Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[N:3]1[C:12]([CH3:20])([CH2:16][CH2:17][CH2:18]O)[C:13]([NH2:15])=[O:14].O>C1(C)C(C)=CC=CC=1>[O:1]=[S:2]1(=[O:21])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[N:3]1[C:12]1([CH3:20])[CH2:16][CH2:17][CH2:18][NH:15][C:13]1=[O:14]
Reactant: CC(CCCO)(C(N)=O)N1C(=O)c2ccccc2S1(=O)=O
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1(N2C(=O)c3ccccc3S2(=O)=O)CCCNC1=O
Yield: 37 %

Procedure:
5 g 2-(2,3-Dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-5-hydroxy-2-methyl-valeramid are dissolved in 150 ml of xylene and the resulting solution is boiled under reflux for several hours, using a water separator. After the theoretical quantity of water has been separated off, the mixture is allowed to cool and concentrated in vacuo to a small volume. The precipitate is filtered off and recrystallized from n-butanol to give 3-(2,3-dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-3-methyl-2-oxo-piperidine in the form of white crystals melting at 211° to 215° C., identical with the product obtained in example 1. The yield is 37% of the theoretical.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:37])[NH:33][CH2:34][CH2:35][NH2:36])([CH3:30])([CH3:29])[CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:36][CH2:35][CH2:34][NH:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:37])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 300 mg (0.82 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 171 mg (1.06 mmol) of tert-butyl-(2-aminoethyl)carbamate are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 204 mg (1.06 mmol) of EDC and 33 mg (0.25 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried under high vacuum.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[CH:18]=[C:17]([O:25][CH:26]([CH3:28])[CH3:27])[CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C>Cl>[CH:22]([O:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([O:25][CH:26]([CH3:28])[CH3:27])[CH:18]=1)[CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]1)([CH3:24])[CH3:23]
Reactant: CC(C)Oc1cc(CN2CCC(NC(=O)OC(C)(C)C)CC2)cc(OC(C)C)c1
Agent: Cl
Product: CC(C)Oc1cc(CN2CCC(N)CC2)cc(OC(C)C)c1
Yield: 32 %

Procedure:
A solution of [1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (3.23 g, 7.95 mmol) in 4 M HCl (100 mL) was stirred at rt for 2 h. The hydrochloric acid was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure yielding 0.78 g (32%) of a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:2]([CH3:4])=O.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.Cl.C([BH3-])#N.[Na+]>CO>[N:21]1([CH:2]([CH3:4])[CH2:1][C:5]2[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: COc1cccc(C2=C(CC(C)=O)C(=O)NCCC2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C2=C(CC(C)N3CCCCC3)C(=O)NCCC2)c1
Reaction time: 24 h

Procedure:
The solution of 8.0 g of 3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 14.95 g of piperidine, 6.6 ml of 5 N methanolic hydrogen chloride and 1.9 g of sodium cyanoborohydride in 120 ml of methanol is refluxed overnight. An additional portion of 0.95 g of sodium cyanoborohydride is added and refluxing continued for 24 hours. The mixture is cooled to 0°, 30 ml of concentrated hydrochloric acid are added and the solution concentrated. The concentrate is diluted with 100 ml of water, the solution washed with benzene and rendered basic with 70 ml of 3 N aqueous sodium hydroxide. It is extracted with diethyl ether, the extract evaporated and the residue crystallized from petroleum ether and hexane, to yield the 3-(2-piperidinopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone of the formula ##STR7## melting at 97° to 99°.
Reaction SMILES: CI.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([C:16]([OH:18])=[O:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:19](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:10]1([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:15][CH2:14][O:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Yield: 143.3 %

Procedure:
Methyl iodide (9.38 ml, 150 mmol) was added to a suspension of 4-(tert-butoxycarbonyl)-2-morpholinecarboxylic acid (14.5 g, 62.6 mmol) and dry potassium carbonate (17.3 g, 125 mmol) in dry dimethylformamide (DMF) (360 ml). The mixture was stirred over night, filtered through Celite and concentrated. The residue was partitioned between dichloromethane and water. The organic phase was dried over magnesium sulfate and concentrated to give 22 g of crude product.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][C:17]2([OH:21])[CH2:20][CH2:19][CH2:18]2)[CH:10]=1)=[O:4]>CCO>[F:1][C:2]([F:22])([F:23])[C:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][C:17]2([OH:21])[CH2:18][CH2:19][CH2:20]2)[CH:10]=1)=[O:4]
Reactant: O=C(NCCOc1cccc(C#CC2(O)CCC2)c1)C(F)(F)F
Solvent: CCO
Product: O=C(NCCOc1cccc(CCC2(O)CCC2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,2,2-Trifluoro-N-(2-(3-(2-(1-hydroxy cyclobutyl)ethynyl)phenoxy)ethyl)acetamide (0.45 g, 1.9 mmol) in EtOH (20 mL) was degassed and purged with nitrogen. To this was added Pd on C (0.09 g, 10%) and the flask was evacuated and filled with hydrogen. The resulting reaction mixture was stirred at room temperature under hydrogen balloon overnight. This was followed by filteration through a pad of Celite. The filter cake was washed with ethanol and the filtrate concentrated to afford 2,2,2-trifluoro-N-(2-(3-(2-(1-hydroxycyclobutyl)ethyl)phenoxy)ethyl)acetamide as yellow oil. Yield (0.3 g, 66%): 1H NMR (400 MHz, DMSO-d6) δ 7.20-7.25 (m, 1H), 6.87 (d, J=7.6 Hz, 1H), 6.78 (s, 1H), 6.72 (dd, J=8.0, 2.4 Hz, 1H), 4.11 (t, J=5.0 Hz, 2H), 3.76-3.81 (m, 2H), 2.67-2.72 (m, 2H), 2.01-2.14 (m, 4H), 1.92-1.96 (m, 2H), 1.22-1.26 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@:10]([CH2:33][CH:34]=[O:35])([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC(C)=[O:38]>O.OS(O)(=O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@:10]([CH2:33][C:34]([OH:38])=[O:35])([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetaldehyde (Example 91, Step E) (125 mg, 0.242 mmol) in acetone (2 mL) was added 3 mL of a mixture of CrO3 in water (2 mL) and concentrated H2SO4 (1 ml). The reaction mixture was stirred at room temperature for 2 hours and then diluted with water (10 mL) and ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reversed phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA) to provide the title compound.
Reaction SMILES: [C:1](OCC)(=O)CC(OCC)=O.[H-].[Na+].[Br:14][C:15]1[C:16](Cl)=[N:17][CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1>C1COCC1>[Br:14][C:15]1[C:16]([CH3:1])=[N:17][CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a cold solution of diethyl malonate (2.2 mL, 14.5 mmol) in THF (30 mL) was added NaH (0.58 g, 60% in mineral oil) over 5 minutes. 3-Bromo-2-chloro-5-nitropyridine (3.13 g, 13.15 mmol) was added in 4 portions over 15 minutes. The reaction mixture was warmed to room temperature and THF was removed under reduced pressure. The mixture was heated at 115° C. for 75 minutes. After the reaction mixture was cooled to room temperature, H2SO4 (6.0 M, 17 mL) was added and the mixture was heated at 110° C. overnight. It was cooled to 0° C. and a KOH solution (25%) in water was added until pH=7.0. The reaction mixture was kept at 0° C. for 30 min. The crude product was collected by filtration and washed with cold water. dichloromethane (100 mL) was added to the solids and stirred at r.t. for 30 min. The solid was filtered off and the filtrate was concentrated to 30 mL. Petroleum ether (60 mL) was added and the solid was filtered off and the filtrate was concentrated to give the product as a red solid (2.3 g, 73%).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([O:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]2[C:20]3[C:27]([CH3:28])=[C:26]([C:29](O)=[O:30])[S:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:6]1)(=[O:3])[CH3:2].[NH2:32][CH2:33][CH2:34][OH:35]>>[OH:35][CH2:34][CH2:33][NH:32][C:29]([C:26]1[S:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([NH:18][C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[O:10][C@H:7]3[CH2:8][CH2:9][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6]3)[C:20]=2[C:27]=1[CH3:28])=[O:30]
Reactant: CC(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)C1
Reactant: NCCO
Product: CC(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NCCO)c(C)c23)C1

Procedure:
Synthesized analogously to example 225.3 from 4-[2-((1S,3S)-3-acetylamino-cyclopentyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (111 mg) and 2-aminoethanol (18 μl). The reaction mixture was concentrated, the residue was partitioned between DCM and water and the organic layer was dried and concentrated again. The crude was purified by chromatography to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([C:32]#[N:33])[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([C:32]5[NH:37][N:36]=[N:35][N:33]=5)[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OC1(c2ccc(Cl)cc2)CCN(CCC=C2Cc3c(cccc3-c3nnn[nH]3)Oc3ncccc32)CC1
Temperature: 100 °C
Reaction time: 36 h
Yield: 73.3 %

Procedure:
To a solution of the product of Example 364 (1.0 g) in DMF (10 ml) were added sodium azide (0.69 g) and ammonium chloride (0.56 g) and the mixture stirred at 100° C. for 36 hour. Water was added to the reaction mixture, and the precipitate was filtered and washed with ethanol to give the titled compound (800 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([Cl:13])[N:4]=1.[CH3:14][N:15]([CH3:25])[C:16]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][S:2][C:3]1[N:4]=[C:5]([Cl:13])[C:6]([N+:10]([O-:12])=[O:11])=[C:7]([O:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:16]([N:15]([CH3:25])[CH3:14])=[O:17])[CH:19]=2)[N:8]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CN(C)C(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cccc(C(=O)N(C)C)c2)n1

Procedure:
In a similar manner, 2-methylthio-5-nitro-4,6-dichloropyrimidine was treated with 3-(dimethylaminocarbonyl)phenol in the presence of cesium carbonate to afford 2-methylthio-5-nitro-4-chloro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine, a compound of formula (M).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[OH:10][C:11]([CH2:13][O:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][N:16]=1)=O.C(N(CC)CC)C>C(Cl)Cl>[O:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:11]([CH2:13][O:14][C:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17][N:16]=2)=[O:10])[CH2:5][CH2:6]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)COc1cc(-c2ccccc2)[nH]n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COc1cc(-c2ccccc2)[nH]n1)NCCN1CCOCC1
Reaction time: 3 h

Procedure:
1.33 ml N-(2-aminoethyl)-morpholine, 2.2 g 3-hydroxycarbonylmethoxy-5-phenylpyrazole and 4.3 ml triethylamine were added in this order to 3.06 g 1-methyl-2-chloropyridinum iodide in methylene chloride. The reaction mixture was then heated to boiling for 3 hours under reflux. After cooling and washing with aqueous sodium hydroxide solution, the organic phase was evaporated, and the crude product obtained was purified chromatographically. 2.3 g 3-(2-morpholinoethylaminocarbonylmethoxy)-5-phenyl-pyrazole were obtained as an oily base. IR-spectrum (as film): 3205 cm-1, 1660 cm-1.
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1>CC(O)(C)C.O>[Br:7][C:15]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C:14]2[C:18](=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=2)[NH:17][C:16]1=[O:20]
Reactant: O=C1Nc2cc(Cl)ccc2C1Cc1cccc(Cl)c1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Yield: 100.3 %

Procedure:
Pyridinium bromide perbromide (0.659 g, 2.06 mmol) (Aldrich) was added in one portion to a solution of 6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (0.5 g, 1.72 mmol) (from Example 30b supra) in t-BuOH (16.2 mL) and H2O (74 uL) at room temperature with stirring. After stirring at room temperature for 4 hours, the crude was diluted with water, extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4. After filtration, the solvent was removed to obtain rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a pale yellow solid (yield: 0.64 g, 84%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1.[Mg].[CH:16](=[O:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[OH:18][CH:16]([CH3:17])[CH2:2][CH:3]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1
Reactant: BrCC1COC(c2ccccc2)OC1
Reactant: CC=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)CC1COC(c2ccccc2)OC1
Temperature: -70 °C
Reaction time: 15 h

Procedure:
To a solution of 19.39 g (75.4 mM) of 5-bromomethyl-2-phenyl-1,3-dioxane m2 in 200 ml of tetrahydrofuran is added 1.923 g (79.17 mM) of magnesium and the mixture is allowed to react for 7 hours under ultrasonic bibration. The mixture is cooled to -70° C. and 21.27 ml (377 mM) of acetaldehyde is added and then the mixture is stirred at 0° C. for 15 hours. The mixture is poured into an ice-cooled saturated aqueous ammonium chloride solution and the product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. By eliminating the polar impurity by passing short column of silica gel, 11.353 g of the crude titled compound m3 is obtained which is used to the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C:10]#[N:11])[C:6]([O:12][CH3:13])=[CH:5][N:4]=1.Cl.NO.C([N:19](CC)CC)C.ClC(OC)=O>O.C(#N)C>[NH2:11][C:10]1[N:9]=[C:7]2[N:8]([C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]2[O:12][CH3:13])[N:19]=1
Reactant: CCN(CC)CC
Reactant: COc1ncc(OC)c(NC#N)n1
Agent: COC(=O)Cl
Agent: Cl
Agent: NO
Solvent: O
Solvent: CC#N
Product: COc1cnc(OC)n2nc(N)nc12
Temperature: 45 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a 25 mL three-neck round bottom flask were added 1.11 g (5.55 mmol) of 90 wt % 2,5-dimethoxy-4-cyanoaminopyrimidine (2), 463 mg (6.66 mmol) of hydroxylamine hydrochloride, and 9.8 g of acetonitrile. To this mixture was added 681 mg (6.72 mmol) of triethylamine in one portion. The reaction mixture was heated to a gentle reflux (˜45° C.) for 2 h. The reaction mixture was cooled in an ice water bath to about 5.8° C. at which time an additional 716 mg (7.08 mmol) of triethylamine was added in one portion. To this mixture was added 662 mg (7.01 mmol) of methyl chloroformate in one portion at which time the internal reaction temperature rose from 5.8° C. to 12.1° C. The ice water bath was removed and the mixture was stirred at ambient temperature for 1 h and then at reflux (˜76° C.) for about 3 h. The reaction mixture was cooled to ambient temperature and an additional 100 μL of triethylamine was added to adjust the reaction pH to about 7-8. To this mixture was added 11.3 g of water; the mixture was transferred to a 100 mL round bottom flask; and the acetonitrile was removed in vacuo at 60 mm Hg and 30° C. The aqueous slurry was then suction filtered over a medium glass frit and the residue from the flask was transferred with ˜2 g of water. After the cake de-liquored, another 1 g displacement water wash was passed through the cake. After suction air drying the cake for 30 min, the mixture was allowed to dry over a nitrogen pad overnight. This afforded 588 mg (˜97% pure by liquid chromatography (LC) analysis) of 2-amino-5,8-dimethoxy-[1,2,4]-triazolo[1,5-c]pyrimidine (I) as a light yellow solid in 52.8% yield from starting 2,5-dimethoxy-4-cyanoaminopyrimidine (2). 1H NMR (DMSO-d6, 400 MHz) δ 3.90 (s, 3H), 4.06 (s, 3H), 6.28 (br s, 2H), 7.48 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 55.37, 57.04, 123.07, 138.60, 143.73, 148.50, 166.02.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl:8][CH2:9][CH2:10][N:11]([CH2:19][CH2:20][Cl:21])[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:8][CH2:9][CH2:10][N:11]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[CH:16][CH:17]=1)[CH2:19][CH2:20][Cl:21]
Reactant: O=C1CCC(=O)O1
Reactant: Oc1ccc(N(CCCl)CCCl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(O)CCC(=O)Oc1ccc(N(CCCl)CCCl)cc1
Yield: 83 %

Procedure:
To a suspension of succinic anhydride (225 mg, 2.25 mmol) in CHCl3 (10 ml) was added under stirring, 4-[N,N-bis(2-chloroethyl)-amino]phenol (compound 6, FIG. 7; 203 mg, 0.75 mmol) followed by triethylamine (75 mg, 0.75 mmol). The mixture was stirred overnight and the solvent evaporated. The crude residue was dissolved in EtOAC/Et2O/H2O and under stirring the pH was adjusted to 3. The organic layer was washed with water, brine, dried (MgSO4), and evaporated. The resulting oil was crystallised from Et2O/hexane and the white solid was filtered off and dried under vacuum to obtain the desired end product (210 mg; yield 83%). Melting point 98-100° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.N1C=CC=CC=1>[C:9]1([C:8]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[O:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC(O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
In a four necked round bottom flask, under Argon atmosphere, 4-hydroxypiperidine (5.32 g, 52.6 mmol) was dissolved in CH2Cl2 (28 mL) and pyridine (28 mL). After cooling at 0° C., benzoyl chloride (6.4 mL, 55.2 mmol), dissolved in CH2Cl2 (7 mL) was drop wise added. The ice bath was removed and the mixture stirred 3 h at rt. The solid was filtered-off and the solvent removed under vacuum. Purification by typical column chromatography, eluting with CH2Cl2/MeOH (20:1) afforded the title compound (7.6 g, 70%) as pale yellow oil. Rf=0.21 (CH2Cl2/MeOH 20:1). MS (ESI) m/z: 206 [M−H]+. FTIR (cm−1): 3349, 3065, 3033, 3005, 2934, 2845, 1607, 1574, 1453, 1365, 1339, 1273, 1238, 1180, 1077, 998, 788, 730, 688.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH2:15][N:16]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CO.[Pd].[C]>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([CH2:13][CH2:14][CH2:15][N:16]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: CS(=O)(=O)N(C/C=C/c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCCCCC(=O)O
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)N(CCCCCCC(=O)O)CCCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 20 h
Yield: 90.4 %

Procedure:
A solution of trans-7-{[3-(3,5-bis-trifluoromethyl-phenyl)-allyl]-methanesulfonyl-amino}-heptanoic acid (210 mg, 0.44 mmol) in MeOH (10 mL) was added to 10% Pd/carbon (200 mg). The mixture was placed on a Parr hydrogenator at 50 psi and was hydrogenated for 20 h. The reaction was filtered through Celite with the aid of MeOH and the solvent was removed in vacuo. Purification by radial chromatography (2 mm rotary plate, 20:80:0.1 v/v/v EtOAc/hexanes/AcOH) provided the title compound (190 mg). 1H NMR (CDCl3 400 MHz) δ 7.69 (s, 1H), 7.63 (s, 2H), 3.20 (t, 2H), 3.14 (t, 2H), 2.81 (m, 5H), 2.28 (m, 2H), 1.94 (m, 2H), 1.32 (m, 4H); MS 495 (M+18).