Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.[CH2:9](Br)[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:3]([CH2:9][CH2:10][CH3:11])[N:4]=[CH:5][C:6]=1[C:7]#[N:8]
Reactant: CCCBr
Reactant: N#Cc1c[nH]nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1ncc(C#N)c1N
Temperature: 80 °C

Procedure:
3-Amino-4-pyrazolecarbonitrile 1 (Acros, 3.24 g, 30.0 mmol), propylbromide (Acros, 4.43 g, 36 mmol) and anhydrous potassium carbonate (Fisher, 5.0 g, 36 mmol) were suspended in 20 mL anhydrous DMF and heated at 80° C. in a sealed tube under argon overnight. The reaction was permitted to cool and the DMF was removed on a rotary evaporator. Water was added (100 mL) and the organics were extracted with dichloromethane (3×100 mL). The combined dichloromethane fractions were washed with water (50 mL) and brine (50 mL) and were dried (magnesium sulfate). Concentration of the organics afforded an oil which was subjected to flash chromatography on silica gel (1-3% methanol/dichloromethane). Two white crystals were obtained: compound 101 (1.88 g, 42%) elutes first and compound 102 (711 mg, 16%) elutes second. Compound 101: mp 85-90° C.; MS (ES+ calculated: 150.18; found: 151.15 M+H). HPLC (99%) purity, retention time 5.8 minutes—Method A); 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 5.52 (s, 2H), 3.82 (t, J=7, 2H), 1.70 (m, 2H), 0.79 (t, J=7, 3H). Compound 102: mp 162-164° C.; MS (ES+ calculated: 150.18; found: 151.18 M+H). HPLC (95%) purity, retention time 6.4 minutes—Method A); 1H 1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H), 6.53 (s, 2H), 3.82 (t, J=7, 2H), 2.95 (m, 2H), 0.81 (t, J=7, 3H).
Reaction SMILES: CN(C)P(=O)(N(C)C)N(C)C.Br[C:13]1[C:14](=[O:24])[O:15][C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=2.[C:25]1([S:31][Si](C)(C)C)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[C:25]1([S:31][C:13]2[C:14](=[O:24])[O:15][C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=c1oc2ccccc2c(O)c1Br
Reactant: C[Si](C)(C)Sc1ccccc1
Solvent: CC#N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=c1oc2ccccc2c(O)c1Sc1ccccc1
Yield: 70.4 %

Procedure:
1 ml of hexamethylphosphoric triamide and 1.0 g (4.15 mmoles) of 3-bromo-4-hydroxycoumarin were added to a solution of 0.91 g (5.0 mmoles) of phenylthio(trimethyl)silane in 25 ml of dry acetonitrile. After refluxing for 1 hour, the mixture was evaporated and the residue was dissolved in 125 ml of ethyl acetate. The solution obtained was washed twice with 125 ml of water and the ethyl acetate layer was dried and evaporated to dryness. The solid residue was washed with 100 ml of heptane and then with three portions of 50% ethanol, was vacuum dried at 40° C. to obtain 0.79 g (70.5% yield) of 3-phenylthio-4-hydroxycoumarin melting at 186°-189° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl.Cl>[CH3:18][S:19]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: N#CCc1ccccc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccccc1CC#N
Temperature: 0 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To an ice-cold solution of 2-aminophenylacetonitrile (500 mg) in dichloromethane (20 ml) were added triethylamine (330 μl) and methanesulfonyl chloride (530 μl) and the mixture was stirred for 16 hours, under argon gas atmosphere. After confirming the completion of the reaction using TLC, the resulting mixture was diluted with 1 N aqueous hydrochloric acid solution (30 ml), and extracted with dichloromethane (50 ml×3). The organic layer was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by column-chromatography (ethyl acetate/hexane=1/2) to yield (2-methanesulfonylaminophenyl)acetonitrile (573 mg, 72%).
Reaction SMILES: [CH3:1][N:2]([CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[C:9](=O)[CH3:10])[N:3]=C(C)C.Cl>C(O)C.O>[CH3:1][N:2]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[C:9]([CH3:10])=[N:3]1
Reactant: CC(=O)C(=CN(C)N=C(C)C)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)c1cn(C)nc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-((1-methyl-2-(propan-2-ylidene)hydrazinyl)methylene)pentane-2,4-dione (Preparation 3, 9.1 g) was dissolved in Ethanol (20 mL) and treated with 1M Hydrogen chloride in Water (20 mL), the reaction solution was stirred at room temperature for 15 minutes. The reaction solution was then concentrated under vacuum with a rotavap to approximately 20 mL total volume. The reaction solution was then treated with saturated aqueous sodium bicarbonate (45 mL), and extracted with methylene chloride (4×50 mL) The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo afford the title compound as a light orange solid. (6.2 g, 97%).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.O=P(Cl)(Cl)[Cl:13].O[C:17]1[C:22]([Cl:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1>>[Cl:13][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Temperature: 120 °C

Procedure:
Quinoline (0.3 mL, 2.34 mmol) was added to POCl3 (0.5 mL 4.68 mmol) at 0° C. under nitrogen. To this stirred mixture was added 2-hydroxy-3-chloro-5-nitro pyridine (816 mg, 4.68 mmol) obtained in step i above. The reaction mixture was heated at 120° C. for 2 hours, cooled to 0° C. followed by addition of ice-cold water. The precipitate obtained was filtered, washed thoroughly with water and dried to obtain 2,3-dichloro-5-nitro pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=3[NH:10][C:9]2=[O:21])[CH:7]=1.[Br:23]Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([Br:23])[C:5]([OH:22])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:11]=3[NH:10][C:9]2=[O:21])[CH:7]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n1-c1cc(Cl)ccc1O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n1-c1cc(Cl)cc(Br)c1O
Reaction time: 0.33 h

Procedure:
A solution of 1,3-dihydro-1-(5-chloro-2-hydroxyphenyl)-5-trifluoromethyl-2H-benzimidazol-2-one (0.2 g, 0.6 mmol) in glacial acetic acid (5 ml) at room temperature was added bromine (45 μl, 0.9 mmol) and, after stirring for 20 minutes, the mixture was poured into water (25 ml). The crude product was collected by filtration, taken up in hot ethanol and precipitated by addition of water yielding the title compound as white crystals, M.p. 254°-255° C.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:23]=[CH:22][C:21]2[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[N+:11]([O-])=O.[OH-].[Na+].O>CCOC(C)=O>[NH2:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[N:2]([CH3:1])[C:14]1[CH:23]=[CH:22][C:21]2[C:20]([CH3:24])([CH3:25])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)[C:7]#[N:8]
Reactant: CN(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C#N)cc1N
Temperature: 80 °C

Procedure:
SnCl2-2H2O (0.17 mol) is added to a solution of 4-[methyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]-3-nitrobenzonitrile (31) (R4=CH3, 34.0 mmol) in EtOAc (125 mL) and the mixture is heated at 80° C. for 1 h. After cooling, to the reaction mixture are successively added 6N NaOH (120 mL), H2O (150 mL), and EtOAc (150 mL). The reaction mixture is filtered through Celite (25 g) and washed with EtOAc. The organic layer is dried over MgSO4 and evaporated in vacuo. The resulting solid is washed with hexane to give (32) (R4=CH3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[OH-].[K+].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>COCCOC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(C[C@H]3CCCN3C)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a stirred solution of (R)-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (10.0 g, 34.1 mmol) in ethyleneglycol dimethylether (50 ml) at 0° C. under a nitrogen atmosphere was added potassium hydroxide flake (9.58 g, 171 mmol) in one portion. Para-toluenesulfonyl chloride (6.83 g, 35.8 mmol) was then added portionwise to the brown slurry over a 5 min period, maintaining the temperature below 5° C. The brown slurry was then warmed to ambient temperature and stirred for a further 2 hr. The mixture was then filtered in vacuo and the filter cake washed with toluene (2×100 ml). The filtrate was then concentrated in vacuo to approximately 20 ml volume which resulted in precipitation of a cream solid. After stirring for 2 hr, the solid was filtered and dried in vacuo at 50° C. for 12 hr to give the title compound (9.91 g, 65%) as a beige solid. m.p. 98-104° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[BrH:11].[Br:12]CC(C1C=C(C)C=CN=1)=O>>[BrH:12].[Br:11][CH2:2][C:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: Cc1ccnc(C(=O)CBr)c1
Reactant: CC(=O)c1ncccc1C
Agent: Br
Product: Cc1cccnc1C(=O)CBr

Procedure:
* 2-Bromoacetyl-3-methylpyridine hydrobromide was prepared from 2-acetyl-3-methylpyridine (T. A. Crabb et al., Org. Magn. Reson., 1982, 20, 242) according to the procedure for preparing 2-bromoacetyl-4-methylpyridine hydrobromide described in step 2 of Example 31.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[CH3:24][C:25]1[O:29][C:28]([C:30]2([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:27][C:26]=1[CH2:37][CH2:38][O:39]S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:24][C:25]1[O:29][C:28]([C:30]2([CH3:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[N:27][C:26]=1[CH2:37][CH2:38][O:39][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH2:6][CH3:7])[C:4]([OH:23])=[O:3])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(CC)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Product: CCC(Cc1ccc(OCCc2nc(C3(C)CCCCC3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
The title compound was prepared from 2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethyl ester and toluene-4-sulfonic acid 2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using the method of Example 46. 1H NMR (400 MHz, CDCl3) δ 7.29 (dd, 2H, J=8.60 Hz, J=7.43 Hz), 7.07-7.03 (m, 1H), 7.02-6.96 (m, 4H), 6.72 (d, 2H, J=8.60 Hz), 4.10 (t, 2H, J=6.25 Hz), 2.38 (s, 2H), 2.95 (t, 2H, J=6.25 Hz), 2.29 (s, 3H), 2.15-2.01 (m, 4H), 1.56-1.36 (m, 8H), 1.30 (s, 3H), 0.91 (t, 3H, J=7.43 Hz); MS (ES+) calcd for C30H38NO5: Found m/e 492.3 (M+1, 100%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([CH2:9]Cl)=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].O>O1CCCC1>[Cl:2][C:3]1[C:8]([CH2:9][NH:20][CH2:19][CH2:17][OH:18])=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1
Reactant: ClCc1c(-c2ccccc2)ccnc1Cl
Reactant: NCCO
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: OCCNCc1c(-c2ccccc2)ccnc1Cl

Procedure:
To a suspension of 2-chloro-3-(chloromethyl)-4-phenylpyridine hydrochloride (12.6 g) obtained in Reference Example 2C in tetrahydrofuran (150 ml) was added ethanolamine (14 ml), and the mixture was heated under reflux for 6 hrs. After cooling the reaction solution, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (13.4 g) as a colorless oil.
Reaction SMILES: C[Al](C)C.CO[C:7](=[O:25])[CH2:8][C:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:13][CH:14]=1.[Br:26][C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1>ClC(Cl)C>[Br:26][C:27]1[C:28]([NH:33][C:7](=[O:25])[CH2:8][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:13][CH:14]=2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: Nc1ncccc1Br
Reactant: COC(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Al](C)C
Solvent: CC(Cl)Cl
Product: O=C(CC1=CCN(C(=O)OCc2ccccc2)CC1)Nc1ncccc1Br
Temperature: 55 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
Trimethylaluminum (0.91 g, 12.61 mmol) was added to a solution of benzyl 4-(2-methoxy-2-oxoethyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.43 g, 8.41 mmol) and 3-bromopyridin-2-amine (1.60 g, 9.25 mmol) in dichloroethane (45 mL) at 0° C. The reaction mixture was slowly warmed to 55° C. After 18 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (4×). The combined organic extracts were washed with Rochelle's salts (1N in water), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (50% hexanes/ethyl acetate→100% ethyl acetate) gave the title compound (1.91 g). MS 430.0 (M).
Reaction SMILES: COC1C=CC(C[NH:8][CH2:9][CH2:10][CH:11]([CH2:24][CH2:25][NH:26]CC2C=CC(OC)=CC=2)[CH2:12][CH2:13][NH:14]CC2C=CC(OC)=CC=2)=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH2:9][CH2:10][CH:11]([CH2:24][CH2:25][NH2:26])[CH2:12][CH2:13][NH2:14]
Reactant: COc1ccc(CNCCC(CCNCc2ccc(OC)cc2)CCNCc2ccc(OC)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NCCC(CCN)CCN
Reaction time: 5 h
Yield: 49.7 %

Procedure:
1,1,1-tris[2-(p-methoxybenzylamino)ethyl]methane (20.0 gram, 0.036 mol) was dissolved in methanol (100 ml) and Pd(OH)2 (5.0 gram) was added. The mixture was hydrogenated (3 bar, 100° C., in an autoclave) and stirred for 5 hours. Pd(OH)2 was added in two more portions (2×5 gram) after 10 and 15 hours respectively. The reaction mixture was filtered and the filtrate was washed with methanol. The combined organic phase was evaporated and the residue was distilled under vacuum (1×10−2, 110° C.) to give 2.60 gram (50%) of 1,1,1-tris(2-aminoethyl)methane.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](CC(=C)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.[CH2:29]1[CH2:53][O:52][C:31]2([CH2:36][CH2:35][C@H:34]3[C@H:37]4[C@H:47]([CH2:48][CH2:49][C@:32]23[CH3:33])[C@:45]2([CH3:46])[C@:40]([OH:51])([CH2:41][C:42](=O)[CH2:43][CH2:44]2)[CH2:39][CH2:38]4)[O:30]1>>[CH2:29]1[CH2:53][O:52][C:31]2([CH2:36][CH2:35][C@H:34]3[C@H:37]4[C@H:47]([CH2:48][CH2:49][C@:32]23[CH3:33])[C@:45]2([CH3:46])[C@:40]([OH:51])([CH2:41][C:42](=[CH2:1])[CH2:43][CH2:44]2)[CH2:39][CH2:38]4)[O:30]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@@]4(O)CC(=O)CC[C@]34C)[C@@H]1CCC21OCCO1
Product: C=C1CC[C@]2(C)[C@H]3CC[C@@]4(C)[C@@H](CCC45OCCO5)[C@@H]3CC[C@@]2(O)C1
Yield: 98 %

Procedure:
Following the procedure described above for the preparation 3,3:17,17-bis(ethylendioxy)-6-methyleneandrostane (Prepn. 8) and starting from 17,17-(ethylendioxy)-5α-hydroxyandrostane-3-one, 17,17-(ethylendioxy)-3-methylene-androstane-5α-ol was obtained in 98% yield. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.62 (m, 1H), 4.50 (m, 1H), 3.78 (m, 4H), 3.42 (s, 1H), 2.36-1.03 (m, 21H), 0.93 (s, 3H), 0.75 (s, 3H).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([C:20]#[N:21])=[C:18]([S:22][CH2:23][C:24]3[N:25]=[C:26]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[S:27][CH:28]=3)[N:17]=[C:16]([NH2:36])[C:15]=2[C:37]#[N:38])[CH2:10][CH2:9]1)=[O:7])(=O)C.[OH-].[Li+]>O1CCOCC1.O>[NH2:36][C:16]1[C:15]([C:37]#[N:38])=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:9][CH2:10]2)[C:19]([C:20]#[N:21])=[C:18]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:17]=1
Reactant: CC(=O)OCC(=O)N1CCC(c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCN(C(=O)CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
29 mg (0.05 mmol) of the compound from Example 25A are dissolved in a mixture of 1.5 ml of dioxane and 0.8 ml of water, and 2.4 mg (0.10 mmol) of lithium hydroxide are added. The reaction mixture is stirred at RT for two hours. After removal of the solvent on a rotary evaporator the residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: C(OC([N:8]([CH2:15][CH3:16])[C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:15]([NH:8][C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH3:16]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN[C@@H](C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-methyl 2-(tert-butoxycarbonyl(ethyl)amino)propanoate (4.40 g, 19.0 mmol) was dissolved in dichloromethane and treated with TFA (10 mL). The reaction mixture was stirred for 2 h at room temperature and concentrated in vacuo. The residue was diluted with brine and NaOH (aq. 50%) was added dropwise until pH=12.5. This was extracted with EtOAc (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as an opaque liquid (1.85 g, 74%). [M+H] calc'd for C6H13NO2, 132; found, 132.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][NH:11][C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:39]([O:41][C:42](Cl)=[O:43])[CH3:40]>C1(C)C=CC=CC=1>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([C:42]([O:41][CH2:39][CH3:40])=[O:43])[C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(CC2(C)CN(C(c3ccccc3)c3ccccc3)CCN2)cc1OC
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1(C)Cc1ccc(OC)c(OC)c1
Yield: 93.4 %

Procedure:
21.6 g of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-piperazine (cf. Example 2) are dissolved with 5.2 g of triethylamine in 200 ml of dry toluene. Then a solution of 5.4 g of chloroformic acid ethyl ester in 50 ml of toluene is added dropwise with stirring. Thereafter, the mixture is stirred for a further two hours. After filtration, the filtrate is washed free of halide with water and evaporated to dryness. A yellowish oil, which is recrystallized from diisopropyl ether, is obtained as the residue. 22.7 g (94 percent of theory) of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-4-carbethoxy-piperazine are obtained. m.p. = 113° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[N:30]=[C:31]=[O:32].C(N(CC)CC)C.Cl>C(#N)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[NH:30][C:31]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2)=[O:32]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4c(Cl)cccc4Cl)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a stirred mixture of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.423 g, 1.15 mmol) and 2,6-dichlorophenyl isocyanate (0.216 g, 1.15 mmol) in acetonitrile (10 mL), was added triethylamine (0.32 mL, 2.30 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (10 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-(2,6-dichloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.156 g, 29% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 3.74 min (99.7%); mp: 238-240° C.; 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 1H, CH), 2.31-2.47 (m, 1H, CH), 2.60 (d, J=17.0 Hz, 1H, CH), 2.84-3.01 (m, 1H, CH), 4.24-4.51 (m, 4H, CH2, CH2), 5.11 (dd, J=5.0, 13.3 Hz, 1H, NCH), 6.96 (t, J=5.9 Hz, 1H, NH), 7.23-7.33 (m, 1H, Ar), 7.42-7.57 (m, 4H, Ar), 7.69 (d, J=7.7 Hz, 1H, Ar), 8.19 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.48, 31.20, 43.02, 47.07, 51.56, 121.66, 122.85, 126.73, 128.12, 128.38, 130.23, 133.88, 134.07, 142.30, 144.96, 155.13, 167.96, 171.01, 172.86; LCMS: MH=461, 463; Anal Calcd for C21H18N4O4Cl2+0.1H2O: C, 54.47; H, 3.96; N, 12.10; Cl, 15.31. Found: C, 54.12; H, 3.71; N, 11.85; Cl, 15.31.
Reaction SMILES: Br[CH2:2][C:3]([CH3:11])([CH3:10])[CH2:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].[CH3:12][Li]>CCOCC>[CH3:12][C:6]1[C:5]([CH3:9])([CH3:8])[CH2:4][C:3]([CH3:11])([CH3:10])[CH2:2][N:7]=1
Reactant: CC(C)(C#N)CC(C)(C)CBr
Reactant: [Li]C
Solvent: CCOCC
Product: CC1=NCC(C)(C)CC1(C)C
Reaction time: 0.5 h

Procedure:
To 22 g of 5-bromo-2,2,4,4-tetramethyl pentane nitrile in 60 ml of anhydrous ether, 0.1 mol of methyl lithium in solution in 200 ml of anhydrous ether is added drop by drop in an inert atmosphere. The reaction medium is maintained between 0° and 5° C. during the addition and then for an additional 30 minutes and then kept at room temperature for 4 hours. After hydrolysis, the aqueous phase is extracted with ether. The 2,3,3,5,5-pentamethyl-3,4,5,6-tetrahydropyridine is then isolated by distillation. There is obtained a colorless liquid of B.P.10 -2 =43° C. in a yield of 70% of Δ1-piperideine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC.[F-].[K+]>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([CH:10]=[CH2:11])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: C=Cc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
A mixture of 2,4-dichloro-5-fluoropyrimidine (5.0 g, 30.0 mmol, 1.0 equiv), tributyl(vinyl)tin (10.4 g, 33.0 mmol, 1.1 equiv) in dichloromethane (50 mL) was degassed with a stream of nitrogen for 10 minutes. Bis(triphenylphosphine)palladium(II) chloride (0.53 g, 0.75 mmol, 0.025 equiv) was added. The resulting mixture was degassed with a stream of nitrogen for an additional 15 minutes and heated at reflux for 24 hours. The reaction mixture was cooled to room temperature and quenched with an aqueous potassium fluoride solution (2 M, 75 mL, 5 equiv). The resulting mixture was allowed to stir for 2 hours and filtered through Celite®. The filtrate was poured into a separatory funnel and separated. The organic layer was washed with water (20 mL) and saturated brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure at 20° C. The resulting crude product was purified on an AnaLogix® (SF40-115 g) column. The gradient utilized for the purification was 10 minutes isocratic pentane, followed by a 20 minutes ramp to 5% diethyl ether in pentane. The pure fractions were combined and concentrated under reduced pressure at 20° C. to give 2-chloro-5-fluoro-4-vinylpyrimidine as an oil (3.65 g, 77% yield).