Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:9][CH2:10][CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>C1C=CC=CC=1>[C:19]([O:12][CH2:11][CH2:10][S:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCCCCCCSCCO
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C=C(C)C(=O)OCCSCCCCCCCC
Temperature: 5 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
2(n-Octylthio)ethanol (13.10 grams, 0.0688 mole) and anhydrous pyridine (65.5 grams) were charged to a three-necked flask fitted with a condenser protected with a drying tube, dropping funnel, thermometer and magnetic stirrer. The solution was cooled to 5° C., and methacrylyl chloride (7.20 grams, 0.0688 mole) was then added dropwise over a 26-minute period. The reaction solution was maintained at 9°-11° C. throughout the addition period, and then at 25° C. for another three hours with stirring. The reaction mixture was then diluted with 150 ml of benzene, and the pyridine hydrochloride present was removed by filtration. The filtrate was washed twice with dilute hydrochloric acid, then with water until neutral and finally dried over anhydrous sodium sulfate. The benzene solvent was stripped off leaving 13.1 grams of crude product which was purified by vacuum distillation to yield 11.8 grams of the desired ester with a boiling point of 111°-124° C./0.07 mm in a yield of 66%.
Reaction SMILES: [CH3:1][N:2]1[CH:9]([CH3:10])[CH2:8][CH:7]2[CH:3]1[CH2:4][N:5](C(OCC)=O)[CH2:6]2.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH3:1][N:2]1[CH:9]([CH3:10])[CH2:8][CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2CC(C)N(C)C2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1CC2CNCC2N1C

Procedure:
7.25 g (34.2 mmol) of ethyl 2,3-dimethyl-2,7diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux overnight with 50 ml of concentrated hydrochloric acid. The mixture is rendered alkaline with potassium carbonate and extracted ten times using 50 ml of chloroform each time, the extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH3:11].[Br:12]NC(=O)CCC(N)=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][Br:12]
Reactant: COc1cc(C)c(Br)c(C)c1
Reactant: NC(=O)CCC(=O)NBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)c(Br)c(CBr)c1
Temperature: 75 °C
Yield: 92 %

Procedure:
A solution of 2-bromo-5-methoxy-1,3-dimethyl-benzene ((Example 192: step a) 1.01 g, 4.70 mmol) in CCl4 (50 mL) was treated with N-bromosuccinamide and AIBN (catalytic amount) and heated to 75° C. 3.5 h. The reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the product 2-bromo-1-bromomethyl-5-methoxy-3-methyl-benzene (1.27 g, 92%) as a pale orange solid. 1H NMR (CDCl3): δ 6.641 (s, 2H), 4.601 (s, 2H), 3.760 (s, 3H), 2.380 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1[S:4][C@H:5]2[O:11][C@H:10]([C@H:12](O)[CH3:13])[C@@H:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C@H:8]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C@H:6]2[N:7]=1.CCN(S(F)(F)[F:42])CC>ClCCl>[F:42][C@H:12]([C@H:10]1[O:11][C@H:5]2[C@H:6]([N:7]=[C:3]([N:2]([CH3:35])[CH3:1])[S:4]2)[C@@H:8]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C@@H:9]1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH3:13]
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(CO[C@H]2[C@H](OCc3ccc(OC)cc3)[C@H]3N=C(N(C)C)S[C@H]3O[C@@H]2[C@@H](C)O)cc1
Solvent: ClCCl
Product: COc1ccc(CO[C@H]2[C@H](OCc3ccc(OC)cc3)[C@H]3N=C(N(C)C)S[C@H]3O[C@@H]2[C@H](C)F)cc1
Yield: 84.9 %

Procedure:
A solution of (R)-1-((3aR,5R,6S,7R,7aR)-2-(dimethylamino)-6,7-bis(4-methoxybenzyloxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)ethanol (280 mg, 0.56 mmol) in dichloromethane (10 mL) was treated with DAST (900 mg, 5.59 mmol) at −78° C. for 10 min and at 0° C. for 1 hr. The reaction was quenched by sat. aqueous Na2CO3 solution (30 mL), and extracted with dichloromethane (2×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue, which was purified by silica gel column, eluted with 1-2% methanol in dichloromethane to give compound 50 as a yellow syrup (240 mg, 85%). (ES, m/z): [M+H]+ 505.0; 1H NMR (300 MHz, CDCl3) δ 7.22-7.43 (m, 4H), 6.83-6.94 (m, 4H), 6.38-6.50 (m, 1H), 4.58-4.78 (m, 6H), 3.75-3.90 (m, 8H), 3.46-3.50 (m, 1H), 3.05-3.18 (m, 6H), 1.27-1.36 (m, 3H).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH:47]([CH3:49])[CH3:48])[CH3:46])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH:47]([CH3:49])[CH3:48])[CH3:46])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:17]2[CH:18]=[C:19]([OH:24])[CH:20]=[CH:21][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC(C)N(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)C(C)C)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 49.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-isopropyl-N-methylacetamide (8.1 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.4 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C1C=NC2N(O)N=NC=2C=1.Cl.C(N=C=NCCCN(C)C)C.[NH2:49][C:50]1[CH:59]=[C:58]2[C:53]([CH2:54][CH2:55][N:56]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:57]2)=[CH:52][CH:51]=1>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:49][C:50]3[CH:59]=[C:58]4[C:53]([CH2:54][CH2:55][N:56]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:57]4)=[CH:52][CH:51]=3)=[O:20])=[CH:21][CH:22]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2C1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc5c(c4)CN(C(=O)OC(C)(C)C)CC5)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a stirred solution of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (86 mg, 0.24 mmol) in N,N-dimethylformamide (0.5 mL) at ambient temperature was added a 0.6M solution of 7-aza-1-hydroxybenzotriazole in N,N-dimethylformamide (0.5 mL, 0.30 mmol), followed by solid 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (51 mg, 0.27 mmol). The resulting solution was stirred at ambient temperature for 1 hour. A solution of tert-butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (66 mg, 0.27 mmol) in N,N-dimethylformamide (0.5 mL) was added. The resulting solution was stirred in an oil bath set to 50° C. for 21 hours. The solution was cooled to ambient temperature and diluted with water (15 mL). After stirring for a few minutes, the resulting precipitate was collected by filtration, washed with water, and dried under vacuum. This crude solid was purified by chromatography on silica gel, eluting with 50/50 hexanes/ethyl acetate, to afford tert-butyl 7-(4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate as an orange oil (84 mg, 59% yield).
Reaction SMILES: [NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:23])[C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19](OC)=O)[CH2:15][CH2:14]2)=[N:11][CH:12]=1)=[O:5])[NH2:2].NC1C=CC([C@H]2CC[C@H](C(C)(C)[C:39]([O:41][CH3:42])=[O:40])CC2)=CC=1>>[NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:23])[C:10]([N:13]2[CH2:14][CH2:15][CH:16]([CH2:19][C:39]([O:41][CH3:42])=[O:40])[CH2:17][CH2:18]2)=[N:11][CH:12]=1)=[O:5])[NH2:2]
Reactant: COC(=O)C1CCN(c2ncc(NC(=O)C(=O)NN)cc2C)CC1
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Product: COC(=O)CC1CCN(c2ncc(NC(=O)C(=O)NN)cc2C)CC1

Procedure:
Prepared following the method of Intermediate 111 part iv). 1H NMR δ 1.23-1.44 (m, 2H), 1.66-1.79 (m, 2H), 1.77-1.93 (m, 1H), 2.16 (s, 3H), 2.30 (d, 2H), 2.59-2.76 (m, 2H), 3.22-3.40 (m, 2H), 3.56 (s, 3H), 4.52 (s, 2H), 7.88 (d, 1H), 8.46 (d, 1H), 10.14 (s, 1H), 10.51 (s, 1H). MS m/e MH+ 350.21.
Reaction SMILES: [C:1]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=2)[CH:13]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[K+].O.NN.O>C(O)COCCO>[CH2:1]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCCCCCCCc1ccc2cc(O)ccc2c1
Yield: 85.5 %

Procedure:
Under a nitrogen atmosphere, 2-decanoyl-6-methoxynaphthalene (9.4 g, 30 mmol) and potassium hydroxide (67 g, 1.2 mol) were dissolved in hydrazine monohydrate (70 ml, 1.4 mol) and diethylene glycol (200 ml). The solution was refluxed for 17 hours, and water (36 ml) was added. Under a stream of nitrogen, the solution was distilled to distill away an excessive amount of hydrazine and water. Further, the solution was refluxed under a nitrogen atmosphere for 41 hours. Subsequently, while using an ice bath, the solution was cooled by putting ice into the reaction solution, hydrochloric acid was slowly added until the solution became neutral. The reaction solution was extracted with ether (100 ml×3), and the obtained organic layer was washed with saturated saline water (100 ml×5). The organic layer was dried with anhydrous magnesium sulfate, and filtered. Then, the solvent was distilled away under reduced pressure. The obtained brown solid was recrystallized from hexane to obtain 6-decyl-2-hydroxynaphthalene (7.3 g, 90%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[C:11](OCC)=[O:12].[NH3:25]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[C:11]([NH2:25])=[O:12]
Reactant: CCOC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: N
Solvent: CCO
Product: NC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In 30 ml of ethanol was dissolved 3.0 g of ethyl 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate. To the resulting solution was added 6 ml of concentrated aqueous ammonia. The resulting mixture was subjected to reaction at 20°-25° C. for 5 hours. Then, the solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: chloroform/methanol=20/1) to obtain 2.1 g of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]([CH3:29])[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]([CH:22]=1)=[N:20][C:19]1[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:18]=1)[CH:13]=2.[N+]([O-])([O-])=O.[Co+2:34].[N+]([O-])([O-])=O>C(O)C>[CH3:4][N:5]([CH3:29])[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]([CH:22]=1)=[N:20][C:19]1[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:18]=1)[CH:13]=2.[Co:34]
Reactant: [Co+2]
Agent: CN(C)CCOc1ccc2cc3ccc(OCCN(C)C)cc3nc2c1
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: [Co]

Procedure:
A suspension of 3,6-bis(2-dimethylaminoethoxy)acridine trihydrochloride and one equivalent of cobalt nitrate in ethanol is refluxed for 2 hours. The solid is collected giving the desired 1:1 complex.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([NH:36][C:37]1[CH:46]=[CH:45][C:40]([O:41][CH2:42][CH2:43]Cl)=[CH:39][CH:38]=1)(=[O:35])[CH3:34]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][N:25]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:43][CH2:42][O:41][C:40]2[CH:45]=[CH:46][C:37]([NH:36][C:33](=[O:35])[CH3:34])=[CH:38][CH:39]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: CC(=O)Nc1ccc(OCCCl)cc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OCCN(CCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)Cc2ccccc2)cc1

Procedure:
A mixture of N-2-(3,4-dibenzyloxyphenyl)ethyl benzylamine (12.0 g.), 2-(4-acetamidophenoxy)ethyl chloride (3.1 g.) and dry dimethylformamide (10 ml.) was boiled under reflux for 10 hours. The solution was cooled, more dimethylformamide (15 ml.) added, and the precipitated solid removed by filtration. The filtrate was evaporated in vacuo to dryness and the resultant solid stirred in chloroform, after which undissolved material was removed by filtration and the filtrate was evaporated in vacuo to dryness to give the crude product, N-[2-(3,4-dibenzyloxyphenyl)ethyl]-N-[2-(4-acetamidophenoxy) ethyl]benzylamine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:15]#[N:16].[Na+]>CN(C)C=O.O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:15]#[N:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClCC1CCCN1Cc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCC1CCCN1Cc1ccccc1
Temperature: 25 °C

Procedure:
Into a 3,000 ml 3-necked roundbottom flask, was placed a solution of 1-benzyl-2-(chloromethyl)pyrrolidine (150. g, 714 mmol) in N,N-dimethylformamide (1,500 ml). This was followed by the addition of a solution of NaCN (54.2 g, 834 mmol) in water (300 ml). The resulting solution was heated to reflux for 2 hours. After cooling to ambient temperature, the solution was dissolved in 6,000 ml of water. The resulting solution was extracted with ethyl acetate (3×3,000 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (ethylacetate/petroleum ether gradient) to afford 2-(1-benzylpyrrolidin-2-yl)acetonitrile.
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C:17](=[CH2:28])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.[OH2:40].C([O-])(O)=O.[Na+]>CC(C)=O>[CH2:28]=[C:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:40])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 87 %

Procedure:
A solution of 3,3:17,17-bis(ethylendioxy)-6-methyleneandrostane (1.05 g) and pTSA.H2O (2.46 g) in acetone (105 mL) was stirred at room temperature for 3 h. The solution was neutralized by addition of 5% aqueous NaHCO3 and acetone was evaporated. The aqueous suspension was extracted with CH2Cl2 (3×). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness to give the title compound II-ac in 87% yield. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.85 (1H, m), 4.50 (1H, m), 2.63-1.02 (20H, m), 0.92 (3H, s), 0.86 (3H, s).
Reaction SMILES: C(OC([N:11]1[CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.C(O)(=O)C>C(O)C.[Pd]>[CH2:12]1[C:13]2[NH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH2:22][CH:23]([C:24]([NH2:26])=[O:25])[NH:11]1
Reactant: NC(=O)C1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=O)C1Cc2c([nH]c3ccccc23)CN1
Yield: 79.5 %

Procedure:
(3RS)-2-Benzyloxycarbonyl-1,2,3,4-tetrahydro-β-carboline-3-carboxamide (2.47 g) is dissolved in ethanol (350 ml) and thereto are added acetic acid (0.02 ml) and 10% Pd-C (1.0 g). The mixture is subjected to catalytic reduction under atmospheric pressure. After the reaction, the catalyst is removed by filtration and washed with ethanol. The filtrate and the washing liquid are combined and distilled to remove the solvent. The residue is crystallized from ether to give the title compound (1.21 g, 79%), m.p. 212°-216° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:27][CH2:28]N(C(C)C)C(C)C.ICC.C(#N)C>CN(C=O)C.CO.CS(C)=O>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH2:27][CH3:28]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCI
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3CC)c2n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 6.9 %

Procedure:
A portion of this solution (0.12 ml, equivalent to 0.12 mmol) was added to a test tube. 2-(Butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine (435 mg, 1.2 mmol) was dissolved in DMF (6.0 ml) and an aliquot (0.5 ml, 0.1 mmole) dispensed to the tube. DIPEA (40 μL, 0.23 mmol) was added, and heated to 50° C. for 18 hours. An additional aliquot of 1-iodoethane in acetonitrile (80 uL, 0.08 mmol) (total added 0.2 mmol) and DIPEA (40 uL, 0.23 mmol) was added and continued stirring with heat at 50° C. for a further 18 hours. DMSO:MeOH (200 uL) was added, the mixture filtered and purified by Mass Directed AutoPrep (Method A). The solvent was evaporated in vacuo using the Genevac. The residue was redissolved in a solution of 4M HCl/dioxane (0.2 ml) and allowed to stand at room temperature for 4 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The material was redissolved in methanol (0.5 ml) and applied to an aminopropyl SPE (0.1 g, 3 ml, preconditioned in methanol (1.5 ml)). The product was eluted with additonal methanol (1.5 ml). The solvent was removed to give the title compound (6 mg).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15](OCC)=[O:16])[C:3]([F:6])([F:5])[F:4].C1COCC1.C([Mg]Cl)(C)C>[NH4+].[Cl-].CCOC(C)=O>[CH3:12][C:9]1[C:8]2[C:13]3[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=3[C:15](=[O:16])[NH:1][CH:2]([C:3]([F:6])([F:5])[F:4])[C:7]=2[O:11][N:10]=1
Reactant: CCOC(=O)c1ccccc1-c1c(C)noc1[C@H](N)C(F)(F)F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1noc2c1-c1ccccc1C(=O)NC2C(F)(F)F
Temperature: -40 °C
Yield: 80.7 %

Procedure:
To a round bottomed flask was added ethyl 2-(5-((S)-1-amino-2,2,2-trifluoroethyl)-3-methylisoxazol-4-yl)benzoate (124.2 mg, 0.378 mmol) and THF (2 mL) before the solution was cooled to −40° C. To this solution was added isopropylmagnesium chloride (473 μl, 0.946 mmol) and the reaction warmed to room temperature. The solution was diluted with NH4Cl solution and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford the titled compound (86 mg, 0.305 mmol). LC/MS m/z 283 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[CH2:9][CH2:10][C:11](Cl)=[O:12])[CH:3]=[CH2:4].C(Cl)Cl.[OH:20][CH:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C>CCOCC>[CH2:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[CH2:9][CH2:10][C:11]([O:20][CH:21]([C:22]([O:24][CH3:25])=[O:23])[CH2:26][CH3:27])=[O:12])[CH:3]=[CH2:4]
Reactant: C=CCNc1cccc(CCC(=O)Cl)c1
Reactant: CCC(O)C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCNc1cccc(CCC(=O)OC(CC)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g. 3-(allylamino)hydrocinnamoyl chloride hydrochloride in 200 ml. methylene chloride is added dropwise a solution of 3 g. methyl 2-hydroxybutyrate and 5 g. triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield 1-(methoxycarbonyl)propyl 3-(allylamino)hydrocinnamate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]O)=[CH:17][CH:16]=1.S(Cl)([Cl:25])=O>C1(C)C=CC=CC=1>[Cl:25][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol (5.00 g) in toluene (40 ml), thionyl chloride (1.85 ml) was added and the mixture was stirred for 30 minutes at room temperature. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated to obtain 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (5.23 g, yield 99%) as crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals. m.p. 108-109° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: CCOC(=O)CCCN
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 5 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A suspension of 4-chloro-3-nitro[1,5]naphthyridine (10.0 g, 47.7 mmol) and ethyl 4-aminobutyrate hydrochloride (9.6 g, 57 mmol) in dichloromethane (200 mL) was cooled to 5° C. Triethylamine (16.6 mL, 119 mmol) was added, and the reaction was allowed to warm to ambient temperature and stirred for two hours. The mixture was diluted with dichloromethane (200 mL) and washed with saturated aqueous sodium bicarbonate (2×150 mL). The combined aqueous fractions were extracted with dichloromethane (100 mL), and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 14.5 g of ethyl 4-(3-nitro[1,5]naphthyridin-4-ylamino)butanoate as a yellow solid.