Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[C:9]1([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:43]=[CH:42][C:29]2[N:30]([CH2:40][CH3:41])[C:31](=[O:39])[C:32]([CH3:38])([CH3:37])[C:33](=[O:36])[N:34]([CH3:35])[C:28]=2[CH:27]=1.C(OC(=O)C)C.Cl>C(OCC)(=O)C.O.CN(C=O)C>[ClH:21].[CH2:40]([N:30]1[C:31](=[O:39])[C:32]([CH3:37])([CH3:38])[C:33](=[O:36])[N:34]([CH3:35])[C:28]2[CH:27]=[C:26]([O:25][CH2:24][CH2:23][CH2:22][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:43]=[CH:42][C:29]1=2)[CH3:41]
Reactant: c1ccc(C2CCCCN2)cc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCCl)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN3CCCCC3c3ccccc3)ccc21
Temperature: 70 °C
Reaction time: 5 h
Yield: 27.7 %

Procedure:
Potassium carbonate(0.54 g), sodium iodide(0.21 g), and 2-phenyl piperidine(0.23 g) were added to a DMF solution(15 ml) of 7-(3-chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.44 g). The mixture was stirred at 70° C. for 5 hours. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was washed with water and then with saturated saline, and dried with anhydrous magnesium sulfate. After condensation under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate=2:1→1:1). The purified product was condensed under reduced pressure. A 4N-Hydrogen chloride ethyl acetate solution(0.2 ml) was added to an ethyl acetate solution (10 ml) of the residue, which was stirred at room temperature. The liquid was condensed to dryness under reduced pressure to give the title compound(0.18 g) as a white amorphous solid.
Reaction SMILES: [N:1]1([C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[O:8][CH2:9][CH:10]2[O:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(O)(C)C>[O:20]1[CH2:21][CH2:22][N:17]([CH2:11][CH:10]([OH:12])[CH2:9][O:8][C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH2:18][CH2:19]1
Reactant: c1ccc(-n2cccc2)c(OCC2CO2)c1
Reactant: C1COCCN1
Solvent: CC(C)O
Product: OC(COc1ccccc1-n1cccc1)CN1CCOCC1

Procedure:
A solution of 15 g of 1-[o-(pyrrol-1-yl)-phenoxy]-2,3-epoxy-propane and 7 g of morpholine in 150 ml of isopropanol is heated for 2 hours to the boil under reflux. After evaporation in vacuo, an oil remains, which crystallises and after recrystallisation from butanone gives 1-morpholino-3-[o-(pyrrol-1-yl)-phenoxy]-2-propanol of melting point 81°-82° C. It forms a neutral fumarate of melting point 136°-137° C (from butanone).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[CH:33]1([CH:36]=O)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH2:36][CH:33]2[CH2:35][CH2:34]2)=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NCC4CC4)C3)sc12
Yield: 93 %

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (81e) (37 mg, 0.071 mmol), cyclopropanecarbaldehyde (6.5 μL, 0.087 mmol) and sodium (triacetoxy)borohydride (44 mg, 0.21 mmol), to obtain 35.3 mg of the title compound as a white solid (93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH:9]=[CH:10][N:11]([CH3:13])C)[CH:5]=[CH:6][CH:7]=1.N[C:16]1[C:20]([C:21]#[N:22])=C[NH:18][N:17]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:18]3[N:17]=[CH:16][C:20]([C:21]#[N:22])=[C:13]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=CC(=O)c1cccc(Cl)c1
Reactant: N#Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3cccc(Cl)c3)ccnc12
Yield: 83.2 %

Procedure:
A mixture of 50.0 g of 3'-chloro-3-dimethylaminoacrylophenone, 25.0 g of 3-aminopyrazole-4-carbonitrile and 500 ml of glacial acetic acid was heated at reflux for 2 hours. The mixture went into solution upon heating and a precipitate formed after one hour of refluxing. The reaction mixture was filtered and the crystals collected were triturated with saturated aqueous sodium bicarbonate, filtered and washed with water and then dried to give 49.0 g of the product of the example as colorless crystals, mp 238°-240° C.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>[OH-].[Na+]>[CH2:15]([O:14][C:12]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 5 °C
Yield: 65 %

Procedure:
400 g (2.72 mol) of (L)-glutamic acid are dissolved in 2.66 liters of 2N sodium hydroxide solution, the resulting solution is cooled to 5° C. and about 400 ml of benzyl chloroformate (3.6 mol) are run in slowly, dilute sodium hydroxide solution (1 to 2N) being added simultaneously to keep the pH at around 9.0. The mixture is stirred for a few hours, washed with 2×200 ml of ether and acidified to around pH 1. After extraction with ethyl acetate, washing several times with a saturated aqueous solution of sodium chloride, drying and evaporation, a thick oil is obtained which crystallizes from hexane. Weight=500 g; yield=65%; melting point=116/7° C.; H+ titer=99%; [α]D22 =-10.4° (1%, acetone).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][N:17]=[C:18]([CH3:26])[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:6]([O-:8])=[O:7].Cl>CO>[CH3:3][O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16]/[N:17]=[C:18](\[CH3:26])/[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(C(=O)[O-])c1ccccc1CON=C(C)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(C(=O)O)c1ccccc1CO/N=C(\C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
1N sodium hydroxide solution (10 ml) was added to a solution of ethyl (E)-(α-methoxy-2-(α-methyl-4-chloro-benzylideneaminooxymethyl)phenylacetate (0.70 g, 1.9 mmol) in methanol (10 ml), and the mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH 4 with 1N hydrochloric acid, extracted with methylene chloride and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave the desired compound (E)-α-methoxy-2-(α-methyl-4-chlorobenzylideneaminooxymethyl)phenylacetic acid (0.50 g, 77%) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(N[C@H]2CCN(Cc3ccccc3)C2)c1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Fc1cccc(N(c2ccc(C(F)(F)F)cc2)[C@H]2CCN(Cc3ccccc3)C2)c1
Yield: 44.5 %

Procedure:
A toluene solution containing 0.7 g of ((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)amine (2.6 mmol), 0.59 g of 4-bromobenzotrifluoride (2.6 mmol), 65 mg of BINAP (0.1 mmol), 23 mg of palladium acetate (0.1 mmol) and 0.28 g of sodium tert-butoxide (2.9 mmol) was heated under reflux under a nitrogen atmosphere for 3 hours. The reaction solution was filtered to remove insoluble matter, and ethyl acetate and water were added to the filtrate to separate the solution into layers. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1→10:1). The eluent solvent was distilled off under reduced pressure to thereby obtain 0.48 g of oily colorless ((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)-(4-trifluoromethylphenyl)amine.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)[CH:4]=1.[C-:25]#[N:26].[K+]>CS(C)=O.C([O-])(O)=O.[Na+]>[C:25]([CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)[CH:4]=1)#[N:26]
Reactant: [C-]#N
Reactant: O=C(OCc1ccccc1)N1CCN(c2cc(CCl)ccn2)CC1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccnc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Yield: 51.3 %

Procedure:
A solution of benzyl 4-(4-(chloromethyl)pyridin-2-yl)piperazine-1-carboxylate (5.0 g, 14.5 mmol) and KCN (2.8 g, 43.5 mmol) in DMSO (30 mL) was stirred at RT overnight, and then diluted with sat. NaHCO3 (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with H2O (50 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated to afford crude product, which was purified by silica gel column chromatography (Petroleum ether:EtOAc=1:1) to give benzyl 4-(4-(cyanomethyl)pyridin-2-yl)piperazine-1-carboxylate as a yellow solid (2.5 g, 51%). MS (ES+) C19H20N4O2 requires: 336, found: 337[M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH2:4][CH2:3]1>CCO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(Oc2ccc([N+](=O)[O-])c(-c3ccccc3)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(Oc2ccc(N)c(-c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-fluoro-2-nitrobiphenyl (0.86 mmol) in toluene/aq.KOH (2 mL/2 mL) are added 1-methylpiperidin-4-ol (1.1 mmol) and TBAB (0.17 mmol) at room temperature. After stirred at 70° C. overnight, the reaction mixture is diluted with AcOEt and water, and extracted with AcOEt (×2). The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography (CH2Cl2:MeOH=10:1) to give 1-methyl-4-(6-nitrobiphenyl-3-yloxy)piperidine as a yellow solid. To a solution of 1-methyl-4-(6-nitrobiphenyl-3-yloxy)piperidine (0.63 mmol) in EtOH (5 mL) is added 5% palladium on activated carbon (50 mg) under N2 atmosphere. The reaction mixture is vigorously stirred at room temperature for 2.5 h under H2, and then filtered through celite (linsed with AcOEt). The filtrate is concentrated in vacuo to the title compound as a brown oil; 1H NMR (CDCl3), δ 1.79-1.87 (2H, m), 1.96-2.01 (2H, m), 2.25-2.31 (2H, m), 2.29 (3H, s), 2.70 (2H, brs), 3.52 (2H, m), 4.15-4.18 (1H, m), 6.70 (1H, d), 6.76-6.80 (2H, m), 7.32-7.38 (1H, m), 7.42-7.45 (4H, m).
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[C:3]#[C:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]3[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]3)[N:12]=2)=[CH:7][CH:6]=1>CCO.[Pd]>[NH2:1][C:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]3[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]3)[N:12]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(N)C#Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cn1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(N)CCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cn1

Procedure:
{4-[6-(3-Amino-3-methyl-but-1-ynyl)-pyridin-3-yl]-pyrimidin-2-yl}-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (105 mg, 0.25 mmol) was dissolved in EtOH (100 ml) and hydrogenated at 1 atm over Pd/C (10%, 105 mg) for 2 hours at room temperature. The reaction mixture was filtered, evaporated, taken up in TBME/MeOH/ammonia (90/9/1) and passed through a bed of silicagel to give the title compound as slightly yellowish crystals, crystallized from ether. Yield: 35 mg (33%).
Reaction SMILES: [CH3:1][Si:2]([CH3:36])([CH3:35])[O:3][C@H:4]1[CH2:27][C@@:26]2([CH3:28])[C@@H:15]([CH2:16][CH2:17][C@:18]2(OC(=O)C)[C:19](=[O:25])[CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@H:14]2[C@H:5]1[C@:6]1([CH3:34])[C:11]([CH2:12][CH2:13]2)=[CH:10][C:9](=[O:33])[CH:8]=[CH:7]1.C([O-])(=O)C.[K+]>CN(C)C=O>[CH3:36][Si:2]([CH3:1])([CH3:35])[O:3][C@H:4]1[CH2:27][C@@:26]2([CH3:28])[C@@H:15]([CH2:16][CH:17]=[C:18]2[C:19](=[O:25])[CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@H:14]2[C@H:5]1[C@:6]1([CH3:34])[C:11]([CH2:12][CH2:13]2)=[CH:10][C:9](=[O:33])[CH:8]=[CH:7]1
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O[Si](C)(C)C)C[C@@]21C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O[Si](C)(C)C)C[C@]12C

Procedure:
4 g of 11β-trimethylsiloxy-17α,21-diacetoxypregna-1,4-diene-3,20-dione (from Example 30) was treated with potassium acetate and dimethylformamide exactly as described in Example 28. There was obtained 11β-trimethylsiloxy-21-acetoxypregna-1,4,16-triene-3,20-dione (compound 55).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[S:25][C:24]([I:26])=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:7][CH:8]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:18]3[S:25][C:24]([I:26])=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(I)sc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(I)sc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {1-(4-chlorobenzyl)-2-[4-(6-iodothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed to afford the product 2-Amino-3-(4-chlorophenyl)-1-[4-(6-iodothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one quantitatively. MS (ESI+) [M+H]+ 528.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@@H:12]([C:17]([OH:19])=[O:18])[NH:13]C(=O)C)([O-:3])=[O:2].[OH-].[NH4+]>S(=O)(=O)(O)O.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@@H:12]([C:17]([OH:19])=[O:18])[NH2:13])([O-:3])=[O:2]
Reactant: CC(=O)N[C@@H](CSc1ccccc1[N+](=O)[O-])C(=O)O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: N[C@@H](CSc1ccccc1[N+](=O)[O-])C(=O)O

Procedure:
A solution of 71 g of S-(o-nitrophenyl)-N-acetyl-L-cysteine in 300 ml of 18M sulfuric acid and 1200 ml of water is heated to reflux for 30 min. The solution is cooled in ice and treated with 700 ml of concentrated ammonium hydroxide. The resulting solid is recrystallized from boiling water to afford S-(o-nitrophenyl)-L-cysteine; m.p. 168°-171° C.; [α]D =+67.3° (c=1.1, 1N hydrochloric acid).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH3:9].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[C:14]([Si:11]([CH3:13])([CH3:12])[O:10][C@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:9])([CH3:17])([CH3:16])[CH3:15]
Reactant: C1CNCCN1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1Br
Product: C[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1N1CCNCC1

Procedure:
To a 25 mL flask containing (S)-(−)-2-bromo-alpha-methylbenzyl alcohol (200 mg, 1.0 mmol), tert-butyldimethylsilyl chloride (165 mg, 1.1 mmol), and imidazole (203 mg, 3.0 mmol) flushed with nitrogen was added 5 mL of dimethylformamide. After stirring overnight, the mixture was quenched with saturated sodium bicarbonate, diluted with ethyl acetate, washed with NaH2PO4, saturated aqueous sodium bicarbonate, water, brine, dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (10 g SiO2, linear gradient 0-10% ethyl acetate/Hexanes, 30 mL/minute, over 30 minutes) gave about 260 mg (0.82 mmol, 82%) of (5)-[1-(2-Bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane as a colorless oil. GC/MS (EI): 315 (M). The (5)-[1-(2-Bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane was coupled to piperazine in a manner similar to Preparation 1A. LRMS (ESI+): 321.5 (M+1)
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([CH2:7][OH:8])[CH2:5][NH:4][CH2:3]1.[CH2:9]=O>>[CH:2]12[CH2:3][NH:4][CH2:5][CH:6]1[CH2:7][O:8][CH2:9][NH:1]2
Reactant: NC1CNCC1CO
Reactant: C=O
Product: C1NC2CNCC2CO1

Procedure:
3-Amino-4-hydroxymethyl-pyrrolidine is reacted with formaldehyde solution analogously to Example Pe).
Reaction SMILES: CN(C=O)C.[C:6]([O:14][C:15]1[C:23]([O:24][CH3:25])=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([N+:26]([O-:28])=[O:27])[CH:16]=1)(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(Cl)(Cl)=O.[CH:33]1[C:45]2[CH:44]([NH2:46])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]=2[CH:36]=[CH:35][CH:34]=1>C1C=CC=CC=1.C(N(CC)CC)C>[CH:33]1[C:45]2[CH:44]([NH:46][C:19](=[O:21])[C:18]3[CH:22]=[C:23]([O:24][CH3:25])[C:15]([O:14][CH2:6][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[CH:16][C:17]=3[N+:26]([O-:28])=[O:27])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]=2[CH:36]=[CH:35][CH:34]=1
Reactant: NC1c2ccccc2-c2ccccc21
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2c3ccccc3-c3ccccc32)c([N+](=O)[O-])cc1OCc1ccccc1
Reaction time: 6 h
Yield: 80.6 %

Procedure:
DMF was added to a stirred suspension of 4-benzoyloxy-5-methoxy-2-nitro benzoic acid (6) (0.500 mg, 1.65 mmol) and thionyl chloride (3 ml) in dry benzene (30 ml) and the stirring was continued for 6 h. The benzene was evaporated in vacuum and the resultant oil dissolved in dry THF (50 ml) and added dropwise over a period of 1 h to a stirred suspension of 9H-9-fluorenamine (326, 15.6 mmol) triethylamine (5 ml). After the completion of addition, the reaction mixture was brought to ambient temperature and stirred for an additional hour. The THF was evaporated in vacuum and the aqueous layer was washed with ethyl acetate. The aqueous phase was then adjusted to pH 3 using 6 N HCl and extracted with ethyl acetate and washed with brine, dried over Na2SO4 and evaporated in vacuum to afford the crude product of (7e) (620 mg in 80% yield). 1H NMR (CDCl3) δ 3.95 (s, 3H), 5.20 (s, 2H), 5.70 (s, 1H), 6.70 (s, 1H), 7.00-7.41 (m, 5H), 7.45-7.706 (m, 9H); FABMS: 466 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O>[Pd].CCO>[O:13]1[CH2:14][CH2:15][N:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)nc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)nc1
Reaction time: 2 h
Yield: 88 %

Procedure:
Into a EtOH (250 mL) solution of 4-(5-nitropyridin-2-yl)morpholine (4.9 g, 23.4 mmol), 10% Pd on activated carbon, 500 mg, was added. Hydrogenation was carried out in a Parr flask at room temperature, at 40 psi for 2 hr. The solids were filtered off and the filtrate was collected. The solvent was removed in vacuo. 6-Morpholinopyridin-3-amine, as a purple solid, was obtained: 3.7 g (88% yield); 1H NMR (300 MHz, DMSO) δ 7.64 (d, J=2.7, 1H), 6.96 (dd, J=2.7, 8.8, 1H), 6.65 (d, J=8.8, 1H), 4.63 (s, 2H), 3.72-3.69 (m, 4H), 3.21-3.18 (m, 4H); LCMS (M+) m/z 180.08.
Reaction SMILES: [NH3:1].F[B-](F)(F)F.C(O[C:10](=[N+:20]1[CH2:28][CH:27]2[CH:22]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:24][CH2:25][C:26]2=[O:29])[CH2:21]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH:1]=[C:10]([N:20]1[CH2:28][CH:27]2[CH:22]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:24][CH2:25][C:26]2=[O:29])[CH2:21]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: N
Reactant: CCOC(Cc1ccccc1OC)=[N+]1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccccc1CC(=N)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 20 h

Procedure:
A 5.4N ethanolic solution (1.3 cc) of ammonia is added to a stirred suspension, cooled to -10° C., of (3aRS,7aRS)-2-[1-ethoxy-2-(2-methoxyphenyl)ethylidene]-4-oxo-7,7-diphenylperhydroisoindolium tetrafluoroborate (5.7 g) in anhydrous dichloromethane (15 cc). The reaction mixture is then allowed to return to room temperature and stirring is continued for 20 hours. The reaction mixture is diluted with dichloromethane (20 cc) and treated with 10% strength aqueous potassium carbonate solution (20 cc). The precipitate present is removed by filtration and the organic phase is then washed with distilled water (25 cc) and with saturated aqueous sodium chloride solution (25 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in acetonitrile (10 cc). The crystals obtained are drained, washed with acetonitrile (10 cc) and dried. and dried. (3aRS,7aRS)-2-[1-Imino-2-(2-methoxyphenyl)ethyl]-7,7-diphenylperhydro-4-isoindolone (1 g), m.p. above 260° C. is obtained.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[CH:19]=[C:18]([CH2:20][O:21]C)[N:17]=[CH:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[Cl:12].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[N:15]=[CH:16][N:17]=[C:18]([CH2:20][OH:21])[CH:19]=2)[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: COCc1cc(Nc2ccc(Cl)c(Cl)c2)ncn1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: OCc1cc(Nc2ccc(Cl)c(Cl)c2)ncn1
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
BBr3 (0.399 ml, 4.22 mmol) was added dropwise to a stirred solution of N-(3,4-dichlorophenyl)-6-(methoxymethyl)pyrimidin-4-amine (0.3 g, 1.056 mmol) in DCM (4.0 mL) at 0° C. The mixture was further stirred for 30 min and poured onto ice water. The pH was adjusted to 10 using sat. Na2CO3 solution. The resulting suspension was extracted with ethyl acetate. The organic layer was isolated and dried over K2CO3 and concentrated to give (6-(3,4-dichlorophenylamino)pyrimidin-4-yl)methanol as a brown solid (0.275 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (1H, br. s.), 8.92 (1H, s), 8.14 (1H, s), 7.71 (1H, d, J=8.78 Hz), 7.60 (1H, dd, J=8.78, 2.51 Hz), 7.05 (1H, s), 4.60 (2H, s). LCMS: R.T.=2.88; [M+H]+=271.96.