Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=1.C(N(CC)CC)C.[CH2:18]([O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH3:34])[C:23]=1[C:24](Cl)=[O:25])[CH2:19][CH3:20]>O1CCCC1>[CH3:8][C:7]([C:4]1[CH:3]=[C:2]([NH:1][C:24](=[O:25])[C:23]2[C:27]([O:31][CH2:32][CH2:33][CH3:34])=[CH:28][CH:29]=[CH:30][C:22]=2[O:21][CH2:18][CH2:19][CH3:20])[O:6][N:5]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1cc(N)on1
Reactant: CCCOc1cccc(OCCC)c1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCOc1cccc(OCCC)c1C(=O)Nc1cc(C(C)(C)C)no1
Temperature: 25 °C
Yield: 10.9 %

Procedure:
To a stirred solution of 2.8 g of 5-amino-3-(1,1-dimethylethyl)isoxazole in 40 ml of tetrahydrofuran containing 4.5 ml of triethylamine was added dropwise over ten minutes a solution of 4.88 g of 2,6-di-n-propoxybenzoyl chloride in 10 ml of tetrahydrofuran. Following the addition, the reaction mixture was heated at reflux for seventy-two hours. The reaction mixture was then cooled to room temperature and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in a mixture of dichloromethane and water, and the organic layer was separated, washed with fresh water, dried, and the solvent was removed by evaporation to provide an oil. The oil was crystallized from Skelly B and diethyl ether to provide 750 mg of N-[3-(1,1-dimethylethyl)-5-isoxazolyl]-2,6-di-n-propoxybenzamide. M.P. 85°-87° C. Yield 10%.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[NH:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([N:11]1[C@@H:12]2[CH2:18][CH2:17][CH2:16][C@@H:13]2[C:14](=[O:15])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]2[CH:22]=[CH:21][CH:20]=[CH:19][C:10]1=2)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccccc1
Product: CC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 100 °C
Reaction time: 0.58 h
Yield: 77 %

Procedure:
A mixture of (3aR*,10aS*)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (1.47 g, 5.0 mmol) and acetic anhydride (5 mL) was stirred for 35 minutes at 100° C. Resulting crystalline precipitate was collected by filtration, which was washed with ethanol to give 1.29 g (yield 77%) of the titled compound, m.p. 209°-210° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:14])(=[O:13])=[O:12].[Na+:15].[Si]([O-])([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[OH-].[Na+].[CH2:27]([O:30][CH2:31][CH2:32][OH:33])[CH2:28][CH3:29]>O>[CH2:27]([O:30][CH2:31][CH2:32][O:33][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:14])(=[O:13])=[O:12])[CH2:28][CH3:29].[Na+:15]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)[O-])c1
Reactant: CCCOCCO
Agent: [Na+]
Agent: [O-][Si]([O-])([O-])[O-]
Agent: [OH-]
Solvent: O
Product: CCCOCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)[O-]

Procedure:
26.0 g of sodium 2-chloro-5-nitrobenzenesulfonate and 5.0 g of sodium silicate (Na2O.nSiO2 wherein n is about 3) were suspended in 120 ml of 2-propoxyethanol. To the suspension was added dropwise with stirring a solution containing 5.0 g of sodium hydroxide dissolved in 5 ml of water at 65° C. for 10 minutes. After completion of the addition, the reaction mixture was stirred at 65° C. for 3 hours and the insoluble materials were removed by filtration under suction. The solids which deposited from the filtrate upon standing were removed by filtration. The filtrate was concentrated to a dry solid. 100 ml of ethanol was added to the residue to form crystals. The crystals were recovered by filtration, washed with isopropyl alcohol and dried at 50° C. Yield: 14.1 g. The compound at first melted at 70° to 74° C., then solidified at about 130° C. and again melted at 206° to 209° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][C:12]([OH:14])=[O:13])=[O:8])[CH2:3][C:4](=[O:6])[OH:5].CC(C)=O.[C:22](Cl)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>O.[OH-].[Na+]>[C:22]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][C:12]([OH:14])=[O:13])=[O:8])[CH2:3][C:4](=[O:5])[OH:6])(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A suspension of 20 g (0.081 mols) of α-aspartylaspartic acid in 80 ml of water was dissolved in a 27-% sodium hydroxide aqueous solution until the pH reached 11, and 40 ml of acetone were added thereto. To the solution were added dropwise 17.7 g (0.081 mols) of lauroyl chloride over a period of 1 hour. When adding lauroyl chloride, the temperature was maintained at 10° C., and 27-% sodium hydroxide was added dropwise simultaneously to keep the pH at 11. After the addition of lauroyl chloride, the reaction solution was warmed at 30° C., and allowed to stand for 30 minutes. Subsequently, the pH was adjusted to 1 with the addition of conc. hydrochloric acid. The solid precipitate was separated by filtration, and dried to obtain 31.7 g of N-(N'-lauroyl-α-aspartyl)aspartic acid in a yield of 91%. This solid was analyzed by infrared spectrophotometry. A peak diagnostic of an amide group was observed at 1,640 cm-1 and a peak diagnostic of a carboxyl group was observed at 1,730 cm-1, respectively.
Reaction SMILES: C([O:3][C:4](=[O:32])/[CH:5]=[C:6](\[CH3:31])/[CH:7]=[CH:8]/[CH:9]=[C:10](\[C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]=1[O:26][CH2:27][CH2:28][CH2:29][CH3:30])/[CH3:11])C.[OH-].[Na+].Cl>C(O)C>[C:22]([C:14]1[C:13]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:12](/[C:10](/[CH3:11])=[CH:9]\[CH:8]=[CH:7]\[C:6](\[CH3:31])=[CH:5]\[C:4]([OH:32])=[O:3])[CH:17]=[C:16]([C:18]([CH3:20])([CH3:21])[CH3:19])[CH:15]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CCCCOc1c(/C(C)=C\C=C\C(C)=C\C(=O)OCC)cc(C(C)(C)C)cc1C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCOc1c(/C(C)=C\C=C\C(C)=C\C(=O)O)cc(C(C)(C)C)cc1C(C)(C)C

Procedure:
520 mg of (2E,4E,6Z)-7-(3,5-di-tert.-butyl-2-butyloxyphenyl)-3,7-dimethyl-2,4,6-heptatrienoic acid ethyl ester was suspended in 5 ml ethanol and treated with 5 ml 6N NaOH and refluxed for 1.5 hr. This was cooled and acidified to pH 3 with dilute HCl . The solid which precipitated was extracted into chloroform. The organic portion was washed with water, dried (Na2SO4), and had the solvent removed. This gave a solid which was crystallized from methylene chloride/hexane to give (2E,4E,6Z)-7-[3,5-di-tert.butyl-2-butyloxyphenyl]-3-methyl-2,4,6-octatrienoic acid. 1H NMR (CDCl3) δ 7.08 (dd, 4H, aromatics), 6.65 (dd, 1H,H-5), 6.22 (d, 1H,H-4), 6.18 (d, 1H,H-6), 3.7 (dt, 2H, —OCH2—), 2.24 (s, 3H), 2.15 (s, 3H). M.p. 148-151° C.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18]2=[O:24])(=O)=O)=CC=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(O)(C)(C)C>[N:26]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:18](=[O:24])[CH2:19][O:20][CH2:21][C:22]2=[O:23])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCN2C(=O)COCC2=O)cc1
Solvent: CC(C)(C)O
Product: O=C1COCC(=O)N1CCCCCCN1CCCCC1

Procedure:
To a solution of 19.6 grams (53.2 millimoles) of 6-(3,5-dioxomorpholino)hexyl p-toluenesulfonate in 54 milliliters of tertiary butyl alcohol was added 5.3 milliliters of tertiary (53 millimoles) of piperidine in 54 milliliters of tertiary butyl alcohol. The reaction mixture was heated at reflux temperature for about 22 hours to obtain 4-(6-piperidinohexyl)-3,5-dioxomorpholine. p-toluenesulfonate product which crystallized from tertiary butyl alcohol-ether mixture in a yield of 13.45 grams (56 percent) as an off-white solid, m.p. 125°-128° C. A portion of this product after purification by (a) chromatographing on Silicar CC4 Special (Silica gel, product of Mallinkrodt) employing 10:1 dichlormethanemethanol as eluant, (b) recovering from the effluent and (c) recrystallizing from tertiary butyl aclohol-ether, was a white solid, m.p. 121°-122.5° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:7]=1.Br[CH2:14][CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Si:18]([O:17][CH2:16][CH2:15][CH2:14][N:10]1[N:11]=[N:12][C:8]([C:6]2[CH:5]=[N:4][CH:3]=[C:2]([I:1])[CH:7]=2)=[N:9]1)([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: Ic1cncc(-c2nn[nH]n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cncc(I)c2)n1
Temperature: 80 °C

Procedure:
The reaction mixture of 3-iodo-5-(2H-tetrazol-5-yl)pyridine (273 mg, 1 mmol, 1 eq), (3-bromopropoxy)-tert-butyldimethylsilane (0.31 mL, 1.3 eq), potassium carbonate (207 mg, 1.5 eq) in anhydrous DMF (4 mL) under nitrogen atmosphere was stirred and heated at 80° C. for 5 hours. The mixture was then diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate, aqueous ammonium chloride, brine, and dried with anhydrous sodium sulfate. The upper liquor was decanted, concentrated under reduced pressure, and the resulting brown oily residue was subject to a gradient column chromatography (EtOAc-Hex 1:50 to 1:4) giving 3-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)-5-iodopyridine as a soft white solid in the amount of 395 mg.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([C:7]2[N:12]=[C:11]([O:13][C@H:14]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]3)[CH:10]=[CH:9][CH:8]=2)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:16]1[CH2:17][CH2:18][C@H:14]([O:13][C:11]2[N:12]=[C:7]([C:4]3[NH:3][C:2](=[O:1])[NH:6][N:5]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc(-c3n[nH]c(=O)[nH]3)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]nc(-c2cccc(O[C@H]3CCNC3)n2)[nH]1
Yield: 14 %

Procedure:
Crude (S)-tert-butyl 3-((6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-2-yl)oxy)pyrrolidine-1-carboxylate was treated with DCM (4 mL) and TFA (2 mL) for 2 hours at RT and then concentrated. The crude product was purified by preparative HPLC eluting with a gradient of 1-25% ACN in water (acid mode) to give the title compound (125 mg, 14.0% over 3 steps).
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][C:10]1[N:11]=[CH:12][C:13]([CH2:16][NH2:17])=[N:14][CH:15]=1.FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[F:42][C:43]1[CH:44]=[C:45]([CH:63]=[C:64]([F:66])[CH:65]=1)[CH2:46][N:47]1[C@H:51]([CH3:52])[CH2:50][N:49]([C:53]2[S:54][C:55]([C:59](O)=[O:60])=[C:56]([CH3:58])[N:57]=2)[C:48]1=[O:62]>>[F:66][C:64]1[CH:63]=[C:45]([CH:44]=[C:43]([F:42])[CH:65]=1)[CH2:46][N:47]1[C@H:51]([CH3:52])[CH2:50][N:49]([C:53]2[S:54][C:55]([C:59]([NH:17][CH2:16][C:13]3[CH:12]=[N:11][C:10]([CH3:9])=[CH:15][N:14]=3)=[O:60])=[C:56]([CH3:58])[N:57]=2)[C:48]1=[O:62]
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3cc(F)cc(F)c3)C2=O)sc1C(=O)O
Reactant: Cc1cnc(CN)cn1
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1cnc(CNC(=O)c2sc(N3C[C@@H](C)N(Cc4cc(F)cc(F)c4)C3=O)nc2C)cn1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (5-methylpyrazin-2-yl)methanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(3,5-difluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid: mp 131-132° C. (ethanol/water); 1H NMR (300 MHz, DMSO-d6) δ 8.58 (t, J=5.7 Hz, 1H), 8.47-8.46 (m, 2H), 7.19-7.08 (m, 3H), 4.60-4.37 (m, 4H), 4.23 (t, J=9.6 Hz, 1H), 3.87-3.80 (m, 1H), 3.59 (dd, J=10.1, 6.7 Hz, 1H), 2.48 (s, 3H), 2.47 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 473.0 (M+1).
Reaction SMILES: [Br:1][CH:2]([OH:5])[C:3]#[CH:4].[OH-].[Na+].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>O.O1CCCC1>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:5][CH:2]([Br:1])[C:3]#[CH:4])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CC(O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C#CC(Br)OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
In a 100 mL 3-necked round bottom flask, equipped with a magnetic stirrer, nitrogen inlet, thermometer, addition funnel, and ice bath, were placed bromopropargyl alcohol (5 g, 0.037 mole) and tetrahydrofuran (10 mL). A cold solution of NaOH (2.2 g, 0.55 mole) in water (10 mL) was added. To the above stirred mixture a solution of p-toluenesufonyl chloride (7.06 g, 0.037 mole) in tetrahydrofuran (10 mL) was slowly added. The reaction mixture was stirred at 0°-5° C. for 4 hrs. The reaction mixture was then poured into ice water and the resultant white precipitate was collected by suction-filtration and washed with water. After drying in air, an off-white solid was obtained yielding 9.9 g (92.5% yield) m.p. =43°-46° C. An NMR (CDCl3) spectrum indicated the desired compound (V, R3 =p-tolyl). This compound is used in the next example without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>N1C=CC=CC=1>[F:32][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:35](=[O:36])[N:34]([CH3:38])[CH3:33])=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:18][CH2:19]3)[C:6]=12
Reactant: Nc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)Nc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 50 °C
Yield: 8.6 %

Procedure:
1-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (100 mg, 0.23 mmol) was dissolved in pyridine (1 mL). Dimethylcarbamyl chloride (0.21 mL, 2.3 mmol) was added and the mixture was heated at 50° C. for 18 h. Solvent was removed in vacuum and the residue was purified using reverse phase prep HPLC to afford the title compound as a pale tan solid (10 mg). 1HNMR (500 MHz, DMSO-D6) δ 8.89 (s, 1H), 8.25 (s, 1H), 7.70-7.59 (m, 5H), 3.67 (m, 2H), 3.44 (m, 2H), 3.37 (m, 2H), 3.20 (m, 2H), 3.11 (s, 3H), 2.88 (s, 3H). LCMS: m/e 507 (M+H)+, ret time 1.04 min (method 3).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1[CH2:37]Br.O>C1COCC1>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH2:37][C:30]2[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:29]=2[Br:28])[NH2:17])=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CN(N)c2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To a solution of [4-(benzyloxy)phenyl]hydrazine hydrochloride (2.0 g) in THF (25 mL) was added dropwise a THF solution (1.9 M, 8.4 ml) of sodium hexamethyldisilazide under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1-bromo-2-(bromomethyl)-4-methoxybenzene (2.23 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.56 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:15])=[CH:12][C:13]=1[OH:14].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:15][C:11]1[CH:10]=[CH:9][C:8]2[N:7]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][O:14][C:13]=2[CH:12]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc(N)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: O
Product: Cc1ccc2c(c1)OCC(c1ccccc1)=N2
Reaction time: 8 h
Yield: 49.4 %

Procedure:
To potassium carbonate (63.89 g, 462 mmol) in water (300 mL) and CH2C2 (200 mL) is added 6-amino-m-cresol (10.0 g, 81.2 mmol) and tetra-n-butyl ammonium hydrogensulfate (0.139 g, 0.41 mmol). With vigorous stirring a solution of 2-bromoacetophenone (16.16 g, 81.2 mmol) is added dropwise over a period of 45 min. The mixture is allowed to stir overnight. The layers are then separated and the organic layer is washed with 1N NaOH (500 mL) and water (2×300 mL), dried over magnesium sulfate and concentrated. Column chromatography (400 g silica gel) using ethyl acetate/hexane (20/80) as eluent gave 8.96 g (49%) of 7-methyl-3-phenyl-2H-1,4-benzoxazine.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[CH3:29][O:30][C:31]1[CH:41]=[CH:40][CH:39]=[C:33]2[C:34]([O:36][C:37](=O)[C:32]=12)=[O:35]>>[CH3:5][O:6][P:7]([CH2:27][N:28]1[C:37](=[O:36])[C:32]2=[C:31]([O:30][CH3:29])[CH:41]=[CH:40][CH:39]=[C:33]2[C:34]1=[O:35])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: COc1cccc2c1C(=O)OC2=O
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Solvent: CC(=O)O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)c2cccc(OC)c2C1=O)OC
Yield: 20.2 %

Procedure:
In a manner analogous to that described in Example 3 (A), from 0.4 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate and 0.178 g of 3-methoxy-phthalic anhydride, there was obtained 0.1 g of [(3-methoxyphthalimido)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester in the form of a colorless foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[S:6][CH2:5][NH:4][CH:3]1[C:7]([OH:9])=[O:8].C(N(CC)CC)C.[C:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)#[C:19][CH2:20][CH3:21]>O1CCOCC1.O.C(OCC)(=O)C>[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:4]2[C@@H:3]([C:7]([OH:9])=[O:8])[C:2]([CH3:10])([CH3:1])[S:6][CH2:5]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:19]#[C:20][CH3:21]
Reactant: CCC#COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)SCNC1C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N2CSC(C)(C)[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a room temperature solution of 4.3 g (32.3 mmol) of 5,5-dimethyl-1,3-thiazolidine4-carboxylic acid (J. Med. Chem. 1989, 32(2 ), 466-472) in 30 ml of dioxane:water (2:1) containing 4.9 mL (35.5 mmol) of triethylamine was added 7.9 g (32.3 mmol) of 4-butynyloxybenzenesulfonyl chloride. The mixture was stirred at 25 ° C. for 18h. The resulting mixture was diluted with ethyl acetate and washed with 1N aqueous hydrochloric acid (3×). The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a foam which was chromatographed on silica gel eluting with methanol/dichloromethane to give (4S)-3-{[4-(2- butynyloxy)phenyl]sulfonyl}-5,5-dimethyl-1,3-thiazolidine4-carboxylic acid as a white solid. Electrospray Mass Spec 368.1 (M−H)−
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:5]=[C:6]([C@@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:19]=[CH:18]3)[C@@H:11]([NH2:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)[CH3:3].CN(C)C(N(C)C)=N.[F:39][C:40]([F:47])([F:46])[C:41](OCC)=[O:42]>CO>[CH2:2]([C:4]1[CH:5]=[C:6]([C@@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[N:19]=[CH:18]3)[C@@H:11]([NH:13][C:41](=[O:42])[C:40]([F:47])([F:46])[F:39])[CH3:12])[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CO
Product: CCc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(F)(F)F)c1

Procedure:
(1R,2S)-1-(3-ethylphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine hydrochloride (50 mg, 0.12 mmol), 1,1,3,3-tetramethylguanidine (100 μl, 0.79 mmol) and ethyl trifluoroacetate (200 μl, 1.68 mmol) in MeOH (2.5 mL) was stirred at r.t. for 1 h. The reaction mixture was concentrated by evaporation, the residual material was purified by
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2.Cl>CCO.[Pt]=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2
Reactant: COc1cccc2cnccc12
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: COc1cccc2c1CCNC2
Reaction time: 4 h
Yield: 11.6 %

Procedure:
To a solution of the product of step (a) (6.11 g, 384 mmol) in EtOH (200 ml) was added platinum oxide (0.611 g) followed by concentrated HCl (3.2 ml, 38.4 mmol). The reaction mixture was hydrogenated at 345 kPa (50 p.s.i.) at room temperature for 4 h after which time the catalyst was filtered off and washed with EtOH. The filtrate was evaporated under reduced pressure to afford the subtitle compound as a colourless solid (7.27 g, 95%). 1H NMR (D6-DMSO) δ: 2.80 (2H, m), 3.35 (2H, m), 3.80 (3H, s), 4.20 (2H, s), 6.80 (1H, d), 6.90 (1H, d), 7.20 (1H, t), 9.45 (2H, bs).
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[CH:13]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]2[C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([N+:41]([O-:43])=[O:42])[CH:35]=2)=[CH:19][CH:18]=1)([CH2:15][CH3:16])[CH3:14]>CN(C=O)C>[CH:13]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]2[C:34]2[CH:39]=[CH:38][C:37](/[CH:40]=[CH:6]/[N:7]([CH3:9])[CH3:8])=[C:36]([N+:41]([O-:43])=[O:42])[CH:35]=2)=[CH:21][CH:22]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(C)c([N+](=O)[O-])c3)nc3ccccc3c2=O)cc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(-n2c(-c3ccc(/C=C/N(C)C)c([N+](=O)[O-])c3)nc3ccccc3c2=O)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
tert-Butoxybis(dimethylamino)methane (0.75 mL, 3.60 mmol) was added to a solution of 3-(4-sec-butylphenyl)-2-(4-methyl-3-nitrophenyl)quinazolin-4(3H)-one (0.500 g, 1.20 mmol) in DMF (30 mL). Stirring at 40° C. for 3 hours and concentrating in vacuo afforded (E)-3-(4-sec-butylphenyl)-2-(4-(2-(dimethylamino)vinyl)-3-nitrophenyl)quinazolin-4(3H)-one (0.565 g, quantitative).