Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-:4])C.[K+].C(C([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][CH2:21][C:22](OCC)=O)[CH2:15]1)C)(OCC)=O.Cl>C1(C)C=CC=CC=1>[N:14]12[CH2:15][CH:16]([CH2:17][CH2:18][CH2:19]1)[C:20](=[O:4])[CH2:21][CH2:22]2
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CCC1CCCN(C(C)C(=O)OCC)C1
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCN2CCCC1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Anhydrous potassium t-butoxide (45.8 g) in anhydrous toluene (1.0 dm3) was heated at reflux and 1-carboethoxyethyl-3-carboethoxyethylpiperidine (35.0 g) in toluene (250 ml) was added over 2 hours. Reflux was maintained for a further 4 hours before cooling to room temperature and concentrated hydrochloric acid (300 ml) was added. The mixture was stirred for 1 hour, then the organic layer was separated and extracted with concentrated hydrochloric acid (225 ml×4). The combined acid extracts were heated at reflux for 16 hours, then basified to pH 10 with potassium carbonate and extracted with chlorofeny (300 ml×6). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to an orange semi-solid (9.7 g). This was purified by chromatography (Alumina grade III) by gradient elution in 3-10% methanol in ethyl acetate. The title compound was isolated as light orange semi-solid (3.5 g). δH (360 MHz, CDCl3), 1.55 (1H, m, CHH), 1.7-1.8 (1H, m, CHH), 1.95 (2H, m, CH2), 2.4 (1H, s, CH), 2.55 (2H, m, CH2CO), 3.1-3.4 (6H, m, 3×CH2N); m/z 139 (M+) (100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[C:4]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])[C:3]1=2.[OH-].[Na+]>>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[CH2:28][O:27][C:4]1[C:3]2[C:2]([CH3:1])([CH3:37])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(C#C[Se]c2cc(OCc3ccc(F)cc3F)c3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(C)(C)c2c(OCc3ccc(F)cc3F)cc([Se]C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
In a manner similar to that of Example 1g, by reacting 790 mg (1.4 mmol) of methyl 4-[5,5,8,8-tetramethyl-4-(2,4-difluorobenzyloxy)-5,6,7,8-tetrahydro-2-naphthylselanylethynyl]benzoate with 240 mg of sodium hydroxide. A yellow crystallized solid is obtained (m=502 mg; yield=65%; m.p.=219° C.).
Reaction SMILES: C[NH2:2].[CH2:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([CH:14]=O)=[C:10]2[CH3:16])[CH3:4].[BH4-].[Na+].O>CO>[CH3:4][CH2:3][C:5]1[C:13]2[NH:12][C:11]([CH2:14][NH2:2])=[C:10]([CH3:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CN
Reactant: CCc1cccc2c(C)c(C=O)[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1cccc2c(C)c(CN)[nH]c12
Temperature: 0 °C
Reaction time: 5 h
Yield: 75.6 %

Procedure:
Methylamine (0.7 mL, 17.6 mmol) was added to a solution of 7-ethyl-3-methyl-1H-indole-2-carbaldehyde (1.1 mg, 5.8 mmol) in methanol (5 mL) and stirred for 5 h. The mixture was cooled to 0° C. and sodium borohydride (218 mg, 5.8 mmol) added slowly. The mixture was warmed to rt and stirred overnight. Water (3 mL) was added slowly at 0° C. and evaporated to a paste. Water was added and the mixture extracted with dichloromethane. The organic phase was washed with water, dried and evaporated to afford the title compound (826 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.01 (t, J=7.6 Hz, 1H), 6.96 (d, J=6.8 Hz, 1H), 3.87 (s, 2H), 2.79 (q, J=7.5 Hz, 2H), 2.45 (s, 3H), 2.24 (s, 3H), 1.31 (t, J=7.6 Hz, 3H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:14][C:15](=[O:18])[CH2:16]Cl)([CH2:12][OH:13])[CH2:10][OH:11])[C:5]([Cl:8])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:12][OH:13])[NH:14][C:15](=[O:18])[CH2:16][O:11][CH2:10]2)[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(CCl)NC(CO)(CO)c1cc(Br)cnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1COCC(CO)(c2cc(Br)cnc2Cl)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of N-[1-(5-bromo-2-chloro-pyridin-3-yl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide (622 mg, 1.74 mmol) in tert.-butanol (10.2 ml) was added at 0° C. potassium tert.-butoxide (292 mg, 2.61 mmol), the reaction mixture was stirred at room temperature for 1 h. Water was added and the tert.-butanol evaporated, the mixture was extracted with EtOAc, the combined organic layers were washed with halfsaturated aq. NaCl, dried with Na2SO4 and evaporated to provide the title compound as beige foam.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH2:19][CH2:20][OH:21])[C:7]2[CH:8]=[CH:9][C:10]([N+:16]([O-])=O)=[C:11]([C:14]#[N:15])[C:12]=2[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:16][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:19][CH2:20][OH:21])[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:13][C:12]=2[C:11]=1[C:14]#[N:15]
Reactant: CC(C)(C)c1cc2c(C#N)c([N+](=O)[O-])ccc2n1CCO
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc2c(C#N)c(N)ccc2n1CCO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
To a solution of 2-tert-butyl-1-(2-hydroxyethyl)-5-nitro-1H-indole-4-carbonitrile (180 mg, 0.63 mmol) in ethanol (6 mL) under N2 atmosphere was added Pd—C (5% wt, 18 mg). The reaction was flushed with N2 (g) and then with H2 (g) and stirred under H2 (atm) at room temperature for 1.5 hours. The reaction was filtered over Celite and concentrated to yield the product (150 mg, 93%). ESI-MS m/z calc. 257.2, found 258.5 (M+1)+. Retention time 1.26 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].O.O.Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:10])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)cc(Cl)c1N
Temperature: 25 °C

Procedure:
3,5-Dichloro-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy, et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25: 839 (1984)). A mixture of 2,4-dichloro-6-nitroaniline (1.00 g, 4.8 mmol) and SnCl2.2H2O (5.41 g, 24.1 mmol) dissolved in 10 mL ethyl acetate and 5 mL absolute ethanol under N2 was heated at 70° C. for 1 h. All the starting material had reacted as evidenced by TLC (silica gel, 3:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 40 mL crushed ice. Sufficient sat'd NaHCO3 solution was added (foaming!) to bring the pH to 5. The orange oil/thick white emulsion was extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a pale orange oil which crystallized on standing to yield 789 mg (93%). 1H NMR (CDCl3) δ 3.69 (br s, 4H, 2(NH2)); 6.61 (s, 1H, H-6); 6.82 (s, 1H, H-4).
Reaction SMILES: [CH:1]([C:4]([CH3:22])([N:7]1[C:11](=[O:12])[CH:10]2[CH2:13][CH2:14][C:15]3[N:16]([CH3:20])[CH:17]=[CH:18][C:19]=3[CH:9]2[C:8]1=[O:21])[C:5]#[N:6])([CH3:3])[CH3:2]>ClC1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH:1]([C:4]([CH3:22])([N:7]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]3[N:16]([CH3:20])[CH:17]=[CH:18][C:19]=3[C:9]=2[C:8]1=[O:21])[C:5]#[N:6])([CH3:3])[CH3:2]
Reactant: CC(C)C(C)(C#N)N1C(=O)C2CCc3c(ccn3C)C2C1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: Clc1ccccc1
Product: CC(C)C(C)(C#N)N1C(=O)c2ccc3c(ccn3C)c2C1=O
Reaction time: 8 h
Yield: 11.2 %

Procedure:
Activated manganese dioxide (27.0 g, 0.310 mol) is added to a solution of 3,3a,4,5,6,8b-hexahydro-α-isopropyl-α,6-dimethyl-1,3-dioxobenzo-[1,2-b:3,4-c']dipyrrole-2(1H)-acetonitrile (51.3 g, 0.167 mol) in chlorobenzene. The reaction mixture is stirred overnight at reflux temperature, cooled and filtered twice through diatomaceous earth with methylene chloride. The filtrate is concentrated in vacuo to a black oil which is flash chromatographed twice with methylene chloride then hexanes:methylene chloride to afford a yellow solid (5.50 g, 11.6%). Recrystallization from hexanes:methylene chloride afforded the title product, mp 123°-128° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(-n2cc(C(=O)c3cc(Br)ccc3O)cn2)cc1
Product: CCOC(=O)COc1ccc(Br)cc1C(=O)c1cnn(-c2ccc(OC)cc2)c1

Procedure:
Prepared from (5-bromo-2-hydroxyphenyl)-[1-(4-methoxyphenyl)-1H-pyrazol-4-yl]ketone and ethyl bromoacetate according to GP2: LC/MS (an10p8): Rt 4.59 min, m/z 458.4/460.4 [M+H]+; 1H NMR (CDCl3): δ 1.26 (t, J=7.1 Hz, 3H), 3.84 (s, 3H), 4.23 (q, J=7.1 Hz, 2H), 4.62 (s, 2H), 6.72 (d, J=8.9 Hz, 1H), 6.97 (d, J=8.7 Hz, 2H), 7.52 (dd, J=8.9, 2.6 Hz, 1H), 7.58 (d, J=2.5 Hz, 1H), 7.64 (d, J=8.9 Hz, 2H), 8.13 (s, 1H), 8.46 (s, 1H); 13C NMR (CDCl3): δ14.3, 55.8, 61.9, 65.6, 114.1, 114.4, 114.8, 121.4, 125.0, 131.6, 132.4, 132.6, 133.2, 134.5, 142.5, 154.1, 159.2, 168.5, 186.9.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:28][C:29]([F:38])([F:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1>O1CCCC1>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:36][C:32]1[CH:31]=[C:30]([C:29]([F:28])([F:37])[F:38])[CH:35]=[CH:34][CH:33]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(C(C)(C)C)cc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(OCC(C)Oc2ccc(C(C)(C)C)cc2)cc1

Procedure:
As described in Example 71, methyl bromo{p-[2-(p-tert-butylphenoxy)propoxy]phenyl}acetate (0.017 mole) is reacted with 2.75 g of α,α,α,-trifluoro-m-cresol in 75 ml of tetrahydrofuran at 80° C. for 18 hrs to give the product as a pale yellow gum.
Reaction SMILES: Br[CH:2]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:3](=[O:12])[C:4]([CH3:11])([S:6][C:7]([F:10])([F:9])[F:8])[CH3:5].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1>C(#N)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH:2]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[C:3](=[O:12])[C:4]([CH3:11])([S:6][C:7]([F:10])([F:9])[F:8])[CH3:5])=[CH:15][CH:16]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(SC(F)(F)F)C(=O)C(Br)Oc1ccc(Cl)cc1
Solvent: CC#N
Product: CC(C)(SC(F)(F)F)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Yield: 36.5 %

Procedure:
29 g (0.075 mol) of crude 1-bromo-1-(4-chlorophenoxy)-3-methyl-3-trifluoromethylthio-butan-2-one and 16 g (0.25 mol) of 1,2,4-triazole in 150 ml of acetonitrile were heated under reflux for 1 hour. Thereafter, the mixture was concentrated and the residue was taken up with methylene chloride/water. The organic phase was separated off, dried over sodium sulphate and concentrated again. The oil residue was chromatographed. 10.4 g (37% of theory) of 1-(4-chlorophenoxy)-3-methyl-1-(1,2,4-triazol-1-yl)-3-trifluoromethylthio-butan-2-one of melting point 66° C. were obtained.
Reaction SMILES: C1(C)C=CC=CC=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]#[N:18])=[CH:11][CH:10]=1.[C:19](OCC)(=[O:22])[CH2:20][CH3:21]>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([C:19](=[O:22])[CH2:20][CH3:21])[C:17]#[N:18])=[CH:13][CH:14]=1
Reactant: N#CCCc1ccc(Br)cc1
Reactant: CCOC(=O)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC(=O)C(C#N)Cc1ccc(Br)cc1
Reaction time: 0.33 h

Procedure:
A 1.7 M solution of potassium tert. pentylate in toluene (81 ml, 139 mmol) was added dropwise to a solution of 3-(4-bromo-phenyl)-propionitrile (9.70 g, 46.2 mmol) in 200 ml of THF at rt, followed by addition of ethyl propionate (18.9 ml, 185 mmol). Stirring was continued for 20 min. The reaction mixture was quenched by careful addition of 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2 SO4 and evaporated. The residue was purified by column chromatography (silica gel, EtOAc/n-hexane 3:7) to yield 1 as a yellow oil.
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:28][C:29]1[CH:45]=[CH:44][C:32]([C:33]2[CH:38]=[C:37]([CH2:39][CH3:40])[C:36]([Pb+3])=[C:35]([CH2:42][CH3:43])[CH:34]=2)=[CH:31][CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]2[CH:34]=[C:35]([CH2:42][CH3:43])[C:36]([CH:4]3[C:5](=[O:10])[C@H:6]4[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]4)[C:3]3=[O:11])=[C:37]([CH2:39][CH3:40])[CH:38]=2)=[CH:44][CH:45]=1
Reactant: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1[Pb+3]
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 12.4 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (0.20 g, 1.30 mmol) and 4-dimethylamino-pyridine (0.792 g, 6.49 mmol) are added to a mixture of chloroform (4 ml) and toluene (1 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4′-Chloro-3,5-diethylbiphen-4-yllead triacetate (0.896 g, 1.43 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×5 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(4′-chloro-3,5-diethyl-biphenyl-4-yl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (0.064 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][CH2:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=O)=[CH:16][CH:15]=1)=[O:4].[F:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[CH2:28][NH:29][CH2:30][CH3:31].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:30]([N:29]([CH2:28][C:27]1[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=1[F:25])[C:20](=[O:22])[CH2:19][O:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][S:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:24][CH:23]=1)[CH3:31]
Reactant: CCNCc1ccccc1F
Reactant: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
[4-(2-{[2-(Methoxycarbonyl)phenyl]thio}ethyl)phenoxy]acetic acid (0.250 g, 0.722 mmol) was dissolved in DCM (10 ml), N-(2-fluorobenzyl)ethanamine (0.105 g, 0.686 mmol) was added. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.255 g, 0.0.794 mmol) and N-ethyl-N,N-diisopropylamine (0.187 g, 1.443 mmol) were added. The solution was stirred for 2 hours at room temperature. The crude was purified by flash chromatography (started with isocratic DCM 100% and then the MeOH concentration was increased from 0.5% to 20%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation. The substance needed to be purified once more and it was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. The ammonium acetate was removed by freeze drying the product overnight to give 0.1 g of methyl 2-{[2-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}benzoate (yield 29.1%).
Reaction SMILES: [S].P12([S:14][P:12]3([S:15]P(S[P:8]([S:11]3)([S:10]1)=[S:9])(=S)S2)=[S:13])=S.[CH:16]1[CH:21]=[CH:20][C:19](S)=[CH:18][CH:17]=1>C1C(Cl)=CC=C(Cl)C=1>[C:16]1([S:10][P:8]2(=[S:9])[S:11][P:12]([S:14][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[S:13])[S:15]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Sc1ccccc1
Agent: [S]
Solvent: Clc1ccc(Cl)cc1
Product: S=P1(Sc2ccccc2)SP(=S)(Sc2ccccc2)S1
Temperature: 190 °C
Yield: 60 %

Procedure:
The method is derived from the reference H. Davy, Sulfur Letters, vol. 3(2) 39, (1985). P4S10 (44.4 g, 0.1 mol) is mixed with 150 ml of dichlorobenzene until this solvent refluxes (160° C.). Phenylthiol (47 ml) is slowly added to the solution over 90 minutes, while increasing the temperature up to 190° C. The solution becomes clear; the reaction temperature is reduced to 100° C. The stirring is stopped in order to allow the residual P4S10 to be separated by settling. The solution is filtered in the hot state. The product crystallizes after filtration. The yield is 60%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH:19]=1)([O-])=O>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[C:15]1([CH3:18])[CH:14]=[CH:13][C:12]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:19][C:8]=3[N:9]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(-c2nc3cc(N)ccc3o2)cc1
Reaction time: 16 h
Yield: 59 %

Procedure:
To 5-nitro-2-p-tolylbenzo[d]oxazole (4.8 g, 18.90 mmol) in ethyl acetate/acetic acid (250 mL/1 mL) was added palladium on carbon (480 mg). The reaction vessel was purged three times with nitrogen, followed by hydrogen three times, and then left stirring under hydrogen for 16 h. The reaction vessel was finally purged three times with nitrogen, before filtration on a pad of Celite®, which was washed with ethyl acetate. The organic solution was washed with saturated aqueous Na2CO3, followed by brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 2.5 g (60%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH:25]4[CH2:26][O:23][CH2:24]4)[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)nc(Nc2ccc(C3CCNCC3)cc2)c1=O
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(Br)nc(Nc2ccc(C3CCN(C4COC4)CC3)cc2)c1=O
Temperature: 48 °C
Yield: 59.6 %

Procedure:
A 100-mL sealed tube with a magnetic stirrer was purged with nitrogen and charged with 214a (390 mg, 1.08 mmol), oxetan-3-one (800 mg, 11 mmol) and methanol (10 mL). A suspension of sodium cyanoborohydride (208 mg, 3.3 mmol) and zinc chloride (225 mg, 1.65 mmol) in methanol (10 mL) was added, and the reaction was heated at 48° C. for 12 hours. After this time, the reaction mixture was concentrated, and the residue was partitioned between ethyl acetate (50 mL) and 10% aqueous potassium carbonate (10 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica, 60:35:5 methylene chloride/diethyl ethyl/methanol) to afford a 60% yield (270 mg) of 5-bromo-1-methyl-3-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenylamino)pyrazin-2(1H)-one (214b) as a yellow solid: MS (ESI+) m/z 421.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)OCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.2 %

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (1 g, 5 mmol) in THF (15 ml) was added sodium hydride (60% in parafin liquid) (220 mg, 5.5 mmol) at 0° C., and the mixture was stirred at room temperature for 15 minutes. To the mixture was added ethyl 2-bromoisobutyrate (1.08 g, 5.5 mmol), and the mixture was stirred at room temperature for 12 hours. To this reaction solution were added ethyl acetate and a saturated aqueous ammonium chloride solution, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate, and the extracts were combined with the organic layer. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resultant was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the title compound (240 mg, 15%).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([Cl:25])[CH:19]=2)=[O:15])=[O:6])#[N:2].[H-].[Na+].[CH3:28]I>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:13][C:14]([C:16]1[N:17]([CH3:28])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([Cl:25])[CH:19]=2)=[O:15])=[O:6])#[N:2]
Reactant: CI
Reactant: N#CCNC(=O)C1CCCCC1NC(=O)c1cc2ccc(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(=O)NC2CCCCC2C(=O)NCC#N)cc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 6-Chloro-1H-indole-2-carboxylic acid [2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide (6.17 g, 17.19 mmol) in DMF (35 ml) were added NaH as a 60% wt suspension in mineral oil (0.687 g, 17.19 mmol) at 0° C. The slurry was stirred for one hour at room temperature and methyl iodide (1.07 ml, 17.19 mmol) was added. The solution was stirred for four hours and partitioned between ethyl acetate (200 ml) and 1 N HCl (300 ml). The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated. Recrystallizing from ethyl acetate: hexane (1:10) yielded 6-Chloro-1-methyl-1H-indole-2-carboxylic acid [2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide (4.76 g, 74%). [M+H=373].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:9]=1.[CH:23]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:25])[CH3:24].C(N(CC)CC)C>O1CCOCC1>[CH2:27]([N:26]([CH:23]([CH3:25])[CH3:24])[C:14]([C:13]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:9][C:10]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[N:11][CH:12]=1)=[O:15])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)NCc1ccccc1
Reactant: O=C(O)c1cnc(N2CCOCC2)nc1-c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)N(Cc1ccccc1)C(=O)c1cnc(N2CCOCC2)nc1-c1ccccc1Cl
Temperature: 160 °C

Procedure:
In a microwave tube was added 1 eq. of 4-(2-chlorophenyl)-2-morpholino pyrimidine-5-carboxylic acid (80 mg), 1.1 eq. of isopropyl benzylamine (43 mL), 2.5 eq. of triethylamine (80 mL) and 1.2 eq. of BtSO2Me in 4 mL of dioxane. The reaction mixture was heated to 160° C./300 W for 1200 sec. The crude product was purified by prep HPLC. ES+=451.0. NMR confirmed the structure.