35][CH2:34][N:33]([CH3:39])[CH3:32])=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(CC(=O)OC)c1
Reactant: CN(C)CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1CCCN(Cc1cccc(CC(=O)OC)c1)C(=O)CCN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.3 %

Procedure:
The product from Example 1 (80 mg) and 3-(dimethylamino)propanoic acid hydrochloride (45 mg) were combined in DCM (5 mL) then TEA (73 mg) and HATU (101 mg) were added. The reaction mixture was stirred at rt for 16 h. The solvents were evaporated, the residue dissolved in MeOH and purified by RPHPLC to give the title compound 32 mg.
Reaction SMILES: [F:1][C:2]([F:38])([CH:8](OC(SC)=S)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]3[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=3)[CH:18]=[C:17]([CH3:32])[CH:16]=2)=[CH:11][N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(P(=O)C2C=CC=CC=2)C=CC=CC=1.C(OOC(C)(C)C)(C)(C)C>O1CCOCC1>[F:38][C:2]([F:1])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]3[N:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][N:23]=3)[CH:18]=[C:17]([CH3:32])[CH:16]=2)=[CH:11][N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)C(OC(=S)SC)c1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Agent: CC(C)(C)OOC(C)(C)C
Agent: O=[PH](c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)C(F)(F)Cc1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1

Procedure:
A mixture of ethyl 2,2-difluoro-3-{[(methylsulfanyl)carbonothioyl]oxy}-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoate (68.5 mg, 0.120 mmol), anhydrous dioxane (5.00 mL), diphenylphosphine oxide (25.6 mg, 0.127 mmol) and di-tert-butyl peroxide (10.0 μL, 0.054 mmol) was heated to reflux for 6 hours under Ar(g). The reaction mixture was concentrate under reduced pressure and the residue was purified by reverse phase HPLC to afford ethyl 2,2-difluoro-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoate. MS APCI C22H20F5N4O2 [M+H]+ 467. found 467.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([OH:17])(=[O:16])[C:10]([CH2:12][C:13](O)=[O:14])=[CH2:11]>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:13](=[O:14])[CH2:12][CH:10]([C:9]([OH:17])=[O:16])[CH2:11]2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(O)cc2)C1
Temperature: 25 °C

Procedure:
A mixture of 2.355 mol of 4-aminophenol and 2.32 mol of itaconic acid was heated gradually: At 60° C., the powder started to become viscous, at 110–120° C. it became liquid and the colour turned to dark brown while the rest of solid material was also dissolved. The exothermic reaction started under boiling, and the temperature rose to 150° C. The sandy product was left to cool down to RT within 1–2 hours. The obtained crude (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid was engaged in the next step without further purification or characterisation.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:21])=[C:9]([C:11](=O)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:22][CH2:23][CH3:24].[OH-].[K+].NN.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(O)CO>[OH:1][C:2]1[C:7]2[C:8]([CH3:21])=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:22][CH2:23][CH3:24]
Reactant: CCCc1ccc2oc(C(=O)c3ccc(OC)cc3)c(C)c2c1O
Agent: NN
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: CCCc1ccc2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A mixture of 4-hydroxy-2-(4-methoxybenzoyl)-3-methyl-5-propylbenzofuran (7.2 g; 22 mmoles), potassium hydroxide pellets (8.7 g; 155 mmoles), ethylene glycol (100 ml) and 99% hydrazine (3.0 ml) was heated with stirring and maintaining the internal temperature between 130° C. and 150° C. for 4 hours. The internal temperature was permitted to rise to 175° C. for 1 hour and excess water was always allowed to escape. The mixture was cooled and poured into excess 20% citric acid solution. The mixture was extracted with ether, washed with water, dried (Na2SO4), filtered, concentrated, and chromatographed to give 4 grams of the title compound.
Reaction SMILES: [N+](C1CCCC1)([O-])=O.C1C=C(C=O)C(C=O)=CC=1.C[O-].[Na+].[CH3:22][O:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]([C:33]2([N+:39]([O-:41])=[O:40])[CH2:38]C[CH2:36][CH2:35][CH2:34]2)[O:25]1>CO>[CH3:22][O:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]([C:33]2([N+:39]([O-:41])=[O:40])[CH2:38][CH2:36][CH2:35][CH2:34]2)[O:25]1
Reactant: COC1OC(C2([N+](=O)[O-])CCCCC2)c2ccccc21
Agent: C[O-]
Agent: O=Cc1ccccc1C=O
Agent: O=[N+]([O-])C1CCCC1
Solvent: CO
Product: COC1OC(C2([N+](=O)[O-])CCCC2)c2ccccc21

Procedure:
Condensation of nitrocyclopentane (5.00 g, 40.0 mmol) with o-phthalaldehyde (3.76 g, 28.0 mmol) in the presence of freshly prepared sodium methoxide (10 mmol) in MeOH is carried out as described above for compound a. The resulting pale green oil (7.21 g, 98%) is pure enough for use in the next step. The following data were obtained on a ca. 1:1 mixture of the cis and trans diastereoisomers. 1H NMR (CDCl3) 7.50-7.25 (m, 3), 7.10-7.00 (m, 1), 6.16 and 5.91 (isomer I, 2 d, 1 total, J=2.3), 5.93 and 5.80 (isomer II, s and d, respectively, 1 total, J=0.7 Hz), 3.49 and 3.30 (isomers I and II, respectively, 2 s, 3 total), 2.50-2.35 (m, 1), 2.30-1.90 (m, 3), 1.75-1.50 (m, 4); IR (film) 1543, 1464, 1398, 1373, 1348, 1113, 1094, 1026, 974, 756; MS (CI/CH4, eE=120 eV), m/z 236 (M-H)+, 219, 206, 191, 175, 159, 149 (base peak), 131, 118, 91, 73; Anal. Calcd for C12H15NO2 (MW=237.3): C, 60.75; H, 6.37; N, 5.90. Found: C, 60.48; H, 6.28; N, 6.00.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22]>>[NH2:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:7]([Cl:8])=[CH:6][N:5]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1N
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1c(Cl)cnc(N)c1[N+](=O)[O-]
Yield: 72 %

Procedure:
In a similar fashion as for the synthesis of Compound A (X═Cl), 4,5-dichloro-3-nitro-pyridin-2-ylamine was reacted with N-((1R,2R)-2-amino-cyclohexyl)-methanesulfonamide to afford N-[(1R,2R)-2-(2-amino-5-chloro-3-nitro-pyridin-4-ylamino)-cyclohexyl]-methanesulfonamide (72%) which was subjected to hydrogenation with iron in acetic acid in a similar fashion as for Compound B to afford N-[(1R,2R)-2-(2,3-diamino-5-chloro-pyridin-4-ylamino)-cyclohexyl]-methanesulfonamide (66%). This latter material was then reacted with 2-methoxy-4-morpholin-4-ylmethyl-benzaldehyde in a similar fashion as for the synthesis of Compound III to afford the title compound as a yellow lyophilate (70%). 1H NMR (d-chloroform): 13.39 (br s, 1H), 8.30 (d, J=8 Hz, 1H), 8.23 (s, 1H), 7.19 (m, 1H), 7.12 (s, 1H), 7.03 (d, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 5.05 (m, 1H), 4.97 (m, 1H), 4.12-3.81 (m, 6H), 3.64 (s, 3H), 3.48 (m, 1H), 3.25 (m, 1H), 3.12 (s, 3H), 3.06 (m, 1H), 2.83 (m, 1H), 2.22 (m, 2H), 2.01-1.60 (m, 4H), 1.44 (m, 2H), 1.25 (m, 1H). MS: 549.0 (M+H). HPLC retention time: 1.85 minutes (G Method).
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:15][NH2:16]>>[CH3:15][NH:16][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Clc1nccnc1Nc1ccccc1
Reactant: CN
Product: CNc1nccnc1Nc1ccccc1
Yield: 57.3 %

Procedure:
3-chloro-N-phenylpyrazin-2-amine (4.5 g, 21.22 mmol) was stirred with methyl amine (20.59 g, 20.9 mmol, 33 wt % in THF) under reflux overnight. The solvent was evaporated and the residue was purified by column chromatography using 50% ethyl acetate and hexanes to give N2-methyl-N3-phenylpyrazine-2,3-diamine (2.4 g, 54.8%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[NH:24][C:25]1[S:26][C:27]2[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][C:28]=2[N:29]=1>O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[NH:24][C:25]1[S:26][C:27]2[CH:33]=[C:32]([NH:34][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[CH:31]=[CH:30][C:28]=2[N:29]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Solvent: O
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)Nc5ccccc5)cc4s3)c2cc1OC

Procedure:
1-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]-3-phenylurea was prepared from phenyl isocyanate (13 μL, 0.113 mmol) and N2-(6,7-di-methoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 3. The mixture was poured into water (20 mL) and the resulting precipitate was purified by preparative HPLC to obtain a yellow solid (10 mg, 21 μmol, 19%). LC/ESI-MS: m/z=473 [M+H]+; m/z=471 [M−H]−; Rt=3.10 min.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]2.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]2[CH2:31][O:30]2)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>CC(O)C.O>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]([OH:30])[CH2:31][N:7]2[CH2:8][CH:1]3[CH2:9][CH:5]([CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]3)[CH2:6]2)=[CH:23][CH:22]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Reactant: CC(C)(C)c1ccc(OCC2CO2)cc1
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(C(C)(C)C)cc3)C2)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 6.7 %

Procedure:
A mixture of tert-butyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (2.2 g; 9.70 mmol; see Example F above) and 4-tert-butyl-1-(2-oxiranylmethoxy)benzene (2.0 g; 9.70 mmol; from step (a) above) in 2-propanol (10 mL) and water (1 mL) was stirred at 60° C. for 18 h. The reaction mixture was concentrated to give an oil which was dissolved in hexanes and allowed to stand until solids formed. The solids were collected and dried to give the desired product (0.28 g; 7%) as a white solid.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH3:13][N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.O>C(O)(=O)C.ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:13][N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cn1cccc1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: Cn1cccc1C1=CC(=O)c2ccccc2C1=O
Yield: 79 %

Procedure:
According to the procedure described in the article Chemistry Express 1990, Vol. 5, No. 10, pages 749-752, the disclosure of which is specifically incorporated by reference herein, 3.16 millimol of 1,4-naphthoquinone were stirred with 25 millimol of N-methylpyrrole and 3.16 millimol of copper acetate in 50 ml of acetic acid in a round-bottomed flask at room temperature for 1 hour. The reaction mixture was diluted with 300 ml of dichloromethane and the resulting mixture was then poured into a large volume of water (300 ml). The organic phase was then separated out and washed four times with 100 ml of water and finally with saturated aqueous NaCl solution. The resulting organic phase was dried over Na2SO4 and then concentrated under vacuum. The product 2-(1-methyl-1H-pyrrol-2-yl)-[1,4]-naphthoquinone was thus isolated in a yield of 79% after purification by chromatography on a column of silica.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([C:1]2[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=2)=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CCCc1ccc(-c2ccccc2)cc1
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 14.4 gm of 4-(4-biphenylyl)-butyric acid in 72 ml of glacial acetic acid at 24°-27° C. 24 ml of fuming nitric acid (d=1.52) were added dropwise. After stirring for 5 minutes, the mixture was poured into ice water while stirring, and the aqueous mixture was extracted with benzene. The benzene phase was washed with water, dried and evaporated; the residue was dissolved in 100 ml of acetone and admixed with 6.8 ml of cyclohexylamine. The thus obtained cyclohexylamine salt had a melting point of 160°-161° C. (after recrystallization from 200 ml of isopropanol). Melting point of the free acid: 124° C. (from carbon tetrachloride).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16](=[S:18])=S.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCOCC>[CH2:19]([N:26]=[C:16]=[S:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: S=C=NCc1ccccc1
Reaction time: 8 h
Yield: 62 %

Procedure:
Dicyclohexylcarbodiimide (10.3 g) and carbon disulphide (20 ml) are stirred in a round-bottomed flask with 20 ml of diethyl ether at -10° C. Benzylamine (5.35 g, 5.5 ml) in 20 ml ether is added slowly when a white precipitate forms immediately. The reaction mixture is stirred overnight, filtered and the ether removed in vacuo. The residue is suspended in ether, filtered and the ether removed in vacuo. The remaining oil is distilled under vacuum (0.5 mm, 100° C. approx.) to give benzylisothiocyanate as an oil (4.7 g, 62%).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10]>>[CH2:7]([NH:11][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][OH:5])[CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCCO1
Reactant: CCCCN
Product: CCCCNC(=O)CCCO
Temperature: 85 °C

Procedure:
To 30 mL (390 mmol) of g-butyrolactone was added 45 ml (455 mmol) of n-butylamine. The solution was heated at 85° C. for 1.5 hr, then the excess n-butylamine was removed in vocuo. The product crystallized on standing to give about 62 g of a colorless, low melting solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH3:22])[CH2:5][CH:6]([OH:21])[CH:7]=[C:8]([CH3:20])[CH:9]=[CH:10][C:11]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][CH2:13][C:12]=1[CH3:19].[C:23](=O)(O)[O-].[Na+]>CO>[OH:1][CH2:2][CH:3]=[C:4]([CH3:22])[CH2:5][CH:6]([O:21][CH3:23])[CH:7]=[C:8]([CH3:20])[CH:9]=[CH:10][C:11]1[C:16]([CH3:17])([CH3:18])[CH2:15][CH2:14][CH2:13][C:12]=1[CH3:19]
Reactant: O=C([O-])O
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CC(O)CC(C)=CCO
Agent: [Na+]
Solvent: CO
Product: COC(C=C(C)C=CC1=C(C)CCCC1(C)C)CC(C)=CCO
Temperature: 0 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
1.52 g (5 mmol) of 1,5-dihydroxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-2,6,8-nonatriene (I) was dissolved in 20 ml of methanol and the mixture was cooled to 0° C. To the mixture was then added 47.6 mg (0.25 mmol) of paratoluenesulfonic acid hydrate. After the mixture was stirred at 0° C. for 3 hours, a saturated aqueous sodium bicarbonate solution was added to the mixture and the resulting mixture was subjected to extraction with ether, followed by washing with a saturated brine. The resulting product was dried over anhydrous magnesium sulfate and the solvent was evaporated to obtain 1-hydroxy-5-methoxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene- 1-yl) -2,6,8-nonatriene (IV) as a mixture of E and Z isomers in a yield of 85%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][C@@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13]1>C(O)(C)C>[CH3:11][C@H:12]1[CH2:17][N:16]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:15][C@@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1
Solvent: CC(C)O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2[N+](=O)[O-])C1
Temperature: 75 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
A mixture of 4-chloro-3-nitropyridine (0.704 g, 4.44 mmol) and tert-butyl [(3S,5R)-5-methylpiperidin-3-yl]carbamate (1.0 g, 4.7 mmol) in isopropyl alcohol (8.7 mL) was stirred at 75° C. overnight. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with water and extracted with EtOAc. The organic extracts were combined and evaporated under reduced pressure. The residue was purified by flash chromatography on 40 g silica gel, eluting with 0-90% EtOAc in hexanes, to give the sub-title compound as a yellow solid (1.14 g, 76.2%). LCMS calc. for C16H25N4O4 (M+H)+: m/z=337.2. found: 337.3.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[S:12][C:11]2=[N:13][CH:14]=[C:15]([I:16])[N:10]2[N:9]=1.[NH2:17][C:18]1[CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:22][C:23]=1[O:24][CH3:25]>O1CCOCC1>[I:16][C:15]1[N:10]2[C:11]([S:12][C:8]([C:20]3[CH:19]=[C:18]([NH2:17])[C:23]([O:24][CH3:25])=[N:22][CH:21]=3)=[N:9]2)=[N:13][CH:14]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: Brc1nn2c(I)cnc2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ncc(-c2nn3c(I)cnc3s2)cc1N
Yield: 66.3 %

Procedure:
Dioxane (5 mL) and 2M aq Na2CO3 (1.5 mL) were added to 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (200 mg) and (5-amino-6-methoxypyridin-3-yl)boronic acid pinacol ester (200 mg), and the suspension was degassed under vacuum and filled with argon (3×). PdCl2(PPh3)2 (90 mg) was quickly added, and the reaction mixture was stirred at reflux for 2 h. Water was added, and a precipitate formed that was filtered off and washed with water followed by ether and ether/MeOH 10:1 and dried to give the desired product (150 mg) that was used without further purification in the subsequent step. HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.12 min, [M+H]+ m/z 373.9.
Reaction SMILES: C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.COB(OC)OC.[C:30]1([CH2:40][O:41][C:42](=[O:46])[NH:43][CH:44]=[CH2:45])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.[CH:47](=[N:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=1)[CH2:48][CH3:49].ClCCl.[OH-].[Na+]>ClCCl.C1(C)C=CC=CC=1.[B]>[C:30]1([CH2:40][O:41][C:42](=[O:46])[NH:43][C@@H:44]2[C:52]3[C:51](=[CH:56][CH:55]=[C:54]([C:57]([F:58])([F:59])[F:60])[CH:53]=3)[NH:50][C@H:47]([CH2:48][CH3:49])[CH2:45]2)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: C=CNC(=O)OCc1cccc2ccccc12
Reactant: CCC=Nc1ccc(C(F)(F)F)cc1
Agent: COB(OC)OC
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Agent: [B]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC[C@@H]1C[C@H](NC(=O)OCc2cccc3ccccc23)c2cc(C(F)(F)F)ccc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flask equipped with a Soxhlet extractor containing 4 Å molecular sieves (pellets), (R)-binaphthol (716 mg) dissolved in dichloromethane (35 ml) was added. To the solution, was added trimethoxyborane (279 μl) and the mixture was heated to reflux under nitrogen atmosphere for 2 hours. The solution was concentrated under nitrogen atmosphere, and the resulting residue was dissolved in dichloromethane to give a dichloromethane solution of a chiral boron catalyst (8.0 ml). Vinyl-carbamic acid naphthalen-1-ylmethyl ester (227 mg) was dissolved in a mixture of toluene (2.5 ml) and dichloromethane (1.5 ml) and a 0.4M propylidene-(4-trifluoromethyl-phenyl)-amine/dichloromethane solution (2.75 ml) was added. Thereto was added the dichloromethane solution of a chiral boron catalyst prepared above (1.6 ml) dropwise under nitrogen atmosphere at 0° C. over 30 minutes. The mixture was stirred at the same temperature for 2 hours, then allowed to warm to room temperature, and the stirring was continued overnight. To the reaction mixture, was added a 0.5N NaOH aq. solution and extracted with ether. The organic layer was washed with a saturated brine twice, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=19:1→7:3) to give the titled compound (331 mg). MS (m/z): 429 [M+H]+. Enantioselectivity was 96% ee determined by HPLC using CHIRALPAK IB (DAICEL CHEMICAL INDUSTRIES, LTD.), hexane:ethanol=9:1, flow rate=5 ml/min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[C:4]([N+:14]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[C:4]([CH:3]=1)[NH2:14]
Reactant: [H][H]
Reactant: CCCS(=O)(=O)c1ccc(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCCS(=O)(=O)c1ccc(C)cc1N
Yield: 93.8 %

Procedure:
A solution of 4-methyl-2-nitro-1-(propylsulfonyl)benzene (Intermediate 227; 11 g, 45 mmol) in methanol (150 ml) was treated with Pd/C (1.1 g) and the reaction mixture was stirred under 3 Kg/cm2 pressure of hydrogen at RT for 5 h. The catalyst was filtered through celite and the solvent was removed under reduced pressure to afford the title compound (9 g, 94%) as pale yellow liquid.