Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].[OH-].[Na+].[N:11](OC)=[O:12]>CO>[OH:12][N:11]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:7]#[N:8]
Reactant: N#CCc1cccs1
Reactant: CON=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC(=NO)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
As described under 3.1, 86 g (0.7 mol) of thiophene-2-acetonitrile are charged, with stirring and in the presence of 28 g (0.7 mol) of sodium hydroxide in 210 ml of methanol, with 0.7 mol of gaseous methyl nitrite at 0-5° C. over 4.5 hours. The ice bath is then removed and the brown solution is stirred overnight at room temperature. The solvent is distilled off and the residue is charged with water and toluene. The aqueous phase is separated, washed twice with ethyl acetate and acidified with conc. HCl. The aqueous phase is extracted twice with toluene, the extracts are washed with water and dried over magnesium sulfate. After filtration, the solvent is distilled off and the remaining brown solid is recrystallised from toluene, giving 28.6 g (39% of theory) of α-hydroxyiminothiophene-2-acetonitrile in the form of a beige solid having a melting point of 105-109° C. The 1H-NMR spectrum is consistent with the proposed structure.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].C=O.C(O)(C)C.[P:13](=[O:17])([OH:16])([OH:15])[OH:14]>>[P:13]([O-:17])([OH:16])([OH:15])=[O:14].[C:2]([OH:6])(=[O:5])[CH:3]=[O:4]
Reactant: O=P(O)(O)O
Agent: C=O
Agent: O=CC(=O)O
Solvent: O
Solvent: CC(C)O
Product: O=P([O-])(O)O
Temperature: 40 °C
Reaction time: 20 h

Procedure:
29.3 g (0.100 mole) of 4-diazodiphenylamine hydrogensulfate was dissolved in 70 ml of an 85% phosphoric acid solution. Then 4.74 g (0.0500 mole) of glyoxylic acid monohydrate (97%) was added to this solution and the mixture was stirred at 40° C. for 20 hours. Then 1.58 g (0.0500 mole) of paraformaldehyde (95% ) was added to the reaction mixture and the mixture was stirred at 40° C. for additional 20 hours. Thereafter, the reaction solution was poured into 800 ml of isopropyl alcohol while stirring, to form yellow precipitate. The yellow precipitate was obtaided by filtering and washed with isopropyl alcohol, to give dihydrogenphosphate of a condensate of 4-diazodiphenylamine with glyoxylic acid.formaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:14][CH2:13][CH2:12]1)[C:7](=[O:15])[C:6]([C:16](OCC)=[O:17])=[C:5]2[OH:21].Cl.[C:23]([O:27][C:28](=[O:31])[CH2:29][NH2:30])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:14][CH2:13][CH2:12]1)[C:7](=[O:15])[C:6]([C:16]([NH:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:17])=[C:5]2[OH:21]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC2)C1=O
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 76.3 %

Procedure:
A mixture of ethyl 6′-chloro-4′-hydroxy-2′-oxo-spiro[cyclobutane-1,1′-naphthalen]-3′-carboxylate (155 mg, 505 μmol) and glycine tert-butyl ester hydrochloride (102 mg, 606 μmol) were mixed in dioxane (4 mL). DIPEA (106 μL, 606 μmol) was added, and the reaction mixture was stirred at 75° C. for 3.5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting yellow solid was purified by silica flash chromatography (0-50% DCM/hexane) to give the desired compound as a white solid (151 mg). MS (m/e)=336.1 (M+H-tBu)+.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:9]1[C:10]([N+:21]([O-:23])=[O:22])=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)(=[O:4])=[O:3].CN(C=O)C.[NH2:36][CH2:37][CH2:38][CH2:39][OH:40].Cl>O=S(Cl)Cl>[CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:9]1[CH:17]=[C:13]([C:14]([NH:36][CH2:37][CH2:38][CH2:39][OH:40])=[O:16])[C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22])(=[O:4])=[O:3]
Reactant: NCCCO
Reactant: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cc(C(=O)O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cc(C(=O)NCCCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 68 %

Procedure:
5-(Bis {2-[(methylsulfonyl)oxy]ethyl}amino)-2,4-dinitrobenzoic acid (8) was heated under reflux in excess SOCl2 (60 mL) and catalytic DMF for 1 h. Evaporation under reduced pressure, followed by azeotroping in benzene, gave the crude acid chloride. This was dissolved in dry Me2CO and treated at 0° C. with 3-amino-1-propanol at 0° C. for 5 min. The mixture was acidified to pH 2-3 with 0.2 N HCl, concentrated to half volume, and then solid NaBr was added, followed by extraction with EtOAc (2×). Evaporation, and chromatography of the residue on silica gel, eluting with EtOAc/MeOH (9:1), gave 2-(5-{[(3-hydroxypropyl)amino]carbonyl}{2-[(methylsulfonyl)oxy]ethyl}-2,4-dinitroanilino)ethyl methanesulfonate (9b) (68%) as a yellow gum;
Reaction SMILES: [I:1]N1C(=O)CCC1=O.CN(C)C=O.[CH2:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[CH2:31][C@H:30]3[O:32][CH2:33][CH2:34][O:35][C@@H:29]3[CH2:28]2)[N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[CH2:14]([C:21]1[C:26]([I:1])=[CH:25][CH:24]=[C:23]([N:27]2[CH2:28][C@H:29]3[O:35][CH2:34][CH2:33][O:32][C@@H:30]3[CH2:31]2)[N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(Cc2cccc(N3C[C@H]4OCCO[C@@H]4C3)n2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Ic1ccc(N2C[C@H]3OCCO[C@@H]3C2)nc1Cc1ccccc1

Procedure:
4.04 g of N-iodosuccinimide was added little by little to a solution of 40 ml of N,N-dimethylformamide containing 4.84 g of 2-benzyl-6-[(3R,4R)-3,4-ethylenedioxypyrrolidine-1-yl]pyridine under stirring in an ice bath, followed by stirring overnight as it was. The reaction solution was poured into water, and extracted with ethyl acetate. The organic phase was successively washed with an aqueous sodium sulfite solution, water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to filtration using silica gel and crystallized from hexane/ethyl acetate, to give 5.12 g of the target compound.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH3:30].[OH-].[Na+]>C(O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:14][CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]([CH3:30])[CH:8]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)COc1ccc(SCC=C(c2ccc(F)cc2)c2ccc(F)cc2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(SCC=C(c2ccc(F)cc2)c2ccc(F)cc2)ccc1OCC(=O)O
Reaction time: 2 h

Procedure:
{4-[3,3-Bis-(4-fluoro-phenyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (10.05 g, 22.8 mmol) was dissolved in warm ethanol (400 ml). 1N NaOH (35.5 ml, 35.5 mmol) was added at room temperature and the reaction mixture was stirred for 2 h. after which it was evaporated. The residue was treated with water (350 ml) and 1N HCl (41.5 ml) and extracted with dichloromethane (2×750 ml). The combined organic phases were dried and evapotated to give the title compound in 9.23 g (95%) yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH3:19])[C:12]2(O)[CH3:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH2:1]([N:8]1[CH2:23][CH2:22][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH3:19])[C:12]2=[CH2:20])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN1C(=O)OC2(CCN(Cc3ccccc3)CC2)C1(C)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C=C1N(CCC)C(=O)OC12CCN(Cc1ccccc1)CC2
Yield: 86.4 %

Procedure:
After refluxing a solution containing 9.6 g of 8-benzyl-4-hydroxy-4-methyl-2-oxo-3-propyl-1-oxa-3,8-diazaspiro[4,5]decane in a mixture of 96 ml of acetic acid and 5.7 ml of acetic anhydride under argon for 5 hours the solvent is evaporated under reduced pressure. After adding 5% by weight aqueous sodium hydroxide solution to the residue up to a pH value of 10, the mixture is extracted with benzene and the organic phase is washed to neutral with water. After drying the organic phase over anhydrous sodium sulfate benzene is evaporated under reduced pressure. After recrystallizing the residue from diisopropyl ether the title compound is obtained in 86.4% yield, m.p.: 70°-71° C.
Reaction SMILES: C([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:23])[CH:13]([CH2:18][S:19][C:20](=[O:22])[CH3:21])[NH:14][C:15](=[O:17])[CH3:16])(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:15]([NH:14][CH:13]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:24])=[O:5])=[O:23])[CH2:18][S:19][C:20](=[O:22])[CH3:21])(=[O:17])[CH3:16]
Reactant: CC(=O)NC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)NC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
N,S-Diacetyl-DL-cysteinyl-L-proline tert-butyl ester (1.9 g) is dissolved in a mixture of anisole (6 ml) and trifluoroacetic acid (12 ml) and the solution is stored at room temperature for one hour. The solvents are removed in vacuo and the residue is precipitated from ethyl acetate-ether-hexane, to obtain N,S-diacetyl-DL-cysteinyl-L-proline, yield 1.08 g, m.p. 80°-140°.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](Cl)=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2].[C:36](#[N:40])[CH2:37][CH:38]=[CH2:39].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C(N)C2CCCCC2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN1CCCC1=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](/[CH:39]=[CH:38]/[CH2:37][C:36]#[N:40])=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2]
Reactant: C=CCC#N
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Cl)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(/C=C/CC#N)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 160 °C
Yield: 63.4 %

Procedure:
A 5 mL microwave vial was charged with (2S,3S,4R,5S,6R)-2-(3-(4-chlorobenzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (7, 208 mg, 0.40 mmol), but-3-enenitrile (0.10 mL, 1.2 mmol), Pd2 dba3 (37 mg, 0.040 mmol), tri(tert-butyl)phosphonium tetrafluoroborate (46 mg, 0.16 mmol), dicyclohexylmethylamine (0.25 mL, 1.2 mmol), and 2 mL of N-methylpyrrolidinone. The reaction was heated in the microwave at 160° C. for 20 min. The reaction was filtered over Celite with excess EtOAc. The organic layer was washed with H2O, saturated aqueous NaHSO4, and brine. It was dried with MgSO4 and concentrated in vacuo. Flash chromatography (gradient 10-80% EtOAc/hexanes) provided the Heck adduct 28 (140 mg, 64% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24-7.31 (m, 2 H), 7.11-7.20 (m, 2H), 7.02-7.09 (m, 3 H), 6.70 (dt, J=15.9, 1.6 Hz, 1 H), 6.01 (dt, J=15.8, 5.7 Hz, 1 H), 5.33 (t, J=9.3 Hz, 1 H), 5.21 (t, J=9.7 Hz, 1 H), 5.12 (t, J=9.6 Hz, 1 H), 4.52 (d, J=9.9 Hz, 1 H), 4.39 (d, J=9.9 Hz, 1 H), 3.95 (d, J=3.5 Hz, 2 H), 3.28 (dd, J=5.8, 1.8 Hz, 2 H), 2.20 (s, 3 H), 2.16 (s, 3 H), 2.09 (s, 3 H), 2.01 (s, 3 H), 1.75 (s, 3 H). MS (ES+) [M+NH4]+=567.
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:27])[CH2:11][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[S:15][CH:16]=2)=[N:6][CH:5]=1)([CH3:3])[CH3:2].C=O.O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:27])[CH2:11][C:12]2[N:13]=[C:14]([N:17]([CH3:31])[CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)[S:15][CH:16]=2)=[N:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)c1cnc(NC(=O)Cc2csc(NCCN3CCN(C)CC3)n2)s1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)c1cnc(NC(=O)Cc2csc(N(C)CCN3CCN(C)CC3)n2)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
N-(5-isopropyl-1,3-thiazol-2-yl)-2-(2-{[2-(4-methyl-1piperazinyl)ethyl]amino}-1,3-thiazol-4-yl)acetamide (1 g, 2.45 mmol) and 40% formaldehyde in water (0.17 ml, 2.45 mmol) were mixed in CHCl3 (10 ml) and then treated with sodium triacetoxyborohydride (0.727 g, 3.43 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The reaction mixture was quenched by adding aqueous saturated sodium bicarbonate and the product was extracted with CHCl3. The organic layer was washed with brine, dried and evaporated. The title compound was obtained after chromatographic purification in 75% yield.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH:10]=[CH:9][C:8]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:7]=4[C:6]=3[C:5]=2[CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH:10]=[CH:9][C:8]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:7]=4[C:6]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c3ccc4c(c3c2c1)C(=O)NC4=O
Agent: BrB(Br)Br
Product: O=C1NC(=O)c2c1ccc1[nH]c3ccc(O)cc3c21
Yield: 79 %

Procedure:
Demethylation of (816) prepared as described in example 416 with BBr3 using the procedure described in example 80 gave (817) (79%), mp 335–345° C. 1H NMR δ [(CD3)2SO] 11.77 (s, 1H), 11.04 (s, 1H), 9.23 (s, 1H), 8.24 (d, J=2.3 Hz, 1H), 7.75 (2d, J=8.2 Hz, 2H), 7.43 (d, J=8.7 Hz, 1H), 7.05 (dd, J=8.7, 2.3 Hz, 1H). Found: C, 64.44; H, 3.45; N, 10.41. C14H8N2O3.1/2H2O requires: C, 64.37; H, 3.47; N, 10.72.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[CH:9]=1)=[O:4].[OH-].[Na+]>CO>[N+:16]([C:12]1[CH:11]=[C:10]([N:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[CH:7]2)[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: COC(=O)c1cn(-c2cccc([N+](=O)[O-])c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cn(-c2cccc([N+](=O)[O-])c2)cn1
Temperature: 70 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
1-(3-Nitro-phenyl)-1H-imidazole-4-carboxylic acid methyl ester 1 (0.7 g; 2.8 mmol) was suspended in MeOH (15 mL) and 2N NaOH aq. (2 mL) was added. The mixture was stirred at 70° C. for 16 h. The MeOH was evaporated and the product was isolated by suction filtration, washed with water and dried under vacuum to afford 0.56 g (86%) of 2 as an off-white solid. HRMS (ESI+): m/z=233.1823 [M+H]
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:15][N:16]([CH3:21])[CH2:17][CH:18]([NH2:20])[CH3:19]>C1COCC1>[CH3:15][N:16]([CH3:21])[CH2:17][CH:18]([N:20]=[C:1]([CH3:2])[CH2:4][C:5](=[O:7])[CH3:6])[CH3:19]
Reactant: CC(N)CN(C)C
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(C)=NC(C)CN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.7 %

Procedure:
To a solution of 10 g (199.76 mmol) acetylacetone in THF at room temperature loaded with 20 g of Na2SO4 was added 24.49 g (239.71 mmol) 1-dimethylamino-2-propylamine. The slurry was stirred for 16 hours at room temperature and reaction deemed to be complete by GC/MS. All volatiles were evaporated off under vacuum and unreacted acetylacetone and diamine were removed by heating at 60° C. under 100 mTorr vacuum for 2 hours. Yellow residual oil was purified via vacuum transfer heating at 130° C. under 100 mTorr vacuum. 13.5 g of light yellow oil was obtained as pure product with a yield of 74%.
Reaction SMILES: CS[C:3]1[NH:4][CH:5]=[CH:6][C:7](=[O:9])[N:8]=1.[Cl:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=2)=[CH:13][C:12]=1[C:27]([F:30])([F:29])[F:28]>N1C=CC=CC=1>[Cl:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:3]3[NH:4][CH:5]=[CH:6][C:7](=[O:9])[N:8]=3)=[CH:18][CH:17]=2)=[CH:13][C:12]=1[C:27]([F:28])([F:29])[F:30]
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CSc1nc(=O)cc[nH]1
Solvent: c1ccncc1
Product: O=c1cc[nH]c(NCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)n1
Yield: 77.8 %

Procedure:
2-Methylsulfanyl-1H-pyrimidin-4-one (70 mg, 0.492 mmol, 1.41 eq) and 2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (110 mg, 0.348 mmol, 1 eq) were heated in a sealed vial at 150° C. in 400 μl of dry pyridine for 16 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 10 g normal phase silica SNAP column and DCM/30% MeOH in DCM solvent system (gradient 2-20% of 30% MeOH in DCM in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and the resulting crude was triturated with diisopropyl ether and cyclohexane to afford 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-1H-pyrimidin-4-one (111 mg, yield=73.8%, purity=95%) as a white powder. MS: [M+H]+=410.33 1H NMR (300 MHz; CDCl3) δ/ppm 2.92 (t, J=6.95 Hz, 2H), 3.61-3.72 (m, 2H), 5.59 (d, J=6.38 Hz, 1H), 6.18 (br.s, 1H), 6.95 (d, J=8.51 Hz, 2H), 7.03 (dd, J=9.07 Hz, J=2.69 Hz, 1H), 7.24 (d, J=8.51 Hz, 1H), 7.30 (d, J=2.69 Hz, 1H), 7.41 (d, J=8.80 Hz, 1H), 7.77 (d, J=6.38 Hz, 1H), 11.77 (br.s, 1H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12](=[O:24])[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH:21]2[CH2:23][S:22]2)[CH2:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8]>C(O)C>[C:7]([O:11][C:12](=[O:24])[NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH:21]([SH:22])[CH2:23][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:18][CH2:19]1)([CH3:9])([CH3:8])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CS2)CC1
Reactant: C1COCCN1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(CC(S)CN2CCOCC2)CC1
Yield: 134.5 %

Procedure:
Morpholine (80 μL, 0.83 mmol, 1.5 eq) is added at room temperature to a stirred solution of (1-thiiranylmethyl-piperidin-4-yl)-carbamic acid tert-butyl ester (300 mg, 0.55 mmol, 1.0 eq) in ethanol (2 mL). The reaction mixture is irradiated under microwave conditions for 4 minutes at 140° C. and 80 W and then solvent is evaporated to afford [1-(2-mercapto-3-morpholin-4-yl-propyl)-piperidin-4-yl]-carbamic acid tert-butyl ester as an off-white semisolid (266 mg, 67% yield).
Reaction SMILES: [C:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CS(O)(=O)=[O:25].OO>C(OCC)(=O)C>[C:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][OH:25])=[O:21])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CS(=O)(=O)O
Reactant: CCCCCCCCCCCC(=O)NCCCCCC(=O)O
Agent: OO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCC(=O)NCCCCCC(=O)OO
Temperature: -15 °C

Procedure:
A 250 mL beaker was charged with 35.0 g (0.112 mol) of N-lauroyl-6-aminocaproic acid and 70 mL of 98% methanesulfonic acid. The resulting solution was cooled in an ice bath and, with stirring, 21.2 g of 90% hydrogen peroxide (19.0 g, 0.559 mol of hydrogen peroxide) was added dropwise at a rate so that the temperature of the reaction mixture did not rise above 20° C. (required 15 min.). The resulting solution was stirred at room temperature for 3 hrs., cooled to -15° C., and poured over ice. Ethyl acetate (150 mL) was added, the mixture was warmed to 60° C. in a water bath, and the water layer separated. An additional 100 mL of water was added, the solution again warmed to 60° C. and the water layer separated and discarded. The ethyl acetate solution was cooled to -15° C., and the crystals which formed were removed by filtration and washed with 2×50 mL portions of -15° C. ethyl acetate. The yield of N-lauroyl-6-aminoperoxycaproic acid was 33.1 g; analysis for available oxygen (AvO) indicated 4.31% (theoretical yield=36.9 g having an AvO of 4.86%), mp 70°-75° C.
Reaction SMILES: CC([S-])C.[Na+].[CH3:6][C:7]([CH:13]1[C:22]2[CH:23]=[N:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[O:34])=[CH:29][CH:28]=3)=[CH:26][C:21]=2[O:20][C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]1=2)([CH3:12])[C:8]([O:10]C)=[O:9]>CN(C=O)C>[CH3:12][C:7]([CH:13]1[C:22]2[CH:23]=[N:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[O:34])=[CH:29][CH:28]=3)=[CH:26][C:21]=2[O:20][C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]1=2)([CH3:6])[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C(C)(C)C1c2ccccc2Oc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ncc21
Agent: CC(C)[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C(=O)O)C1c2ccccc2Oc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ncc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 106.5 %

Procedure:
Sodium 2-propanethiolate (58.5 mg, 0.596 mmol) was added to a solution of methyl 2-methyl-2-(3-(4-(morpholine-4-carbonyl)phenyl)-10H-chromeno[3,2-c]pyridin-10-yl)propanoate (140.9 mg, 0.298 mmol) in DMF (5 mL) and the mixture was heated to 50° C. After 1 h at 50° C., additional sodium 2-propanethiolate (58.5 mg) was added. The mixture was stirred at 50° C. overnight. Another portion of sodium 2-propanethiolate (200 mg) was added. After another hour at 50° C., the mixture was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (4×20 mL). The combined extracts were washed with brine (5 mL), dried (MgSO4) and concentrated to give 2-methyl-2-(3-(4-(morpholine-4-carbonyl)phenyl)-10H-chromeno[3,2-c]pyridin-10-yl)propanoic acid as a solid (145.5 mg). MS (ES+) m/z: 459 (M+H); HPLC retention time: 3.51 min (Analytical HPLC Method D).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=1)=[O:15].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[OH:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:14](=[O:15])[CH2:13][N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[C:6]([O:8][CH3:9])=[O:7])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc[nH]1
Reactant: O=C(CBr)c1ccc(CO)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccn1CC(=O)c1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
To a chilled solution of methyl 2-pyrrolecarboxylate (500 mg, 4.0 mmol) in dry DMF (15 mL) was added sodium hydride (60% dispersion in mineral oil, 300 mg, 7.5 mmol) portion wise. The mixture was stirred at 0° C. for 1 hour and a solution of 2-bromo-1-[4-(hydroxymethyl)phenyl]ethanone (750 mg, 3.3 mmol) in DMF (5 mL) was added and the mixture was allowed to warm to room temperature and stirred for 1.5 hour. A saturated aqueous solution of NH4Cl (35 mL) was added followed by EtOAc (100 mL). The organic layer was then washed with brine (35 mL), dried (MgSO4), filtered and concentrated in vacuo to yield a oil. The material was purified by flash chromatography (Biotage SP4, 40 g cartridge, gradient 0-80% EtOAc in hexanes) to give methyl 1-{2-[4-(hydroxymethyl)phenyl]-2-oxoethyl}-1H-pyrrole-2-carboxylate as a white solid (150 mg, yield: 17%). ESI-MI m/z [M+H]+: 273.8.