Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9](=[NH:12])OC)[CH:6]=[CH:7][CH:8]=1.[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH2:18])[CH3:14]>CO>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH:18][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Br:2])[CH:4]=1)=[NH:12])[CH3:14]
Reactant: COC(=N)c1cccc(Br)c1
Reactant: CCOC(CN)OCC
Agent: Cl
Solvent: CO
Product: CCOC(CNC(=N)c1cccc(Br)c1)OCC
Temperature: 25 °C

Procedure:
To a solution of methyl 3-bromobenzenecarboximidoate hydrochloride (Step 1 above) in MeOH (10 mL) at 0° C. was added [2,2-bis(ethyloxy)ethyl]amine (1.74 mL; 12 mmol) in one portion and the mixture was gradually warmed to room temperature (overnight). The mixture was concentrated in vacuo, partitioned between CH2Cl2/1M NaOH and the layers were separated. The aqueous layer was extracted with CH2Cl2 (×2), combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo affording the title compound as a light brown oil which was used directly for Step 3 below. LC/MS (method A) tR 1.25 min, m/z 315, 317 (M+H, Br isotopes, 4%), 223, 225 (M+H−2EtOH, Br isotopes, 100%).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Br[C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1>>[CH3:1][C@@H:2]1[N:7]([C:16]2[CH:21]=[N:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Yield: 49.9 %

Procedure:
The procedures described in Example 104 and starting with (3S)-tert-butyl 3-methylpiperazine-1-carboxylate (10.0 g, 50 mmol) and 5-bromo-2-nitropyridine (10.5 g, 50 mmol) afforded 113a as a yellow solid (8.05 g, 50%). See FIG. 13. MS-ESI: [M+H]+ 323
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:24])[C:8]([CH2:22][CH3:23])=[C:9]([C:20]#[N:21])[C:10]=1B1OC(C)(C)C(C)(C)O1)=[O:5])[CH3:2].Br[C:26]1[CH:31]=[CH:30][C:29]([N:32]([CH3:42])[CH2:33][CH2:34][NH:35][S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:24])[C:8]([CH2:22][CH3:23])=[C:9]([C:20]#[N:21])[C:10]=1[C:26]1[CH:27]=[CH:28][C:29]([N:32]([CH3:42])[CH2:33][CH2:34][NH:35][S:36]([CH:39]([CH3:40])[CH3:41])(=[O:37])=[O:38])=[CH:30][CH:31]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(B2OC(C)(C)C(C)(C)O2)c(C#N)c(CC)n1C
Reactant: CC(C)S(=O)(=O)NCCN(C)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(N(C)CCNS(=O)(=O)C(C)C)cc2)c(C#N)c(CC)n1C
Yield: 55 %

Procedure:
Prepare the title compound in a manner analogous to the procedure set forth in Example E-281, using 4-cyano-5-ethyl-1-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (817 mg, 2-4 mmol, prepared in preparation 50), propane-2-sulfonic acid {2-[(4-bromo-phenyl)-methyl-amino]-ethyl}-amide (550 mg, 1.6 mmol, prepared in preparation 81), aqueous sodium carbonate (4.0 mL, 8.0 mmol, 2N), and [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloropalladium(II) complex with methylene chloride (1:1) (39 mg, 0.05 mmol) to give 404 mg (55%) of the title compound. Mass spectrum (ES+)=461.1 (M+1).
Reaction SMILES: 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.[CH2:47]1[C:51]2([CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:50][CH2:49][N:48]1[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58].Cl.Br[C:66]1[CH:71]=[CH:70][N:69]=[CH:68][CH:67]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:60]([O:59][C:57]([N:48]1[CH2:49][CH2:50][C:51]2([CH2:52][CH2:53][N:54]([C:66]3[CH:71]=[CH:70][N:69]=[CH:68][CH:67]=3)[CH2:55][CH2:56]2)[CH2:47]1)=[O:58])([CH3:63])([CH3:62])[CH3:61]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: Brc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccncc3)CC2)C1
Reaction time: 0.25 h
Yield: 43.3 %

Procedure:
BINAP (293 mg, 0.47 mmol) and Pd(OAc)2 (317 mg, 1.4 mmol) was added to a mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (5.66 g, 23.6 mmol), 4-bromopyridine HCl (4.58 g, 23.6 mmol) and sodium tert-butylate (6.8 g, 70.8 mmol) in toluene and the reaction mixture was degassed under argon for 20 minutes and heated under reflux for 4 h. The mixture was then diluted with ethyl acetate, stirred for 15 minutes and filtered over Celite. The organic phase was washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography. Yield: 43.3%
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:28])[C:16]([CH:24]2[CH2:27][CH2:26][CH2:25]2)([OH:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH3:15][C:16]([CH3:24])=[CH:17][CH2:18][CH2:6][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:28])[C:16]([CH:24]2[CH2:25][CH2:26][CH2:27]2)([OH:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)C(O)(c2ccccc2)C2CCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)=CCCN1CCC(NC(=O)C(O)(c2ccccc2)C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 174.1 %

Procedure:
1.0 g of N-(1-t-butoxycarbonylpiperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetamide was dissolved in 25 ml of a 4N hydrochloric acid solution in dioxane, and this solution was stirred at room temperature overnight. Then, the reaction mixture was evaporated to dryness under reduced pressure to obtain 0.83 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1.O1CCCC1.[OH-].[Li+]>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A mixture of 5-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-2-methoxypyridine (382 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (400 mg), sodium carbonate (170 mg) and sodium iodide (240 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 65% ethyl acetate/hexane) to give ethyl 3-[{[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate. The obtained ethyl 3-[{[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.7 mL) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (153 mg, 25%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.CCN(CC)CC.[Cl:29][C:30]1[C:31]([CH3:57])=[C:32]([NH:38][C@H:39]([C:53]([OH:56])([CH3:55])[CH3:54])[C:40]([NH:42][NH:43][C:44](=[O:52])[C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)=O)[CH:33]=[CH:34][C:35]=1[C:36]#[N:37]>C(Cl)Cl.C1COCC1>[Cl:29][C:30]1[C:31]([CH3:57])=[C:32]([NH:38][C@@H:39]([C:40]2[O:52][C:44]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)=[N:43][N:42]=2)[C:53]([OH:56])([CH3:55])[CH3:54])[CH:33]=[CH:34][C:35]=1[C:36]#[N:37]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)cc2)C(C)(C)O)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)cc3)o2)C(C)(C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of triphenylphosphine (5.35 g, 20.4 mmol) in DCM (100 mL) was added I2 (5.18 g, 20.4 mmol) at 0° C. After all the Iodine was dissolved completely, Et3N (5.7 mL, 40.9 mmol) was added, followed by a solution of (R)—N′-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)-4-fluorobenzohydrazide (4.27 g, 10.2 mmol) in DCM (20 mL) and THF (20 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 30 min. The reaction was quenched with saturated aq. sodium thiosulfate (20 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound (R)-2-chloro-4-(1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxy-2-methylpropylamino)-3-methylbenzonitrile (3.31 g, 81%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.06 (dd, J=5.3, 9.0 Hz, 2H), 7.47 (d, J=8.6 Hz, 1H), 7.33 (t, J=9.0 Hz, 2H), 6.79 (d, J=8.6 Hz, 1H), 5.70 (d, J=8.7 Hz, 1H), 5.09 (d, J=8.7 Hz, 1H), 2.39 (s, 3H), 1.52 (s, 3H), 1.36 (s, 3H).
Reaction SMILES: [CH:1]1([C:14]2([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15]2)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.[C:21](Cl)(=[O:23])[CH3:22]>>[C:21]([N:2]1[CH2:3][CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH:1]1[C:14]1([C:18]([OH:20])=[O:19])[CH2:15][CH2:16][CH2:17]1)(=[O:23])[CH3:22]
Reactant: O=C(O)C1(C2NCCc3c2[nH]c2ccccc32)CCC1
Reactant: CC(=O)Cl
Product: CC(=O)N1CCc2c([nH]c3ccccc23)C1C1(C(=O)O)CCC1

Procedure:
The procedure is as in Example 55, using as substrate the compound of Example 35 and as reagent acetyl chloride.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12]([Br:16])=[C:11]([O:17][CH2:18][C:19]#[N:20])[CH:10]=[CH:9]3)=[CH:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:16][C:12]1[C:13]2[C:8](=[CH:7][C:6]([C:5]3[S:1][C:2]4[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=4[C:4]=3[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[O:17][CH2:18][C:19]#[N:20]
Reactant: N#CCOc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Br
Reactant: CCCCC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)sc2ccccc12
Temperature: 25 °C
Yield: 5.6 %

Procedure:
To a 0° C. suspension of (6-benzo[b]thiophen-2-yl-1-bromo-naphthalen-2-yloxy)-acetonitrile (5.27 g, 13.4 mmol) in chloroform (400 mL) was added valeryl chloride (2.1 mL, 17 mmol) and tin (IV) chloride (2.3 mL, 20 mmol). The reaction mixture was refluxed for 22.5 hours. During reflux, valeryl chloride (8.5 mL, 70 mmol) in four portions and tin (IV) chloride (8.9 mL, 76 mmol) were added in four portions. After cooling to ambient temperature, the reaction mixture was poured into ice water. The phases were separated, and the organic phase was washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was purified by flash chromatography using (1) 100% chloroform, (2) 20–60% methylene chloride in hexane and 100% methylene chloride and (3) HPLC in 86% acetonitrile (0.1% trifluoroacetic acid) in water. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at 60° C. for 30 minutes yielded (0.356 g, 5.23%) of the title compound as a clear brown gum: mass spectrum (+EI, [M+H]+) m/z 478/480. 1H NMR (500 MHz, DMSO-d6): δ8.24–8.28 (m, 2H), 8.20 (d, 1H, J=1.83 Hz), 8.10 (dd, 1H, J=6.49 Hz and 1.48 Hz), 7.96–7.97 (m, 1H), 7.81 (dd, 1H, J=8.71 Hz and 1.84 Hz), 7.73 (d, 1H, J=9.15 Hz), 7.46–7.52 (m, 2H), 5.47 (s, 2H), 2.42 (t, 2H, J=7.26 Hz), 1.41–1.46 (m, 2H), 0.97–1.04 (m, 2H), 0.57 ppm (t, 3H, J=7.33 Hz). Elemental Analysis for C25H20BrNO2S+0.6 mole H2O: Calcd: C, 61.38; H, 4.37; N, 2.86; Found: C, 61.07; H, 4.21; N, 2.67.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]([CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])=[CH:14][CH2:15][CH2:16][C:17](=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:9]1[C:27]([CH3:29])([CH3:28])[CH:26]1[CH2:25][CH2:24][C:13]([CH3:12])=[CH:14][CH2:15][CH2:16][C:17](=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CC(=O)CCC=C(C)CCC=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CC(=O)CCC=C(C)CCC1OC1(C)C
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 48.6 %

Procedure:
A solution of 5.1 g of m-chloroperbenzoic acid in 50 ml of methylene chloride was added dropwise at -40° C. under a nitrogen atmosphere to a solution of 6 g of the product of Example 3 in 60 ml of methylene chloride and after stirring for 15 minutes at -20° C., the mixture was poured into a saturated aqueous sodium bicarbonate solution. The mixture was extracted with methylene chloride and the organic phase was washed with aqueous sodium bicarbonate solution and then with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and was eluted with a 7-3 benzene-ethyl acetate mixture to obtain 3.1 g of methyl 10-epoxy-7,11-dimethyl-3-oxo-6-dodecenoate in the form of a colorless liquid with a refractive index nD25 = 1.4680.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][C:3]=1[C@:17]12[O:25][CH2:24][CH2:23][C@H:22]1[CH2:21][S:20][C:19]([NH:26]C(=O)OC(C)(C)C)=[N:18]2.C(O)(C(F)(F)F)=O>ClCCl>[NH2:26][C:19]1[S:20][CH2:21][C@@H:22]2[CH2:23][CH2:24][O:25][C@:17]2([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:6]=[CH:7][C:2]=2[F:1])[N:18]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccccn4)ccc3F)OCC[C@H]2CS1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ccccn4)ccc3F)OCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of tert-butyl ((4aR,7aR)-7a-(2-fluoro-5-(picolinamido)phenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (Preparation 5, 12 mg, 0.025 mmol) in dichloromethane (254 μL) was added TFA (39.1 μL, 0.508 mmol) at rt, and the reaction mixture was stirred at rt for 3 h. The crude product was directly purified by prep TLC eluting with 90% CH2Cl2/9% MeOH/1% NH4OH to give the title compound (5 mg, 0.013 mmol, 52.9% yield) a colorless oil. 1H NMR (500 MHz, CHLOROFORM-d) δ 10.04 (s, 1H), 8.68-8.62 (m, 1H), 8.31 (dt, J=7.8, 1.0 Hz, 1H), 8.01 (ddd, J=8.9, 4.1, 2.9 Hz, 1H), 7.93 (td, J=7.7, 1.7 Hz, 1H), 7.72 (dd, J=6.9, 2.8 Hz, 1H), 7.51 (ddd, J=7.5, 4.8, 1.1 Hz, 1H), 7.08 (dd, J=10.9, 8.8 Hz, 1H), 4.11 (t, J=7.2 Hz, 3H), 3.50 (s, 1H), 3.15 (dd, J=12.8, 4.0 Hz, 1H), 2.97 (ddd, J=13.0, 7.5, 1.8 Hz, 1H), 2.77 (dd, J=7.0, 4.0 Hz, 1H), 2.22-1.98 (m, 2H). MS (M−1): 371.2.
Reaction SMILES: [OH-].[Na+].[C:3](#[N:6])[CH:4]=[CH2:5].[CH2:7]([OH:10])[CH2:8][OH:9]>>[CH2:8]([CH2:7][O:10][CH2:5][CH2:4][C:3]#[N:6])[O:9][CH2:5][CH2:4][C:3]#[N:6]
Reactant: OCCO
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Product: N#CCCOCCOCCC#N

Procedure:
To a 2000 ml. flask fitted with a stirrer, reflux condensor and an additional funnel and immersed in an ice water bath was added 248 g. of ethylene glycol and 20 g. of 40% aqueous NaOH. The stirrer was started and the 424 g. of acrylonitrile was added from the funnel over a period of about 15 minutes. The temperature remained in the range of 25°-35° C. during the addition of the acrylonitrile. The stirring was continued for one additional hour after which 170 g. of the reaction mixture was withdrawn from the flask and neutralized by contacting with 70 g. of a sulfonic acid resin. The withdrawn mixture contained more than 95 wt. % of 3,3'-ethylenedioxy-bis(propionitrile), and essentially no acrylonitrile. This run was performed with gradual addition of acrylonitrile to produce the 3,3'-ethylenedioxy-bis(propionitrile) for use in the subsequent run with rapid addition of acrylonitrile.
Reaction SMILES: [CH:1]1([C:4]2([OH:14])[CH2:13][CH2:12][C:7]3(OCC[O:8]3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.O.Cl>CC(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2([OH:14])[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: OC1(C2CC2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C1CCC(O)(C2CC2)CC1
Reaction time: 8 h
Yield: 35.7 %

Procedure:
8-Cyclopropyl-1,4-dioxaspiro[4.5]decan-8-ol (1.8 g) was dissolved in acetone (30 mL). A solution of water (15 mL) and conc. HCl was added. The reaction mixture was stirred overnight. The reaction mixture was taken in ethyl acetate and washed with sat. NaHCO3. Purification by silica chromatography produced 4-cyclopropyl-4-hydroxycyclohexanone (0.5 g, 27%). 1H NMR (400 MHz, CDCl3): δ 2.80-2.69 (m, 2H), 2.50-2.42 (m, 2H), 1.99-1.78 (m, 4H), 1.01-0.99 (m, 1H), 0.50-0.47 (m, 4H); MS (ESI) m/z: Calculated for C9H14O2: 154.1. found: 155.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[Br:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1>C1COCC1>[Br:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:3])[CH:9]=1
Reactant: CI
Reactant: BrCCc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(CCBr)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with NaH (900 mg, 37.52 mmol), MeI (3.14 mL, 50.00 mmol) and THF (7.5 mL). The resulting grey suspension was stirred at rt for 5 min, then a solution of 3-(2-bromethyl)-indol (1.12 g, 5.00 mmol) in THF (25 mL) was added dropwise. After stirring for 18 h at rt, the reaction mixture was concentrated, redissolved in DCM and washed with H2O (3×). The org. layer was dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield the title compound as an yellow oil which was used as such in the next step. LC-MS conditions A: tR=0.95 min, [M+H]+=no ionization.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:20])[CH:9]=2)[N:4]=1.C([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].C(O)(C(F)(F)F)=O>ClCCl.CCCCCCC.CN(C=O)C>[NH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][NH2:28])[CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:20])[CH:9]=2)[N:4]=1
Reactant: Nc1nc(-c2cccc(O)c2)c2cc(Cl)ccc2n1
Reactant: CC(C)(C)OC(=O)NCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NCCCCCOc1cccc(-c2nc(N)nc3ccc(Cl)cc23)c1
Reaction time: 16 h
Yield: 58.6 %

Procedure:
A mixture of 100 mg of 2-amino-6-chloro-4-(3-hydroxyphenyl)quinazoline hydrochloride, 90.69 mg of 5-(BOC-amino)-1-pentyl bromide, 100 mg of potassium carbonate and 1 ml of DMF is stirred at 40° for 16 hours. The mixture is dissolved in 2 ml of dichloromethane, 1 ml of TFA is added, and the mixture is stirred at room temperature for 4 hours. 3 ml of n-heptane are added, the solvents are removed in vacuo, and the residue is chromatographed, giving 67.9 mg (58.6%) of 2-amino-6-chloro-4-[3-(5-aminopentyloxy)phenyl]quinazoline (“A141”), MW 357.86.
Reaction SMILES: N([O-])=O.[Na+].Cl.[CH3:6][C:7]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[C:10]([CH3:17])[C:8]=1N.[C:18]([O-])(=[O:20])C.[K+].C=O.Cl.NO.[Na]>O.Cl.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:6][C:7]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[C:10]([CH3:17])[C:8]=1[CH:18]=[O:20]
Reactant: CC(=O)[O-]
Reactant: Cc1cc(C(C)C)cc(C)c1N
Agent: [Cu+2]
Agent: C=O
Agent: Cl
Solvent: O
Product: Cc1cc(C(C)C)cc(C)c1C=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 16.3 %

Procedure:
A solution of NaNO2(1.75 g, 25 mmol) in water (4 mL) was added to a stirred solution of 2,6-dimethyl-4-isopropylaniline hydrochloride (Schubert, W. M. et al. J. Amer. Chem. Soc. 1954, 76:1) (5 g, 25 mmol) in concentrated HCl (4.5 mL) at 0° C. The mixture was allowed to stir at 0° C. for 1.5 hours. Potassium acetate (6 g) was then added. At the same time, a solution of paraformaldehyde (1.15 g), hydroxylamine hydrochloride (2.63 g, 37.84 mmol) and potassium acetate (5.1 g) in water (17 mL) was heated under reflux for 15 min. To this solution, cooled to 10-15° C., was added potassium acetate (16.5 g) in water (18 mL), copper sulfate (0.625 g) and sodium suffite (0.1 g). The neutral diazonium solution was then added immediately to the paraformaldehyde mixture and the resulting solution was allowed to stir at room temperature for 2 hours. The mixture was acidified with 20 mL of concentrated HCl and heated at reflux for 2 hours. The cooled mixture was extracted with ether (3×30 mL) and the solvent was removed under reduced pressure. The yellow liquid was purified by column chromatography using as eluent hexane-EtOAc (97:3) to give 0.72 g (16%) of the title compound as a white liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].[Cl-].[NH4+]>C1COCC1>[S:25]([O:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:10]=1)([CH3:24])(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)c1
Temperature: -50 °C
Yield: 109.5 %

Procedure:
1-[3-[(tert-Butoxycarbonyl)amino]phenyl]methanol (10 g, 44.8 mmoles) (Ref.: F. J. Brown, P. R. Bernstein, L. A. Cronk, D. L. Dosset, K. C. Hebbel. T. P. Maduskuie, Jr., H. S. Shapiro, E. P. Vacek, Y. K. Lee, A. K. Willard, R. D. Krell and D. W. Snyder, J. Med. Chem., 32, 1989, 807-826) and triethylamine (13 g, 17.9 mL, 138.4 mmoles) were dissolved in anhydrous THF (169 mL) and the solution was stirred and cooled to −50° C. Methanesulfonyl chloride (10.26 g, 7.02 mL, 89.6 mmoles) in anhydrous THF (85 mL) was added dropwise over a period of 20 min at −50° C. under an argon atmosphere. The mixture was stirred at −50° C. for an additional 20 min. A saturated aqueous solution of ammonium chloride (12.9 g) was added and the mixture was warmed to 25° C. The mixture was filtered and the filtrate was extracted twice with ethyl acetate. The ethyl acetate was washed with brine, water, dried (MgSO4), filtered and evaporated to dryness to give the title compound (14.78 g). The material was used without further purification.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[O:7]1[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]1>CS(O)(=O)=O>[C:1]([O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Product: C=C(C)C(=O)OC1CCCCO1
Yield: 71.9 %

Procedure:
2-Tetrahydropyranyl methacrylate (THPMA) was prepared in an analogous manner to the THF-ester above using 24.5 g (0.29 mol) of methacrylic acid, 25.6 g (0.305 mol) of 4,5-dihydropyran and 0.05 g of methanesulfonic acid to yield 35.5 g (72%) of the desired product after distillation at reduced pressure.