Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[C:13]([C:18]#[CH:19])[NH:12]4)[CH2:5][C@H:4]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:3]1.C(N(CC)CC)C.I[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1>CN(C)C=O.[Cu]I>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[C:13]([C:18]#[C:19][C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[NH:12]4)[CH2:5][C@H:4]([NH:20][C:21](=[O:27])[N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])[CH2:3]1
Reactant: Ic1cccs1
Reactant: C#Cc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C[C@H](NC(=O)N(CC)CC)CN1C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C#Cc5cccs5)c(c34)C[C@H]2N(C)C1

Procedure:
Under argon, 72 mg of 3-(6-methyl-2-ethynyl-8α-ergolinyl)-1,1-diethylurea is heated in 2 ml of dimethylformamide with 2 ml of triethylamine, 1.5 mg of copper(I) iodide, 0.069 ml of 2-iodothiophene, and 4.8 mg of palladium(O) tetrakis(triphenylphosphine) for 2 hours to 80° C. After evaporation, the mixture is taken up in ethyl acetate and washed in succession with dilute ammonia solution and saturated sodium chloride solution. After chromatography over silica gel with ethyl acetate:ethanol=1:1 and recrystallization from ethanol/hexane, 26 mg of 3-[6-methyl-2-(thien-2-ylethynyl)-8α-ergolinyl]-1,1diethylurea is obtained, mp 252°-256° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14](OS(C(F)(F)F)(=O)=O)=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:26])[C:9]=2[C@H:27]([OH:33])[C:28]([O:30]CC)=[O:29])=[CH:4][CH:3]=1.[BH4-].[Na+].BrC1C=[C:45]2[C:40]([CH:41]=C(C)C(C(=O)C(OCC)=O)=C2C2C=CC(Cl)=CC=2)=[CH:39]C=1.[C:62]([C:64]1([NH2:70])[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1)#[CH:63]>>[NH2:70][C:64]1([C:62]#[C:63][C:15]2[CH:16]=[C:17]3[C:12]([CH:11]=[C:10]([CH3:26])[C:9]([C@H:27]([O:33][C:40]([CH3:45])([CH3:41])[CH3:39])[C:28]([OH:30])=[O:29])=[C:8]3[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:13][CH:14]=2)[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1
Reactant: CCOC(=O)[C@@H](O)c1c(C)cc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1-c1ccc(Cl)cc1
Reactant: C#CC1(N)CCCCC1
Reactant: CCOC(=O)C(=O)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cc2ccc(C#CC3(N)CCCCC3)cc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-(7-((1-Aminocyclohexyl)ethynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (100) was prepared by the method of Example 67 using the reduction method of Example 51 step 3 for (S)-ethyl 2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-hydroxyacetate instead of step 5, NaBH4 step, from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate. The remainder of the sequence follows the method of Example 67 using 1-ethynylcyclohexanamine in Step 7. 1H-NMR: 400 MHz, (CD3OD) δ: 7.82 (d, J=8 Hz, 1H), 7.72 (s, 1H), 7.56 (m, 3H), 7.47 (d, J=8 Hz, 1H), 7.37 (s, 1H), 7.31 (d, J=8 Hz, 1H), 5.20 (s, 1H), 2.60 (s, 3H), 2.11 (m, 2H), 1.63-1.85 (m, 8H), 0.99 (s, 9H). LCMS-ESI+ (m/z): [M—NH2]+ calcd for C31H32ClO3: 487.2; found: 487.2.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([Cl:24])=[O:23])#[N:18]>>[ClH:24].[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[C:19]([C:17]#[N:18])[CH:20]=3)=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1
Product: Cl
Product: N#Cc1cccc(C(=O)Nc2ccc(N3CCN4CCC3CC4)cc2)c1

Procedure:
Was prepared by Method G from 4-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-phenylamine and 3-cyanobenzoyl chloride. Mp. 250° C. (decomp.).
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[CH:9](C=C)=O.C1CC=CC=1>>[CH:5]12[CH2:9][CH:2]([CH:1]([CH:7]=[O:8])[CH2:6]1)[CH:3]=[CH:4]2
Reactant: O=CC1CC=CCC1
Reactant: C=CC=O
Agent: C1=CCC=C1
Product: O=CC1CC2C=CC1C2

Procedure:
Examples of suitable cyclic polyaldehydes are trans-1,3-cyclohexanedicarboxaldehyde; cis-1,3-cyclohexanedicarboxaldehyde; trans-1,4-cyclohexanedicarboxaldehyde; cis-1,4-cyclohexanedicarboxaldehyde; a mixture of 1,3-cyclohexanedicarboxaldehydes and 1,4-cyclohexanedicarboxaldehydes, preferably a 1-to-1 mixture thereof; exo,exo-2,5-norbornanedicarboxaldehyde; exo,exo-2,6-norbornanedicarboxaldehyde; exo,endo-2,5-norbornanedicarboxaldehyde; exo,endo-2,6-norbornanedicarboxaldehyde; endo,endo-2,5-norbornanedicarboxaldehyde; endo,endo-2,6-norbornanedicarboxaldehyde product (endo and exo mixture); 3-(3-formylcyclohexyl)propanal; 3-(4-formylcyclohexyl)propanal; 2-(3-formylcyclohexyl)propanal; 2-(4-formylcyclohexyl)propanal; and cyclododecane-1,4,8-tricarbaldehyde. The trans-1,3-cyclohexanedicarboxaldehyde; cis-1,3-cyclohexanedicarboxaldehyde; trans-1,4-cyclohexanedicarboxaldehyde; and cis-1,4-cyclohexanedicarboxaldehyde can be prepared by a process comprising hydroformylating 3-cyclohexene-1-carboxaldehyde using the hydroformylating conditions described later. The 1:1 mixture of 1,3- and 1,4-cyclohexanedicarboxaldehydes can be prepared by a process comprising reacting acrolein and 1,3-butadiene in a Diels-Alder reaction to give 3-cyclohexenecarboxaldehyde (also called 1,2,3,6-tetrahydrobenzaldehyde), and hydroformylating the 3-cyclohexenecarboxaldehyde. The exo,exo-2,5-norbornanedicarboxaldehyde; exo,exo-2,6-norbornanedicarboxaldehyde; exo,endo-2,5-norbornanedicarboxaldehyde; exo,endo-2,6-norbornanedicarboxaldehyde; endo,endo-2,5-norbornanedicarboxaldehyde; and endo,endo-2,6-norbornanedicarboxaldehyde product (endo and exo mixture) can be prepared by a process comprising reacting acrolein and cyclopentadiene in a Diels-Alder reaction to give a 2-norbornene-5-carboxaldehyde, and hydroformylating the 2-norbornene-5-carboxaldehyde. The 3-(3-formylcyclohexyl)propanal; 3-(4-formylcyclohexyl)propanal; 2-(3-formylcyclohexyl)propanal; and 2-(4-formylcyclohexyl)propanal can be prepared by a process comprising hydroformylating vinyl cyclohexene. The cyclododecane-1,4,8-tricarbaldehyde can be prepared by a process comprising trimerizing 1,3-butadiene to give 1,4,8-cyclododecatriene, and hydroformylating the 1,4,8-cyclododecatriene.
Reaction SMILES: C1([N:7]([C@H:21]2[CH2:26][CH2:25][C@H:24](COC3C=CC=CC=3)[CH2:23][CH2:22]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16]C(O)=O)=[CH:13][N:14]=2)CCCCC1.C1(N[C@H:42]2[CH2:47][CH2:46][C@H:45]([CH2:48][O:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:44][CH2:43]2)CCCCC1.C([O:58][C:59](=[O:69])[CH:60](SC1SC(N)=NC=1)C)C>>[CH:21]1([N:7]([C@H:42]2[CH2:43][CH2:44][C@H:45]([CH2:48][O:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:46][CH2:47]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][CH2:60][C:59]([OH:69])=[O:58])=[CH:13][N:14]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(O)CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](COc3ccccc3)CC2)s1
Reactant: CCOC(=O)C(C)Sc1cnc(N)s1
Reactant: c1ccc(OC[C@H]2CC[C@H](NC3CCCCC3)CC2)cc1
Product: O=C(O)CCSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](COc3ccccc3)CC2)s1

Procedure:
Prepared in an similar manner to {2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclohexyl-(trans-4-phenoxymethyl-cyclohexyl)-amine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][CH:16]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[C@H:2]([C:4]([NH:6][C@H:7]([C:9](O)=[O:10])[CH3:8])=[O:5])[CH3:3].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][OH:37])=[CH:32][CH:31]=1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C1COCC1.CC(O)C.C(OCC)(=O)C>[CH:18]1[C:17]2[CH:16]([CH2:15][O:14][C:12](=[O:13])[NH:1][C@H:2]([C:4](=[O:5])[NH:6][C@H:7]([C:9](=[O:10])[NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][OH:37])=[CH:32][CH:31]=3)[CH3:8])[CH3:3])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Nc1ccc(CO)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)Nc1ccc(CO)cc1
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of Fmoc-Ala-Ala-OH (1 g, 2.61 mmol, Eq: 1.00) and (4-aminophenyl)methanol (483 mg, 3.92 mmol, Eq: 1.5) in THF (20 ml) was treated with EEDQ (970 mg, 3.92 mmol, Eq: 1.5). The solution was stirred over night at room temperature. The mixture was diluted with 10% 2-propanol/ethyl acetate (100 mL) and the solution was washed with KHSO4 5%/K2SO4 10% (2×), water (1×) and brine (1×), dried over MgSO4 and evaporated in vacuo. The residue was sonicated in diethyl ether for several minutes and the solid was collected by filtration to obtain the product (1.27 g, 1.2 mmol) as light brown solid. MS (ISP): (M+H) 488.3.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>C(OCC)(=O)C.O>[CH3:16][S:17]([O:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4]1)(=[O:19])=[O:18]
Reactant: C[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)O[C@H]1CC[C@H](C)CC1

Procedure:
To a solution of trans-4-methylcyclohexanol (4.55 g) in ethyl acetate (50 ml) were added successively triethylamine (7.22 ml) and methanesulfonyl chloride (3.38 ml) with stirring under ice-water bath. The mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added ethyl acetate (50 ml), water (50 ml) and 1N hydrochloric acid (20 ml) with stirring. The organic layer was separated, washed successively with water, saturated aqueous sodium hydrogen carbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give trans-4-methylcyclohexyl methanesulfonate (8.36 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Na].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1>CN(C=O)C>[N+:8]([C:7]1[C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1-n1cncn1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A solution of 10 g of 2-chloro-3-nitropyridine dissolved in 30 ml of dry DMF was added dropwise to a suspension containing 6.9 g of 1,2,4-triazole sodium salt (90%, Aldrich Chemical Co.) in 40 ml of dry DMF. After a slow exotherm had subsided, the suspension was heated at 60° for three hours then cooled to 25° C. and poured onto 500 ml of ice-water to yield a precipitate. After the mixture was filtered, the isolated solid was washed 2×50 ml of water and suction-dried to yield 12 g of crude product. The product was recrystallized from 2-propanol to yield 8 g of the subject compound; m.p. 131°-133°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=4)[CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc(-c3c(C)nnn3-c3ccc(F)cc3)c2)nc1
Temperature: 120 °C
Yield: 38.5 %

Procedure:
A mixture of 1-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-4-methyl-1H-[1,2,3]triazole (500 mg, 2.06 mmol), methyl 6-chloronicotinate (353 mg, 2.06 mmol) and potassium carbonate (568 mg, 4.11 mmol) in DMF (10 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 16 h. After cooling to room temperature the mixture was poured into water (150 mL) and the solid that formed was filtered off and dried to afford the title compound (300 mg, 39%) as a light brown solid. MS: m/e=379.3 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>C(Cl)Cl>[Br:33][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)c1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
4-hydroxymethyl-benzene-sulphonamide (0.105 mg, 0.56 mmoles) was dissolved in DCM (5 mL). Polymer supported triphenylphosphine (294 mg, 2.4 mmoles/g, 1.12 mmoles) was added, and the mixture was stirred with a shaker at room temperature for 10 minutes. CBr4 (557 mg, 1.68 mmoles) was then added, and stirring was continued for 3 hours. The supported reagent was removed by filtration, the solvent was evaporated, and the crude material was purified by flash chromatography (SiO2, petroleum ether/AcOEt 9/1) to yield the title compound as a light-yellow solid (70 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.C[Si](C#N)(C)C.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]2[N:25]=[CH:26][NH:27][C:23]=2[CH:22]=1.C(N(CC)CC)C.[C:37](N1C=CN=C1)([N:39]1C=CN=[CH:40]1)=[O:38]>[Pd]>[NH:25]1[C:24]2[CH:28]=[CH:29][C:21]([N:20]3[CH:10]([C:9]4[CH:12]=[CH:13][C:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=4)[CH2:40][NH:39][C:37]3=[O:38])=[CH:22][C:23]=2[N:27]=[CH:26]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: COCCCc1ccc(C=O)cc1
Agent: [Pd]
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: COCCCc1ccc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized according to method 2 starting from 4-(3-methoxypropyl)benzaldehyde (1.5 g, 8.42 mmol), trimethyl silylcyanide (1.6 mL, 16.84 mmol), 5-amino benzimidazole (1.23 g, 9.26 mmol), 10% Pd—C (300 mg), triethylamine (5.8 mL, 41.97 mmol), 1,1′-carbonyldiimidazole (0.84 g, 5.24 mmol). Yield: 0.055 g (0.6%); MS m/z 293.4 (M+H)+; 1H NMR (DMSO, 400 MHz): δ 2.21 (s, 3H); 3.05-3.09 (m, H); 3.83-3.87 (m, H); 5.49-5.53 (m, H); 7.01-7.10 (m, 2H); 7.15 (d, H, J=7.9 Hz); 7.19 (s, H); 7.52-7.55 (m, H), 7.60 (d, H, J=8.7 Hz); 7.84 (s, H); 9.16 (s, H), HPLC (λ=214 nm, [B]: rt 8.05 min (100%).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:21][C@H:22]([CH2:26][CH3:27])[C:23]([NH2:25])=[O:24])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[NH2:25][C:23](=[O:24])[C@H:22]([NH:21][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[C:3]([C:1]([NH2:2])=[O:34])=[N:4][CH:5]=1)[CH2:26][CH3:27]
Reactant: CC[C@@H](Nc1cnc(C#N)c(Nc2ccc3c(c2)CCC(=O)N3)n1)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc3c(c2)CCC(=O)N3)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound (R)-2-(5-cyano-6-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)pyrazin-2-ylamino)butanamide (72 mg, 0.197 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (48 mg). MS 384.3 (M+H); UV 207.8, 308.9 nm; t 0.465 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:16])[CH3:15]>C(=S)=S>[CH2:1]([C:3]1[CH:8]=[C:7]([C:14](=[O:16])[CH3:15])[CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCc1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCc1cc(C(C)=O)ccc1O
Temperature: 25 °C
Yield: 52.9 %

Procedure:
To a stirred solution of 2-ethylphenol (13 g, 106.4 mmol) in carbon disulfide (30 ml) was added aluminum chloride (30 g, 225 mmol) portionwise at 0° C. Then, acetyl chloride (8.4 ml, 118.1 mmol) was added, and the mixture was heated at reflux temperature for 16 hours. The reaction mixture was cooled down to room temperature, and poured into ice. The whole was extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was recystallized with hexane-toluene to give title compound (9.24 g, 53% yield).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1([CH:19]([CH2:25][CH3:26])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Br:27][CH2:28][CH2:29][CH2:30]Br>CCCCCC.O1CCCC1>[Br:27][CH2:28][CH2:29][CH2:30][C:19]([CH2:25][CH3:26])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: CCC(CC(=O)OC)c1ccccc1
Reactant: BrCCCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC(CCCBr)(CC(=O)OC)c1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
15 g (0.081 mol) of n-butyl lithium as a 2.5-molar solution in hexane are added dropwise to a solution of 11.35 ml (0.081 mol) of diisopropylamine in 200 ml of anhydrous tetrahydrofuran at −30° C. and stirred for 10 minutes at −10° C. 14.4 g (0.081 mol) of methyl 2-phenylbutanecarboxylate are added dropwise at −76° C. and stirred for 30 minutes at this temperature. Then 8.62 ml (0.085 mol) of 1,3-dibromopropane are added, when the addition has ended the cooling bath is removed and the mixture is stirred for 14 hours at ambient temperature. The reaction solution is poured onto 1.2 l of water and extracted with diethylether. The organic phases are extracted with water, dried over sodium sulphate and the solvent is eliminated. The residue is distilled under high vacuum.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][CH:28]([NH:27][C:4]([C:6]2[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]3[C:15]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:5])[CH2:29][CH2:30]1
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nn1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CCOCC2)nn1
Yield: 73 %

Procedure:
As described for example 59, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using 4-aminotetrahydropyran instead of aminomethylcyclopropane, to the title compound (120 mg, 73%) which was obtained as a white solid after recrystallization from heptane:ethyl acetate. MS: m/e=413.3 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1.Cl.CC1CC[C@@H](C(C)=C)CC=1.N(Cl)=[O:23].CN(C)C=O>C(O)(C)C.N([O-])=O.[Na+]>[CH3:1][C:2]1[C:7](=[O:23])[CH2:6][C@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1
Reactant: C=C(C)[C@H]1CC=C(C)CC1
Reactant: O=NCl
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: C=C(C)[C@@H]1CC=C(C)C(=O)C1

Procedure:
Synthesis of the exemplary Formula VI terpene compound L-Carvone (2-cyclohexen-1-one, 2-methyl-5-(1-methylethenyl)-(R); Millenium Chemicals) from D-limonene is described in Ikan, Natural Products—A Laboratory Guide pp. 151-155 (Academic Press, 1969), incorporated herein by reference. Briefly, a solution of D-limonene in isopropanol is cooled to below 10° C. Solutions of HCl in isopropanol and concentrated aqueous sodium nitrite are added dropwise to the D-limonene solution to generate limonene nitrosochloride. The limonene nitrosochloride and dimethylformamide is refluxed with isopropanol. After cooling, crystallization is induced and the precipitate filtered and washed with water. The resulting L-carvoxime is refluxed with 0.5 M oxalic acid and the mixture is steam distilled. The distillate is extracted with ether, dried over anhydrous magnesium sulfate, and the excess ether evaporated to leave L-carvone.
Reaction SMILES: C([O:5]O)(C)(C)C.C(CC(C)(C)C)(C)C.[CH2:15]([OH:27])/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:18]([C@@H:17]1[O:5][C@H:16]1[CH2:15][OH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCC/C=C/CO
Reactant: CC(C)(C)OO
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: O
Solvent: CC(C)CC(C)(C)C
Product: CCCCCCCCC[C@@H]1O[C@H]1CO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 1.00 g of 4a powdered molecular sieves in 50 ml of dry CH2Cl2 was cooled to 0° C. under argon. To the cooled suspension was added 308 mg (1.09 mmole) of Ti(OiPr)4 and 356 mg (1.52 mmole) of L(+)diisopropyl tartrate via syringe. The mixture was stirred for 15 min and cooled to -20° C. A solution of tert-butyhydroperoxide in isooctane (3.8 M, 4.30 ml, 16.4 mmole) was added slowly to the mixture and the catalyst was allowed to "age" for 30 min at -20° C. A solution of 2.00 g (10.9 mmole) of E-2-dodecen-1-ol in 10 ml of CH2Cl2 was dried over 3A molecular sieves for 15 ml before being added to the mixture slowly, with stirring, at -20°. The solution was then placed in the freezer (-30° C.) and allowed to stand for 24 H. The mixture was warmed to 0° C. and poured into a solution of 1.00 g of citric acid and 3.50 g of FeSO4 in 15 ml H2O. The organic layer was separated and the acqueous layer washed twice with 20 ml of CH2Cl2. The CH2Cl2 layers were combined, dried over MgSO4, filtered and evaporated to yield a sticky white solid. Recrystallization from Et2O:petroleum ether afforded 1.98 g of white solid, mp 62-4° C. 1H NMR δ 3.92 (ddd, 1, J=2.5, 6, 12 Hz), 3.63 (ddd, 1, J=4, 7, 12 Hz), 2.95 (m, 2), 1.69 (dd, 1, J=7, 6 Hz), 1.6-1.2 (m, 16), 0.88 (t, 3, J=6 Hz). Mass Spectra: M-31(--CH2OH)(0.4)169, M(100)55.1.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[OH:23])[C:6]([C@H:8]2[C@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9]2)=[O:7])[CH2:3][CH2:2]1>C(#N)C.C(O)(C(F)(F)F)=O>[CH:1]1([CH2:4][N:5]2[C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[O:23][C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@@H:8]([OH:9])[C:6]2=[O:7])[CH2:2][CH2:3]1
Reactant: O=C([C@@H]1O[C@H]1c1ccccc1)N(CC1CC1)[C@@H]1CCCC[C@H]1O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C1[C@H](O)[C@H](c2ccccc2)O[C@@H]2CCCC[C@H]2N1CC1CC1
Yield: 80.9 %

Procedure:
A solution of (2R,3S)—N-(cyclopropylmethyl)-N-[(1R,2R)-2-hydroxycyclohexyl]-3-phenyloxirane-2-carboxamide (117b) (1.05 g, 3.33 mmol) in 125 mL acetonitrile/TFA (0.4%) was stirred for 6 hours. After evaporation the crude oil was purified by chromatography (CHCl3) to afford the title compound (850 mg, 81%). HPLC: 4.54 min (Method B). 1H NMR (300 MHz, CDCl3) δ0.37-0.44 (m, 2H), 0.49-0.57 (m, 2H), 0.85 (m, 1H), 1.03 (m, 1H), 1.14-1.50 (m, 2H), 1.66-1.80 (m, 2H), 1.83-2.02 (m, 1H), 2.03-2.16 (m, 2H), 3.32 (dd, 1H, J=7 Hz, J=14 Hz), 3.60 (in 1H), 3.74 (m, 1H), 3.85 (dd, 1H, J=7 Hz, J=14 Hz), 4.34 (m, 1H), 4.60 (m, 1H), 7.27-7.40 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].Cl.Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH:4]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:5]#[N:6]
Reactant: ClCCCN1CCCCC1
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#CC(CCCN1CCCCC1)c1ccc(Cl)cc1Cl

Procedure:
This intermediate (10 g.) was prepared using the procedure described in Example 14a except using 10.0 g. (0.054 mole) of 2,4-dichlorobenzyl cyanide, 11.0 g. (0.054 mole) of 1-(3-chloropropyl)piperidine hydrochloride, 11.0 g. (0.135 mole) of 50% aqueous sodium hydroxide, and 50 ml. of DMSO.