Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12](#[N:14])[CH3:13].[C:15]1([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[OH:30][CH:29]([C:28]1[CH:31]=[CH:32][C:25]([O:24][CH2:23][CH2:22][CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:26][CH:27]=1)[CH2:13][C:12]#[N:14]
Reactant: O=Cc1ccc(OCCCc2ccccc2)cc1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCC(O)c1ccc(OCCCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To dry tetrahydrofuran (14 mL), n-butyl lithium (0.94 mL; a 1.6 M hexane solution) and dry acetonitrile (0.082 mL) were successively dropped at −78° C. After stirring for 30 minutes, a solution of 4-(3-phenylpropoxy)benzaldehyde (300 mg) in dry tetrahydrofuran (3 mL) was dropped into the mixture at −78° C. The reaction mixture was stirred at room temperature for 1 hour, then poured into ice-water and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with a mixed solvent of diethyl ether and hexane and filtered to give the title compound (238 mg) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:26][CH2:27][C:28]#[CH:29])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=O)=[CH:4][CH:3]=1.C1C=CC=CC=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:45]2)=CC=1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:26][CH2:27][C:28]#[CH:29])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[S:45])=[CH:4][CH:3]=1
Reactant: C#CCOc1ccc(CCNC(=O)C(OCC#C)c2ccc(Cl)cc2)cc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: C#CCOc1ccc(CCNC(=S)C(OCC#C)c2ccc(Cl)cc2)cc1OC
Reaction time: 7 h

Procedure:
2-(4-Chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-(prop-2-ynyloxy)-acetamide (0.822 g) and benzene (30 ml) are stirred at +55° C. 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (“Lawesson's reagent”; 1.61 g) is added. The reaction mixture is stirred for additional 7 hours at +55° C. to +60° C. After cooling to room temperature diethylether (100 ml) is added. The mixture is then filtered. The solvent of the filtrate is evaporated. 2-(4-Chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-(prop-2-ynyloxy)-thioacetamide is obtained which is purified by flash-column-chromatography on silica gel using ethyl acetate/hexane. The purified product is in form of a resin. 1H-NMR (300 MHz, CDCl3, δ(ppm)): 2.45–2.55(m, 2H), 2.95(t, 2H), 3.85(s, 3H), 3.9–4.2(m, 4H), 4.75(d, 2H), 5.35(s, 1H), 6.65–6.8(m, 2H), 7.0(d, 1H), 7.2–7.4(m, 4H), 8.4–8.6(m, 1H).
Reaction SMILES: [CH:1]1(/[C:4](=[N:15]\[O:16][CH3:17])/[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:18]([CH:20]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)[CH2:21][C:22]([O:24]C)=[O:23])#[N:19]>>[C:18]([CH:20]([C:26]1[CH:31]=[CH:30][C:29]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](/[CH:1]3[CH2:3][CH2:2]3)=[N:15]/[O:16][CH3:17])=[CH:8][CH:9]=2)=[CH:28][CH:27]=1)[CH2:21][C:22]([OH:24])=[O:23])#[N:19]
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Reactant: CO/N=C(/COc1ccc(CO)cc1)C1CC1
Product: CO/N=C(/COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)C1CC1
Yield: 44.24 %

Procedure:
Compound 104 was synthesized from (4-{[(2E)-2-cyclopropyl-2-(methoxyimino)ethyl]oxy}phenyl)methanol (0.5 g, 2.12 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.44 g, 2.12 mmol) by following the procedure described in scheme 5 (0.008 g, yield: 44.24%); Purity: 85.80%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](Cl)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Al+3].[Cl-].[Cl-].[Cl-]>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:12](=[O:13])[CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:18][CH:17]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)CCc1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Yield: 61.2 %

Procedure:
A procedure similar to step 2 of Example 1 was used. 3-(4-nitro-phenyl)-propionyl chloride prepared in the step 2 of Example 6 and fluorobenzene were used as starting materials, and anhydrous AlCl3 was used as catalyst. The obtained product was a white solid in a yield of 61.2%, mp: 122-124 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.19 (2H, t, J=7.28 Hz), 3.32 (2H, t, J=7.28 Hz), 7.14 (2H, t, 3JFH=3JHH=8.40 Hz, ArH), 7.42 (2H, d, J=8.40 Hz, ArH), 7.99 (2H, dd, 3JHH=7.84, 4JFH=5.60 Hz, ArH), 8.16 (2H, d, J=8.40 Hz, ArH); EI-MS m/e (%): 273.1 (M+, 55), 123.0 (100).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:9])([C:5](=[O:8])[CH2:6][CH3:7])[CH3:4].[N:10](OCCCC)=[O:11]>C(OCC)C.C1(C)C=CC=CC=1>[OH:11][N:10]=[C:6]([CH3:7])[C:5](=[O:8])[C:3]([CH3:9])([CH3:4])[CH3:2]
Reactant: CCC(=O)C(C)(C)C
Reactant: CCCCON=O
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=NO)C(=O)C(C)(C)C
Temperature: -10 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
A solution of 40 g of hydrogen chloride in 156 g of diethyl ether is added dropwise at room temperature to 96 g (0.84 mol) of 2,2-dimethyl-3-pentanone in 960 g of toluene. After cooling to −10° C., a solution of 95 g of n-butyl nitrite in 470 g of diethyl ether is added dropwise. The mixture is stirred at from −10° C. to 0° C. for 4 hours and then allowed to come to room temperature. After a total of 16 h, the reaction mixture is washed three times with 1 l of ice-water each time and then extracted twice with 1 l of 1M sodium hydroxide solution each time. The alkaline phase is separated off and neutralized with 20% strength sulfuric acid. The crude product is filtered off with suction and, after drying, recrystallized from n-hexane. 66 g (55%) of the title compound are obtained as a pale yellow powder of melting point 107-110° C.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[C:16]([S:17]([NH:20][C:21]4[CH:42]=[CH:41][C:24]([C:25]([NH:27][C@H:28]([C:36]([O:38]CC)=[O:37])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:26])=[CH:23][CH:22]=4)(=[O:19])=[O:18])[C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.C(O)(=O)C>[OH-].[Na+]>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[C:16]([S:17]([NH:20][C:21]4[CH:42]=[CH:41][C:24]([C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:26])=[CH:23][CH:22]=4)(=[O:19])=[O:18])[C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NS(=O)(=O)c2cccc3c2ccc2nc(C)[nH]c(=O)c23)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1nc2ccc3c(S(=O)(=O)Nc4ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc4)cccc3c2c(=O)[nH]1

Procedure:
A solution of diethyl N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-7-yl)sulfonamido)benzoyl)-L-glutamate (0.16 g, 0.3 mmoles) in 0.1 N NaOH (10 ml) was stirred at room temperature under a nitrogen atmosphere for 48 hrs, after which time the solution was acidified (pH 3.5) with acetic acid. The precipitate was collected, washed with water and dried to give N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-7-yl)sulfonamido)benzoyl)-L-glutamic acid as an off-white solid. (0.12 g, 86%) 1H NMR (DMSO-d6, 200 MHz) δ: 1.72-2.08 (m, 2H, glu-CH2); 2.26 (t, J=Hz, 2H, glu-CH2); 2.43 (s, 3H, CH3); 4.18-4.35 (m, 1H, glu-CH); 7.07 (d, J=8.4 Hz, 2H, Ar); 7.63 (d, J=8.3 Hz, 2H, Ar); 7.82 (t, J=7.3 Hz, 1H, Ar); 7.84 (d, J=8.9 Hz, 1H, Ar); 8.32 (m, 2H, glu-NH+Ar); 9.07 (d, J=9.3 Hz, 1H, Ar); 10.16 (d, J=8.8 Hz, 1H, Ar); 12.71 (br s, 1H, NH). Anal. Calculated for C25H22N4O8S.7/4H2O: C, 52.67; H, 4.51; N, 9.83. Found: C, 52.52; H, 4.36; N, 9.70.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]=[C:37]=[S:38])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][C:37]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[C:17]([F:23])[CH:18]=2)=[S:38])=[O:35])=[CH:30][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (78 mg, yield 96%).
Reaction SMILES: Cl[P:2]1[O:7][CH:6]([CH:8]([CH3:10])[CH3:9])[C:5]([CH3:12])([CH3:11])[CH2:4][O:3]1.[CH3:13][C:14]1([CH3:40])[CH2:19][CH:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]2)[CH2:17][C:16]([CH3:39])([CH3:38])[NH:15]1>>[CH3:11][C:5]1([CH3:12])[CH2:4][O:3][P:2]([N:20]([CH:18]2[CH2:19][C:14]([CH3:40])([CH3:13])[NH:15][C:16]([CH3:39])([CH3:38])[CH2:17]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([P:2]2[O:7][CH:6]([CH:8]([CH3:9])[CH3:10])[C:5]([CH3:11])([CH3:12])[CH2:4][O:3]2)[CH:28]2[CH2:29][C:30]([CH3:37])([CH3:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH2:33]2)[O:7][CH:6]1[CH:8]([CH3:10])[CH3:9]
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CC(C)C1OP(Cl)OCC1(C)C
Product: CC(C)C1OP(N(CCCCCCN(C2CC(C)(C)NC(C)(C)C2)P2OCC(C)(C)C(C(C)C)O2)C2CC(C)(C)NC(C)(C)C2)OCC1(C)C

Procedure:
If 2-chloro-5,5-dimethyl-4-isopropyl-1,3,2-dioxaphosphorinane is reacted with N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)hexamethylenediamine in a procedure analogous to Example 1, N,N'-bis(5,5-dimethyl-4-isopropyl-1,3,2-dioxaphosphorinan-2-yl)-N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)hexamethylenediamine is obtained, which melts at 95°-97° (Compound No. 7).
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[S:8][C:9]=1[C:10]([OH:12])=[O:11])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:25]O>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:7]2[S:8][C:9]([C:10]([OH:12])=[O:11])=[C:5]([CH2:4][C:1]([O:3][CH3:25])=[O:2])[N:6]=2)=[CH:18][CH:17]=1
Reactant: CO
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)O

Procedure:
Mix 4-carboxymethyl-2-(4-chloro-phenyl)-thiazole-5-carboxylic acid (145 g, 482 mmol) in MeOH (900 mL) and treat with sulfuric acid (1.20 mL, 21.68 mmol). Stir the mixture at reflux overnight and then begin distilling the MeOH to concentrate the solution. Collect about 300 mL of MeOH and then reflux for an additional 5 h. Filter the reaction mixture and cool the filtrate in an ice bath for one hour. Collect the yellow precipitate by filtration and rinse with cool MeOH. Dry the solid in a vacuum oven at 45° C. overnight to give 105 g of the title compound. Concentrate the above filtrate to about 200 mL volume and collect 20 g of additional material. 1H NMR (DMSO-d6, 500 MHz): δ 13.72 (br s, 1H), 8.00 (d, 2H, J=8.4), 7.59 (d, 2H, J=8.8), 4.21 (s, 2H), 3.64 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:31]=[CH:30][C:11]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([O:24]C3CCCC3)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[CH:10][CH:9]=2)[C:6](=[O:32])[CH:5]=[CH:4][C:3]=1[C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1.[Li+].[OH-]>C1COCC1.O>[NH2:1][C:2]1[N:7]([C:8]2[CH:31]=[CH:30][C:11]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[CH:10][CH:9]=2)[C:6](=[O:32])[CH:5]=[CH:4][C:3]=1[C:33](=[O:41])[C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1
Reactant: CC(C)C[C@H](NC(=O)COc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1)C(=O)OC1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](NC(=O)COc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
From Example 56. To a solution of cyclopentyl N-({4-[6-amino-5-(4-fluorobenzoyl)-2-oxopyridin-1(2H)-yl]phenoxy}acetyl)-L-leucinate (35 mg, 0.06 mmol) in THF (1 ml) and water (1 ml) was added LiOH (30 mg, 1.24 mmol, 20 eq). The mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure and water (5 ml) added. The pH was adjusted to 7 using 1M HCl and the aqueous layer extracted with 1-butanol (3×5 ml). The combined organic extracts were concentrated under reduced pressure. The solid residue was triturated with Et2O, filtered and dried under reduced pressure to provide the title compound as a cream solid (11 mg, 36% yield).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>>[CH3:21][S:18]([CH2:2][CH2:3][CH:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1)(=[O:20])=[O:19]
Reactant: CC1(C)OCC(CCO)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CCS(C)(=O)=O)O1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
4-(2-Hydroxylethyl)-2,2-dimethyl-1,3-dioxolane (25 g, 170 mmol), triethylamine (55.9 mL, 400 mmol), and a stir bar were added to a 1000 mL round bottom flask. The flask was sealed and flushed with nitrogen. Anhydrous DCM (600 mL) was added, and the mixture cooled to approx −5° C. (ice and NaCl). Mesyl chloride (19.9 mL, 255 mmol, 1.5 eq) was added slowly via syringe over a 60 minute period, and the reaction stirred at −5° C. for a further 1.5 hours. At this point TLC showed that the starting material had been consumed. The solution was diluted with DCM (350 mL), divided into two (˜500 mL) portions, and each portion worked up as follows: the solution was transferred to a 1000-mL separating funnel and washed with saturated NaHCO3 (2×200 mL). The organic phase was then dried (MgSO4), filtered, and concentrated (rotovap). The crude product was purified by column chromatography. Final yield: 32.0 g, 84.1%.
Reaction SMILES: [NH3:1].[CH2:2]([O:9][C:10]([NH:12][CH:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH:14]([OH:23])[C:15]([F:22])([F:21])[C:16](OCC)=[O:17])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(OCC)C>[CH2:2]([O:9][C:10]([NH:12][CH:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH:14]([OH:23])[C:15]([F:22])([F:21])[C:16]([NH2:1])=[O:17])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(F)(F)C(O)C(CC(C)C)NC(=O)OCc1ccccc1
Reactant: N
Solvent: CCOCC
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(O)C(F)(F)C(N)=O

Procedure:
A stream of dry ammonia was bubbled at -78° C., through a solution of 0.820 g (2.2 mmol) of 4-benzyloxycarbonylamino-2,2-difluoro-3-hydroxy-6-methylheptanoic acid, ethyl ester in anhydrous diethyl ether (10 mL). After saturation, the temperature was allowed to rise to room temperature with stirring. The excess ammonia was removed, and the solvent evaporated in vacuo. The residue was taken off in pentane to yield the expected amide in quantitative yield as a solid.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].[H-].[Na+].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[Cl:19]>CN(C=O)C>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH:3]([C:2](=[O:1])[CH2:6][CH3:7])[C:4]#[N:5]
Reactant: CCC(=O)CC#N
Reactant: Clc1cccc(CBr)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)C(C#N)Cc1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of 3-oxopentanenitrile (500 mg, 5.2 mmol) in DMF (10 mL) was added NaH (248 mg, 6.2 mmol) and stirred at 0° C. for 1 h. Then 1-(bromomethyl)-2,3-dichlorobenzene (1.23 g, 5.2 mmol) was added to the mixture and warmed to room temperature, stirred for 20 h. The mixture was concentrated under reduced pressure to give the crude titled product (1.2 g, 92%), which was used for next step without further purification.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([NH:19][CH3:20])[CH:16]=[CH:15][C:14]=3[Cl:21])[C:5]2=[N:4][C:3]=1[CH3:22].N1C=CC=CC=1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([N:19]([CH3:20])[S:29]([CH3:32])(=[O:31])=[O:30])[CH:16]=[CH:15][C:14]=3[Cl:21])[C:5]2=[N:4][C:3]=1[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CNc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc2c(OCc3cc(N(C)S(C)(=O)=O)ccc3Cl)cccn2c1Br
Temperature: 25 °C
Reaction time: 9 h
Yield: 34.6 %

Procedure:
To a solution of 3-bromo-8- (2-chloro-5-methylaminobenzyloxy)-2-methylimidazo[1,2-a]pyridine (60 mg), pyridine (16 mg) and 4-dimethylaminopyridine (10 mg) in methylene chloride (2 ml) was added mesyl chloride (22 mg) in one portion at 5° C., and the mixture was stirred for 9 hours at ambient temperature. The precipitate was filtered off and the residue was washed with methylene chloride and diethyl ether respectively. The filtrate was concentrated in vacuo and the residue was purified by preparative thin-layer chromatography on silica gel (methanol:methylene chloride=1:10, V/V) to give 3-bromo-8-[2-chloro-5-(N-methyl-N-methylsulfonylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (25 mg).
Reaction SMILES: [CH3:1][C:2]1[C:8]([S:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[CH2:12][CH:13]=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[C:8]([S:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:12][CH:13]=[O:14]
Reactant: CSc1cccc(N)c1C
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CSc1cccc(NCC=O)c1C
Temperature: 150 °C

Procedure:
2-Methyl-3-methylthioaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated to about 150°C for a period of about 8 hours. After this time the mixture is filtered and the filrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-3-methylthioanilino)acetaldehyde.
Reaction SMILES: [CH2:1]([OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16]C.[O:19]1CCC[CH2:21][CH:20]1OC1CCCCO1.C(Cl)(=O)C>C(O)(=O)C>[C:20]([O:18][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH3:16])(=[O:19])[CH3:21]
Reactant: CCCCC/C=C\CCCCCCCCCCO
Reactant: C1CCC(OC2CCCCO2)OC1
Solvent: CC(=O)Cl
Solvent: CC(=O)O
Product: CCCC/C=C\CCCCCCCCCCOC(C)=O
Reaction time: 3 h
Yield: 55.7 %

Procedure:
9 g. of (Z)-11-hexadecenol-tetrahydropyranyl ether (Formula III, R=H, Y=tetrahydropyranyl) are dissolved in 25 ml. of acetic acid. 6 ml. of acetyl chloride are added, and the solution is boiled on an oil bath of about 80° C. for 3 hours. The mixture is cooled, poured onto 50 g. of ice, and extracted thrice with a total amount of 200 ml. of hexane. The extracts are combined, washed with 30 ml. of water, dried over magnesium sulfate, filtered, and the solvent is evaporated. The residue is distilled off in fine vacuo. 5.3 g. (55.7%) of (Z)-11-hexadecenyl acetate are obtained; b.p.: 142°-144° C./0.25 mmHG.; 120°-122° C./0.05 mmHg.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4](NC1CC1)=[O:5].[C:13]1([CH2:19][CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4]([NH:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: NCCc1ccccc1
Product: CC[C@H](N)[C@H](O)C(=O)NCCc1ccccc1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide, Representative Procedure B, using 2-phenylethanamine in the seventh step (step B7).
Reaction SMILES: Cl.[CH2:2]([NH2:5])[CH2:3][CH3:4].[O:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[C:10]=2[O:9][CH:8]=[CH:7]1.C(Cl)CCl>CN(C)C=O>[CH2:2]([NH:5][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]1[C:10]2[O:9][CH:8]=[CH:7][O:6][C:11]=2[CH:12]=[CH:13][CH:14]=1)[CH2:3][CH3:4]
Reactant: O=C(O)CCCc1cccc2c1OC=CO2
Reactant: CCCN
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCNC(=O)CCCc1cccc2c1OC=CO2
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A suspension of 0.29 g (2.6 mmol) of n-propylamine hydrochloride in 7 ml of anhydrous N,N-dimethylformamide is cooled to 0° C. and then 0.33 g (3.54 mmol) of N,N-dimethylaminopyridine are added to the mixture. After the addition of 0.41 g (2.36 mmol) of the acid obtained in Step F of Example 40, 0.5 g (2.6 mmol) of EDC is added to the mixture. The solution is stirred for 12 hours under argon at room temperature and then the solvent is evaporated off in vacuo. The residue is taken up in a water/ethyl acetate (1/1) mixture and then the aqueous phase is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. Chromatography over silica gel (eluant:AcOEt/PE:70/30) yields the title amide in the form of a clear syrup.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1.[Sn](Cl)Cl>CO.ClCCl>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](CSCc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](CSCc1ccc(N)cc1)NC(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
A mixture of (2R)-methyl-2-tert-butoxycarbonylamino-3-(4-nitro-benzylsulfanyl)-propionate (3.75 g, 10.1 mmol) and tin (II) chloride (5.76 g, 30.0 mmol) in methanol (50 mL) was stirred at 50° C. Upon completion (TLC: 5% methanol in dichloromethane), the mixture was cooled to room temperature, quenched with saturated potassium fluoride solution (75 mL) and extracted with diethyl ether (3×75 mL). The combined extract was washed sequentially with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Flash chromatography purification (SiO2; 1-2% methanol in dichloromethane as eluent) yielded the titled compound as an off-white solid. 1H NMR (CDCl3, 300 MHz) δ 7.08 (2H, d, J=8 Hz, ArH), 6.25 (2H, d, J=8 Hz, ArH), 4.53 (1H, m, CHN), 3.75 (3H, s, OCH3), 3.63 (2H, s, PhCH2S), 2.84 (2H, m, CH2CHN), 1.46 (9H, s, CMe3); ESI-LCMS e/z calculated for C16H24N2O4S 340.146. found 341 (M+H)+, 363 (M+Na)+.