Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[H][H].[NH2:9][C@H:10]([C:18](O)=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>O>[NH2:9][C@H:10]([CH2:18][OH:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: N[C@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dry THF (1.5 L) was distilled into a 3-L three-necked flask equipped with a mechanical stirrer, a reflux condenser closed by a septum carrying nitrogen inlet and exit needles, and a stopper. Lithium aluminum hydride (38 g, 1 mole) was added cautiously through the side neck over a period of 40 min. When hydrogen evolution had subsided, the mixture was refluxed with stirring for 30 min and then cooled to room temperature. Phenylalanine (100 g) was added in small portions to the stirred suspension. The mixture was refluxed overnight and cooled to room temperature. Celite (40 g) was poured into the reaction flask, the side neck stopper was replaced by a dropping funnel, and the mixture was cooled in an ice-bath. Water (40 mL) followed by 10% w/v aqueous sodium hydroxide (40 mL) were then added dropwise with stirring. Finally, water (120 mL) was added. The mixture was filtered on a sintered filter funnel and the solid was washed with ethyl acetate (2×200 mL). Insoluble material from the filtration was replaced in the original reaction vessel and stirred for 30 min with ethyl acetate (300 mL). The mixture was filtered, and the filtrate was combined with the first filtrate, concentrated to remove THF, and diluted with ethyl acetate to about 500 mL. The solution was washed with 10% w/v aqueous sodium hydroxide and the aqueous phase was extracted with ethyl acetate (1×200 mL). The combined organic extracts were dried (MgSO4) and evaporated. The residual oil was dissolved in the minimum amount of refluxing ethyl acetate and the solution was allowed to cool to room temperature and then kept at 0° C. overnight. The first crop of product (57.2 g, after drying under oil-pump vacuum at room temperature) had mp 92°-94° C. [lit.1 mp 92°-94° C⟧ The mother liquor was evaporated and the residue was crystallized by the above procedure to furnish a second crop (5.2 g, after drying) with the same mp. The new mother liquor was processed in the same way to give a third crop (4.3 g) which was yellowish and was saved for chromatographic purification. The yield of pure (S)-phenylalaninol (crops 1 and 2) amounted to 62.4 g (68%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([Si](C)(C)C)#[C:20][CH2:21][CH3:22].[F:27][C:28]1[CH:29]=[C:30](I)[CH:31]=[C:32]2[C:36]=1[N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:34]=[CH:33]2>C(OCC)(=O)C.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.[Cu]I>[C:19]([C:30]1[CH:31]=[C:32]2[C:36](=[C:28]([F:27])[CH:29]=1)[N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:34]=[CH:33]2)#[C:20][CH2:21][CH3:22]
Reactant: CCC#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)n1ccc2cc(I)cc(F)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Product: CCC#Cc1cc(F)c2c(ccn2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
To a degassed (3× vacuum/nitrogen cycles) solution of TBAF (4.0 mL, 0.5 M THF, 2.00 mmol), but-1-yn-1-yltrimethylsilane (267 mg, 2.11 mmol; Intermediate 39) was added. The solution was stirred at room temperature for a few minutes before transferring into a reaction vessel containing tert-butyl 7-fluoro-5-iodo-1H-indole-1-carboxylate (360 mg, 1.00 mmol), Pd(PPh3)4 (232 mg, 0.20 mmol), and CuI (76 mg, 0.40 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate (100 mL), washed (50 mL water then 50 mL brine), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield the title compound as brown oil (260 mg, 91%). 1H NMR (300 MHz, DMSO-d6): δ 7.85 (d, 1H), 7.58 (d, 1H), 7.21 (dd, 1H), 6.83 (dd, 1H), 2.51 (q, 2H), 1.68 (s, 9H), 1.26 (t, 3H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[C:13]=3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:33]([Si:35]([C:40]#[CH:41])([CH2:38][CH3:39])[CH2:36][CH3:37])[CH3:34].O>CN(C=O)C.[Cu]I.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>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[C:13]=3[C:12]([C:34]#[C:33][Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#C[Si](CC)(CC)CC
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2c(N3CCCCC3)ncnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[Si](C#Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCCCC3)c12)(CC)CC
Yield: 80.7 %

Procedure:
To a flamed-dried flask under nitrogen was charged 211 mg (0.5 mmol) of the product from Method R, 19 mg (0.1 mmol) of copper (I) iodide and 58 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium. To this mixture was then added 0.14 mL (1.0 mmol) of triethylamine and 0.27 mL (1.5 mmol) of triethylsilylacetylene as a solution in 1.5 mL of dry DMF. The resulting mixture stirred at room temperature for 3 hours, at which time, 5.0 mL of water were added and the mixture extracted with ethylacetate. The ethyl acetate extract was dried over MgSO4 and concentrated in vacuo. The resulting crude product was then purified by silica-gel chromatography (7:1 hexanes/ethyl acetate) affording 194 mg (89%) of the title compound. LRMS: 481 (M+1), 341.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[CH3:7][O:8][N:9]([CH3:13])[C:10](Cl)=[O:11]>C(#N)C.CCOCC>[CH3:7][O:8][N:9]([CH3:13])[C:10]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1)=[O:11]
Reactant: Cn1cncn1
Reactant: CON(C)C(=O)Cl
Solvent: CCOCC
Solvent: CC#N
Product: CON(C)C(=O)c1ncnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 1-methyl-1H-1,2,4-triazole (3.15 mL, 55.56 mmol) and methoxy(methyl)carbamic chloride (7.55 g, 61.11 mmol) in acetonitrile (60 mL) was cooled in an ice water bath before addition of TEA (8.52 mL, 61.11 mmol). The mixture was allowed to slowly warm to room temperature and was then stirred overnight. The material was diluted with ether and solids were filtered and rinsed well with ether. The filtrate was concentrated and the residue was taken up in ether. Insoluble solids were filtered off and rinsed well with additional ether. The filtrate was concentrated to give and oil that was chromatographed on silica gel (100% CH2Cl2 followed by gradient elution to 40% EtOAc in CH2Cl2) to afford product as an oil that slowly solidified. 6.13 g (65% yield).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][N:8]1[C:7]2=[O:21])[CH3:3].Cl[CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:24]([CH2:23][O:19][C:18]([C:16]1[CH:15]=[CH:14][C:9]2[N:8]([CH:17]=1)[C:7](=[O:21])[C:6]1[C:11](=[CH:12][CH:13]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=1)[N:10]=2)=[O:20])#[N:25]
Reactant: N#CCCl
Reactant: CC(C)c1ccc2nc3ccc(C(=O)O)cn3c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc2nc3ccc(C(=O)OCC#N)cn3c(=O)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A suspension of 20 g of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, 6.3 ml of chloroacetonitrile and 13.2 g of potassium carbonate in 100 ml of dimethylformamide was stirred 18 hours at room temperature. The reaction mixture was diluted with 200 ml of water and the precipitated product collected to give 21.63 g (95%) of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid cyanomethyl ester, mp 186°-188° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:11]2([CH2:14][CH:13]([OH:15])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([CH2:12][CH:13]([O:15][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:14]2)[CH2:16][CH2:17]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(OS(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
After dissolving 106 mg of 7-(tert-butoxycarbonyl)-2-hydroxy-7-azaspiro[3.5]nonane in 10 ml of tetrahydrofuran, 0.04 ml of methanesulfonyl chloride and 0.07 ml of triethylamine were added and the mixture was stirred overnight at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After adding water to the residue, extraction was performed with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (148 mg, 100% yield).
Reaction SMILES: [OH-].[Na+].[C:3](#[N:6])[CH:4]=[CH2:5].[CH:7](=[O:11])[CH:8]([CH3:10])[CH3:9]>>[CH3:9][C:8]([CH3:10])([CH2:5][CH2:4][C:3]#[N:6])[CH:7]=[O:11]
Reactant: C=CC#N
Reactant: CC(C)C=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C=O)CCC#N

Procedure:
Starting Materials: 50% caustic soda solution; reaction temp.; choice between 20° to 50° C.; mole ratio acrylonitrile:isobutyraldehyde as 1.1:1. Feed of acrylonitrile and isobutyraldehyde/hour: 280 ml.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][C:48](=[O:50])[CH3:49])[CH2:15]2)=[CH:10][CH:9]=1.O1CCCC1.B>C1COCC1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@@H:16]([CH2:47][C@@H:48]([OH:50])[CH3:49])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(C)=O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: B
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@H](C)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reaction time: 3 h

Procedure:
To a stirred solution of 1.0 mmol of 1-[(2R,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-propan-2-one in 10 ml of THF are added 2.0 mmol of borane tetrahydrofuran complex (1M in THF) at RT. The reaction mixture is stirred for 3 h, quenched with 60 ml of MeOH and concentrated under reduced pressure. The resulting diastereomeric mixture is separated by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on its Rf-value.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:20](=O)[C:19]2[CH:22]=[CH:23][C:24]([S:26][CH:27]([CH3:29])[CH3:28])=[N:25][C:18]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[Cl-].[NH4+]>C(OCC)C.O>[CH2:7]([N:14]1[CH2:20][C:19]2[CH:22]=[CH:23][C:24]([S:26][CH:27]([CH3:29])[CH3:28])=[N:25][C:18]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)Sc1ccc2c(n1)OCCN(Cc1ccccc1)C2=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(C)Sc1ccc2c(n1)OCCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a mixture of lithium aluminum hydride (0.061 g) and diethyl ether (2.0 mL) was added a solution of the compound obtained in step 1 (0.35 g) in diethyl ether (3.0 mL), and the resulting mixture was stirred at room temperature for 2 hr under a nitrogen atmosphere. 1N Aqueous sodium hydroxide solution (0.061 mL), saturated aqueous ammonium chloride (0.061 mL) and water (0.061 mL) were added, and the resulting mixture was stirred at room temperature for 3 hr. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate/hexane) to give 4-benzyl-8-(isopropylthio)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.26 g, 79%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][C:12]=2[O:19][CH3:20])[CH:3]=1.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(OCC)(=O)C.C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:24][CH3:23])=[CH:13][C:12]=2[O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(C=O)ccc1Oc1cc(Cl)ccc1C#N
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CNCc1ccc(Oc2cc(Cl)ccc2C#N)c(OC)c1
Yield: 80.1 %

Procedure:
4-Chloro-2-(4-formyl-2-methoxy-phenoxy)-benzonitrile (0.98 g, 3.4 mmol), methylamine (2M in methanol, 5.1 ml, 10.2 mmol) and sodium cyanoborohydride (0.24 g, 3.8 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (125 ml) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% aqueous sodium carbonate and extracted with ethyl acetate. Fumaric acid (0.41 g, 3.5 mmol) was added to the separated ethyl acetate layer and the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, filtered and dried to give 4-chloro-2-(2-methoxy-4-methylaminomethyl-phenoxy)-benzonitrile fumarate (1.14 g, 80%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33]CC3C=CC(OC)=CC=3)=[CH:29][CH:28]=2)[C:10]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(COC2C=CC(N)=CC=2)=CC=1>CC(O)=O>[CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:10]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OCc2ccc(OC)cc2)cc1
Agent: COc1ccc(COc2ccc(N)cc2)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(O)cc1
Temperature: 105 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-((4-methoxybenzyl)oxy)phenyl)-1H-pyrrole-2-carboxylate (35) [prepared using the same procedure as Example B except 4-((4-methoxybenzyl)oxy)aniline used in step (i)] (46 mg, 0.07 mmol) in AcOH (5 mL) was stirred at 105° C. for 18 h. The volatiles were removed in vacuo and the residue was purified by silica gel chromatography (4 g, 0-10% MeOH in DCM) to afford ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-hydroxyphenyl)-1H-pyrrole-2-carboxylate (36) (35 mg, 91%) as a yellow solid: m/z 515 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 9.63 (1H, s), 7.47-7.42 (m, 2H), 7.41-7.29 (m, 8H), 6.99-6.91 (m, 2H), 6.73-6.66 (m, 2H), 5.10 (s, 2H), 4.95 (s, 2H), 3.99 (q, J=7.1 Hz, 2H), 2.69 (s, 3H), 2.67 (s, 3H), 1.00 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Cl:12]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[NH2:1][C:2]1[S:3][C:4]([Cl:12])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1nc(N)sc1Cl
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Ethyl 2-aminothiazole-4-carboxylate (4.72 g, 27.4 mmol) was combined with N-chlorosuccinimide (4.0 g, 30 mmol) and dissolved in acetonitrile (50 mL). The mixture was heated at mild reflux (>81.5° C.) for 5 hours. Subsequently, the flask was cooled to rt and decolorizing carbon was added to the mixture which was further diluted with EtOAc. The resulting slurry was filtered through a pad of silica and concentrated under reduced pressure to provide 5.57 g (98%) of the desired product ethyl 2-amino-5-chlorothiazole-4-carboxylate (1H). The analytical data on this compound corresponded to that previously reported (see, South, M. S. J. Heterocyclic Chem. 1991, 28, 1003.).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=3[N+:13]([O-:21])=[N:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH3-])(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[N+:13]([O-:21])=[N:12][C:11](=[O:22])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:30]4[N:29]=[CH:28][C:27]5[O:26][CH2:25][CH2:24][O:23][C:32]=5[CH:31]=4)[CH2:7][CH2:6]3)[C:15]=2[CH:16]=1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: NC1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1n[n+]([O-])c2ccc(Cl)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-chloro-1,2,4-benzotriazin-3(4H)-one 1-oxide (Intermediate 205, (0.25 g) was reacted with 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (0.14 g) and sodium acetoxyborohydride (0.34 g) as described for Example 107. Chromatography on silica gel with 0-20% methanol in dichloromethane gave 60 mg of the title compound as acetic acid salt (0.37 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([N:31]([CH2:40][CH2:41]O)[CH:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:41][CH2:40][N:31]([CH:32]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH3:33])[C:29](=[O:30])[C:10]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(c1ccccc1)N(CCO)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(c1ccccc1)N1CCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To a stirred solution of 5-(benzyloxy)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-(2-hydroxyethyl)-N-(1-phenylethyl)pyrimidine-4-carboxamide (36) (158 mg, 270 μmol, Eq: 1.00) in dichloromethane (15 ml) at room temperature was added triphenylphosphine (106 mg, 404 μmol, Eq: 1.5). The reaction mixture was stirred for 10 min. Then diisopropyl azodicarboxylate (81.8 mg, 78.6 μl, 404 μmol, Eq: 1.5) was added. The reaction mixture was stirred for 18 hrs, concentrated, and chromatographed (silica gel, gradient 0 to 5% methanol-dichloromethane) to obtain 9-(benzyloxy)-6-((1-(4-chlorophenyl)cyclopentyl)methyl)-2-(1-phenylethyl)-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (37) (colorless of 1,120 mg, 211 μmol, 78.4% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=1)[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:5][CH2:4][CH2:3][CH2:2][O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=1)[CH:12]=[O:13]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cc(OCCCCl)ccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
Compound b2 may be prepared according to reported methods (see, e.g., Gumbley, P.; Koylu, D.; Thomas, S. W. Macromolecules 2011, 44, 7956). 1-Bromo-3-chloropropane (0.650 mL, 0.00658 moles) was added to a solution of 5-hydroxy-2-nitrobenzaldehyde (1.0 g, 0.00598 moles), and potassium carbonate (1.66 g, 0.0120 moles) in anhydrous DMF (6 mL). The solution was stirred at 40° C. for 24 hours. The reaction was diluted with ethyl acetate (75 mL) and washed with saturated sodium bicarbonate solution (75 mL), water (75 mL), and brine (75 mL). The organic layer was dried with anhydrous magnesium sulfate, which was removed by filtration. The filtrate was concentrated, and the resulting residue was subject to silica gel chromatography using a gradient of 100% hexanes to 50% ethyl acetate in hexanes. The fractions containing the product were collected, and volatiles were removed by rotary evaporation. The resulting residue was dried overnight to yield 5-(3-chloropropoxy)-2-nitrobenzaldehyde as a bright-green yellow solid (yield 87%*). 1H NMR (400 MHz, CD2Cl2) δ 10.42 (s, 1H), 8.15 (d, J=9.1 Hz, 1H), 7.32 (d, J=2.9 Hz, 1H), 7.18 (dd, J=9.0, 2.9 Hz, 1H), 4.27 (t, J=5.9 Hz, 2H), 3.76 (t, J=6.3 Hz, 2H), 2.35-2.24 (m, 2H). 13C-NMR (100 MHz, CD2Cl2) δ 189.05, 163.84, 135.04, 127.84, 119.16, 114.57, 66.28, 41.74, 32.35 HRMS m/z: calculated for C10H10ClNO4 [M+H]+, 244.0371. found, 244.0366.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:24][CH2:25][Cl:26])[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>Cl>[Cl:1][CH2:2][CH2:3][N:4]([CH2:24][CH2:25][Cl:26])[C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCOc1cc(C(=O)OC)ccc1N(CCCl)CCCl
Agent: Cl
Product: CCCCCCCCOc1cc(C(=O)O)ccc1N(CCCl)CCCl
Yield: 89.9 %

Procedure:
A suspension of methyl 4-bis(2'-chloroethyl)amino-3-octoxybenzoate (1.8 g, 4.5 mmol) in concentrated HCl (37% w/w in H2O, 50 mL) was heated to refluxing under N2 for 0.5 hour. The reaction mixture was treated with ice/H2O (100 mL), extracted with chloroform (3×50 mL). The organic extract was concentrated to give a brown oil. Flash chromatographic purification (silica gel, 2% methanol in chloroform) gave the product 4-bis(2'-chloroethyl)amino-3-octoxybenzoic acid as an off-white solid (1.58 g, 88%). 1H NMR (300 MHz, CDCl3): 7.67 (dd, J=8.1, 1.5 Hz, 1H), 7.56 (d, J=1.5 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 4.40 (d, J=6.6 Hz, 2H), 3.65 (m, 8H), 1.85 (J=7.8 Hz, 2H), 1.35 (m, 10H), 0.90 (t, J=6.6 Hz, 3H). ESMS calcd (C29H29Cl2NO3): 389.2; found: 390.2 (M+H)+.