Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[C:10]=1[O:11][CH3:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[CH:8]=[N:7][C:6]=2[C:10]=1[O:11][CH3:12]
Reactant: COc1c(Br)ccc2nc[nH]c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: COc1c(Br)ccc2c1ncn2C1CCCCO1
Temperature: 90 °C
Yield: 60.3 %

Procedure:
A 500 ml tube was charged with 6-bromo-7-methoxy-1H-benzoimidazole (36 g, 0.16 mol, 1.0 equiv.), dihydropyran (40.01 g, 0.48 mol, 3.0 equiv.) and pyridinium-p-toluenesulfonate (7.96 g, 0.032 mol, 0.2 equiv.) in EtOAc (400 mL), sealed and the reaction mixture was heated at 90° C. overnight. The reaction mixture was concentrated in vacuo and the crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (30-40% EtOAc) to afford 5-bromo-4-methoxy-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole (30 g, 60% yield) as a brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].BrCC1OC(C(F)(F)F)=CC=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2([CH2:39][O:38][C:37]3[CH:40]=[C:41]4[C:45](=[CH:46][C:36]2=3)[CH2:44][CH2:43][O:42]4)[C:28]1=[O:47].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[O:47]=[C:28]1[C:29]2([CH2:39][O:38][C:37]3[CH:40]=[C:41]4[C:45](=[CH:46][C:36]2=3)[CH2:44][CH2:43][O:42]4)[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]1[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using N-(3-bromopropyl)phthalimide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 2-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione was obtained (39%) as a pale yellow solid: mp 214-217° C.; 1H NMR (300 MHz, CDCl3) δ 7.84 (dd, J=5.6, 3.0 Hz, 2H), 7.72 (dd, J=5.5, 3.0 Hz, 2H), 7.31-7.28 (m, 1H), 7.18 (dd, J=7.4, 0.8 Hz, 1H), 7.04 (ddd, J=8.4, 7.5, 0.8 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.58 (s, 1H), 6.40 (s, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.6 Hz, 2H), 3.98-3.89 (m, 1H), 3.85-3.75 (m, 3H), 3.01 (ddd, J=10.6, 8.4, 1.7 Hz, 2H), 2.20-2.10 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.7, 168.1, 161.7, 161.2, 141.9, 134.0, 133.0, 131.9, 128.7, 124.0, 123.3, 123.2, 120.2, 119.9, 118.9, 108.2, 93.1, 80.4, 72.4, 57.6, 38.0, 35.7, 29.0, 26.8; MS (ES+) m/z 466.9 (M+1).
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:23])[N:12]([CH3:22])[C:13]3[C:18]([C:19]=2[Cl:20])=[CH:17][C:16](O)=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:26])=O>>[Cl:20][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:26])[CH:17]=2)[N:12]([CH3:22])[C:11](=[O:23])[C:10]=1[C:8]#[N:7]
Reactant: Cn1c(=O)c(C(=O)NC2CCCCC2)c(Cl)c2cc(O)ccc21
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1c(=O)c(C#N)c(Cl)c2cc(Cl)ccc21
Yield: 48 %

Procedure:
A solution of Compound 67 (2.2 g, 6.57 mmol) in 20 mL neat phosphorus oxychloride was heated at 90° C. for 5 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 0.8 g (48%) of yellow solids. M.P. 256° C. 1H NMR (DMSO-d6): δ 3.65 (s, 3H), 7.60 (d, J=9.0 Hz, 1H), 7.94 (dd, J=2.1, 9.0 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H). EIMS m/z 254 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[O:20][C:19]([CH2:21][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:18][CH:17]=4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(F)c4)c3c2)o1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(F)c4)c3c2)o1

Procedure:
Prepared according to Procedure D from 5-(4-{3-fluoro-4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 400 MHz (DMSO-d6) 9.61 (bs, 2H); 9.28 (bs, 1H); 8.80 (s, 1H); 8.34 (d, 1H); 7.87 (m, 2H); 7.59 (d, 1H); 7.44 (m, 1H); 7.2-7.38 (m, 4H); 7.18 (m, 1H); 6.83 (s, 1H); 5.25 (s, 2H); 4.42 (s, 2H); 3.60 (m, 2H); 3.45 (m, 2H, obscured by water peak); 3.16 (s, 3H); MS m/z 565 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([NH:25][CH3:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][C:10]=2[O:23][CH3:24])=[N:6][CH:7]=1.[CH2:27]([Sn](CCCC)(CCCC)C#CC)[CH2:28][CH2:29]C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][O:23][C:10]1[CH:11]=[C:12]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[N:4]=[C:3]([NH:25][CH3:26])[C:2]([C:27]#[C:28][CH3:29])=[CH:7][N:6]=1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OC)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC#Cc1cnc(Nc2ccc(C(=O)N3CCOCC3)cc2OC)nc1NC
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of (4-(5-bromo-4-(methylamino)pyrimidin-2-ylamino)-3-methoxyphenyl)(morpholino)methanone (140 mg, 0.233 mmol), Pd(PPh3)4 (50 mg, 0.04 mmol) and tributyl(prop-1-ynyl)stannane (0.20 mL, 0.66 mmol) in toluene (5 mL) was stirred in a sealed tube at 110° C. for 1 hour. The reaction mixture was filtered and concentrated. Purification of the crude product was achieved by reverse phase HPLC (9 mg, 10%). Additional compounds made using the above procedure are shown in Table 4 above.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1

Procedure:
A solution of Compound 9 (22.96 g, 100 mmol), cyclohexylamine (15.31 g, 154 mmol) and TEA (13.57 g, 134 mmol) in 100 mL acetonitrile was refluxed overnight. The reaction mixture was poured into icy water and the precipitated crystals were collected by means of filtration, washed three times with water then was dried over phosphorous pentoxide in high vacuum to yield Compound 10.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([S:19][CH2:20][CH3:21])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)(Cl)Cl.C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([S:19]([CH2:20][CH3:21])=[O:27])[N:3]=1
Reactant: CCSc1ncc(C(=O)c2cc(C)ccc2OC)c(N)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1ncc(C(=O)c2cc(C)ccc2OC)c(N)n1
Reaction time: 1 h

Procedure:
A solution of (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-methoxy-5-methyl-phenyl)-methanone, 571 mg, 1.885 mmol, Example 324) in chloroform (16 mL) was cooled to −15° C. and treated with 3-chloroperoxybenzoic acid (503.7 mg, ˜2.25 mmol, ˜70% purity from Aldrich) and the reaction was stirred at the same temperature for 1 hour. The reaction mixture was diluted with methylene chloride (20 mL) and washed with 10% aqueous sodium thiosulfate (2×5 mL), 10% aqueous sodium carbonate (2×5 mL), brine, dried and concentrated to give (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2-methoxy-5-methyl-phenyl)-methanone as a white solid. MS (M+H)+: 320.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[Br:8].[CH2:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1)[CH2:11][CH3:12].O>C(NCC)C.[Cu](I)I>[F:1][C:2]1[CH:3]=[C:4]([C:20]#[C:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: Fc1cc(I)ccc1Br
Agent: I[Cu]I
Solvent: CCNCC
Solvent: O
Product: CCCc1ccc(C#Cc2ccc(Br)c(F)c2)cc1
Yield: 100 %

Procedure:
To a solution of 33 mmol of 3-fluoro-4-bromo iodobenzene, 0.6 mmol of copper iodide and 1.1 mmol of dichlorobistriphenylphosphine palladium in 100 ml of diethylamine were added dropwise 33 mmol of 4-propyl phenylacetylene under an argon stream while stirring. After completion of the addition, the solution was stirred at room temperature for a further 2 hours and placed into water. The solution was extracted with heptane, washed with water and concentrated under reduced pressure to afford a brown oily product. The product was isolated and purified by a silica gel column chromatography to afford 33 mmol of 2-fluoro-4-[2-(4-propylphenyl)ethynyl]bromobenzene as a pale yellow oily product.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.[CH:34](N(C(C)C)CC)(C)[CH3:35].C(Cl)(=O)C=C>O1CCOCC1.C(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([NH:7][C:6](=[O:5])[CH:34]=[CH2:35])[CH2:13][CH2:12]2)=[CH:16][CH:17]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CC(=O)NC1CCN(Cc2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.5 %

Procedure:
[1-(4-Benzyloxycarbonylamino-benzyl)piperidin-4-yl]-carbamic acid tert-butyl ester (0.14 g, 0.32 mmol) was suspended in a 4M solution of HCl in Dioxane (5 ml). The resulting suspension was stirred at room temperature for 3 hours. After this time the solution was concentrated under vacuum and the resulting residue dissolved in THF (10 ml). To this solution was added diisopropylethylamine (0.28 ml, 1.6 mmol) was added in one portion, followed by the drop wise addition of acryloyl chloride (0.03 ml, 0.38 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (20 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue was purified by flash column chromatography (elution: 100% DCM to 90% DCM, 10% Methanol) to give the title compound (0.012 g, 10% yield) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6].[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][C:30](=[O:32])[C:29]5([CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[N:28]=4)=[CH:23][CH:22]=3)[N:20]=2)[CH2:12][CH2:11]1>CN(C)C=O>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:28][C:29]4([C:30]([NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:32])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)=[O:31])=[CH:25][CH:26]=3)[N:20]=2)[CH2:12][CH2:11]1
Reactant: CSCC[C@H](N)CO
Reactant: CN1CCN(c2nc(-c3ccc(C4=NC5(CCCCC5)C(=O)O4)cc3)cs2)CC1
Solvent: CN(C)C=O
Product: CSCC[C@@H](CO)NC(=O)C1(NC(=O)c2ccc(-c3csc(N4CCN(C)CC4)n3)cc2)CCCCC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
100 mg (0.74 mmol) of L-methioninol was added to a solution of 250 mg (0.68 mmol) of 2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 20 ml of dimethylformamide. After the mixture was stirred at 80° C. for 15 hours, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue to wash the crystal to obtain 319 mg (86%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].C(N(C(C)C)C(C)C)C.[Cl-].[Li+].C(OP([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(OCC)=O)C>CC#N>[N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1/[CH:6]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.8 %

Procedure:
To a mixture of 2,4-dinitrobenzaldehyde (12.0 g, 61.2 mmol), N-ethyl-N-isopropylpropan-2-amine (11.9 g, 91.8 mmol) and lithium chloride (3.1 g, 24.1 mmol) in CH3CN (100 mL) was added slowly ethyl 2-(diethoxyphosphoryl)acetate (16.5 g, 64.3 mmol) and the reaction mixture was stirred at ambient temperature for 12 h. After filtration, the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 4% EtOAc in petroleum ether) to give (E)-ethyl 3-(2,4-dinitrophenyl)acrylate (13 g, 84%). 1H NMR (CDCl3, 400 MHz): δ 8.83 (s, 1H), 8.42 (d, J=8.8 Hz, 1H), 8.02 (d, J=16.0 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 6.39 (d, J=16.0 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([O:13][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCN(C)C(=O)OC(C)(C)C
Yield: 99.2 %

Procedure:
To a solution of 3-(tert-butoxycarbonyl(methyl)amino)propanoic acid (7.0 g, 0.032 mol) and K2CO3 (13.3 g, 0.096 mol) in DMF (100 mL) was added MeI (9.0 g, 0.064 mol) at rt. The resultant solution was stirred at rt for 3 hrs. The reaction mixture was quenched with ice water and extracted with ethyl acetate (2×). The combined organic layer was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution 0%˜10% EtOAc/petroleum ether) to afford methyl 3-(tert-butoxycarbonyl(methyl)amino)propanoate (6.9 g, 92%) as a white solid. ESI-MS (EI+, m/z): 118 [M−100+H]+.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[S:3]Cl.C(N(CC)CC)C.C1([N:17]2[C:21](=[O:22])[CH2:20][NH:19][C:18]2=[O:23])CC1>N1CC(=O)NC1=O>[Cl:1][C:2]([Cl:6])([Cl:5])[S:3][N:19]1[CH2:20][C:21](=[O:22])[N:17]([S:3][C:2]([Cl:6])([Cl:5])[Cl:1])[C:18]1=[O:23]
Reactant: O=C1CNC(=O)N1C1CC1
Reactant: ClSC(Cl)(Cl)Cl
Agent: O=C1CNC(=O)N1
Solvent: CCN(CC)CC
Product: O=C1CN(SC(Cl)(Cl)Cl)C(=O)N1SC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.9 %

Procedure:
At about 25° C., 37.2 g (0.2 mole) of trichloromethylsulfenyl chloride and subsequently 20.2 g (0.2 mole) of triethylamine are dripped, while stirring thoroughly, into a suspension of 14.0 g (0.1 mole) of 3-cyclopropylhydantoin in 150 ml of anhydrous hydantoin. After stirring for 12 hours at room temperature, the precipitated triethylamine hydrochloride is filtered off and the reaction mixture is worked up as in Example 1. There is obtained 23.5 g (59% of theory) of 1,3-bis-(trichloromethylthio)-hydantoin; m.p. 140°-142° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[N:3][CH:2]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:18]2[CH2:19][CH2:20][CH:15]([C:13]([N:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[CH2:12][CH2:11]3)=[O:14])[CH2:16][CH2:17]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C(C1CCNCC1)N1CCN(c2ccncn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CCN(S(=O)(=O)c2ccc(Cl)cc2)CC1)N1CCN(c2ccncn2)CC1
Yield: 26 %

Procedure:
4-(1-(4-Pyrimidinyl)piperazin-4ylcarbonyl)piperidine (412 mg; 1.5 mmol) was dissolved in CH2Cl2 (16 ml), cooled in an ice bath, stirred and treated dropwise with a mixture of 4-Chlorobenzenesulfonyl chloride (338 mg; 1.6 mmol) and Et3N (0.3 ml; 2 mmol) in CH2Cl2 (16 ml). The reaction mixture was allowed to reach room temperature and stirred thus for 18 h before treating with saturated NaHCO3 (aq) This mixture was then extacted twice with CH2Cl2. The combined organic extracts were washed twice each with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to a yellow solid. The solid thus obtained was chromatographed through a 10 g silica "bond elut" prepacked column, eluting with 1% methanol, 1% ammonimum hydroxide and 98% CH2Cl2 to obtain 1-(4-chlorophenylsulphonyl)-4-(1-(4-pyrimidinyl)piperazin-4-ylcarbonyl)piperidine (178 mg; 26% yield based on the amine ), a white solid, m.p. 125-128° C.;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10](#[N:12])[CH3:11]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:11][C:10]#[N:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CC#N
Reactant: O=Cc1cccc(Br)c1
Product: N#CCC(O)c1cccc(Br)c1

Procedure:
Alkylation of 3-bromobenzaldehyde with acetonitrile following the method described in Example 50 gave 3-(3-bromophenyl)-3-hydroxypropanenitrile as a light yellow oil. Yield (2.75 g, 81%): 1H NMR (400 MHz, DMSO-d6) δ 7.60 (t, J=1.6 Hz, 1H), 7.46 (ddd, J=7.6, 2.0, 1.2 Hz, 1H), 7.40 (dd, J=7.6, 2.0 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 6.05 (d, J=4.8 Hz, 1H), 2.94-2.80 (m, 2H).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH2:15].[C:17]([CH:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22])(=O)[CH3:18]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][C:17](=[C:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22])[CH3:18]
Reactant: Cc1cc(C)c(-c2ccncc2N)c(C)c1
Reactant: CC(=O)C1CCOC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(Nc1cnccc1-c1c(C)cc(C)cc1C)=C1CCOC1=O
Yield: 77.5 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.2 g, 1.18 mmol) was added to a solution of 4-mesityl-3-pyridinamine (5.0 g, 24 mmol) and α-acetyl-γ-butyrolactone (6.0 g, 47 mmol) in toluene (100 mL), followed by heating under reflux for three days while removing water using a Dean-Stark apparatus. The mixture was evaporated, and the resulting crystals were washed with 60% diethyl ether/ethyl acetate, to give the title compound (6.0 g) as white crystals.
Reaction SMILES: [CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH:3]([CH3:5])[CH3:4].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: BrCCCCCCBr
Reactant: CC(C)CCOCCCCO
Product: CC(C)CCOCCCCOCCCCCCBr

Procedure:
Using 4-isopentyloxy butanol and 1,6-dibromo-hexane, the above compound is produced. B.P.: 142°-145°/0.7 mm.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.CC[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1CCCCC1.C1(O)CCCC1>[C:10]1([CH3:20])[CH:11]=[CH:12][C:13]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1.[CH:23]1([O:8][C:7](=[O:9])[C@@H:2]([NH2:1])[CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CCCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OC1CCCC1
Solvent: C1CCCCC1
Product: CC(C)C[C@H](N)C(=O)OC1CCCC1
Yield: 85 %

Procedure:
To a suspension of (S)-leucine (15 g, 0.11 mol) in cyclohexane (400 ml) was added cyclopentanol (103.78 ml, 1.14 mmol) and p-toluene sulfonic acid (23.93 g, 0.13 mol). The suspension was heated at reflux to effect solvation. After refluxing the solution for 16 hours it was cooled to give a white suspension. Heptane (500 ml) was added to the mixture and the suspension was filtered to give the product as a white solid (35 g, 85% yield). 1H NMR (300 MHz, MeOD), δ: 1.01 (6H, t, CH3×2, J=5.8 Hz), 1.54-2.03 (11H, m, 11×CH), 2.39 (3H, s, CH3), 3.96 (1H, t, CH, J=6.5 Hz), 5.26-5.36 (1H, m, CH), 7.25 (2H, d, ArH x 2, J=7.9 Hz), 7.72 (2H, d, ArH×2, J=8.3 Hz).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:22])[O:4]1.[CH3:23][C:24]([CH3:26])=O>>[CH:24]([NH:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:22])[O:4]1)([CH3:26])[CH3:23]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CN)O[C@H]2n1cnc2c(N)ncnc21
Reactant: CC(C)=O
Product: CC(C)NC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21

Procedure:
reacting 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine with acetone to yield 9-((3aR,4R,6R,6aR)-6-((isopropylamino)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine;
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[Cl:21][Si](C)(C)C>C(#N)C>[Cl:21][CH2:12][C:11](=[O:13])[C:3](=[N:2][OH:1])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(=NO)C(=O)CCl
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
In 15 ml of acetonitrile was dissolved 1.07 g of tert-butyl 2-hydroxyimino-3-oxobutyrate, followed by addition of 2.8 ml of triethylamine. Then, 2.5 ml of chlorotrimethylsilane was added dropwise with ice-cooling and the mixture was stirred at 20°-25° C. for 1.5 hours, after which it was concentrated under reduced pressure. The residue was suspended in 15 ml of tetrahydrofuran and the suspension was filtered in a nitrogen gas stream to remove insolubles. This filtrate containing tert-butyl 2-trimethylsilyloxyimino-3-trimethylsilyloxy-3-butenoate was cooled to -30° C. and 0.46 ml of sulfuryl chloride was added dropwise. After the temperature of the system was increased to 20° C., the reaction mixture was concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and elution was carried out with 100 ml of hexane-ether (1:1, v/v). The eluate was concentrated under reduced pressure to give 1.08 g of tert-butyl 4-chloro-2-hydroxyimino-3-oxobutyrate. Yield 85.2%.