Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CN(C=O)C.CCOC(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1cnc(OC2CCC3(CC2)OCCO3)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
As shown in step 7-i of Scheme 7, to a solution of 1,4-dioxaspiro[4.5]decan-8-ol (compound 1021, 1.0 g, 6.32 mmol) in DMF (10 mL) was added NaH (370 mg, 9.25 mmol). The reaction mixture was stirred for 20 minutes before the addition of 2-chloropyrimidine (869 mg, 7.59 mmol). The mixture was stirred for 30 minute at RT and then heated to 100° C. for 9 hours. After cooling, the mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0-40% EtOAc/hexanes) to produce 2-(1,4-dioxaspiro[4.5]decan-8-yloxy)pyrimidine (compound 1022) as a colorless oil: 1H NMR (300 MHz, Chloroform-d) δ 8.52 (d, J=4.8 Hz, 2H), 6.92 (t, J=4.8 Hz, 1H), 5.15 (ddd, J=10.7, 6.5, 4.2 Hz, 1H), 4.05-3.87 (m, 4H), 2.14-1.85 (m, 6H), 1.79-1.65 (m, 2H); ESMS (M+H+)=237.12.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]1[CH:19]2[CH2:20][CH2:21][CH:15]1[CH2:16][C:17](=O)[CH2:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S([CH2:33][N+:34]#[C-])(C1C=CC(C)=CC=1)(=O)=O.C(O)C>C(COC)OC>[C:33]([CH:17]1[CH2:16][CH:15]2[N:14]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:19]([CH2:20][CH2:21]2)[CH2:18]1)#[N:34]
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1CC2CCC(C1)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
Potassium t-butoxide (2.5 g) was added portion wise to a stirred mixture of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (2.0 g), tosylmethyl isocyanide (2.36 g) and ethanol (2 ml) in dimethoxyethane (50 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 0.5 hours and then overnight at room temperature. The mixture was then filtered and the solid residue washed with dimethoxyethane. The combined filtrates were evaporated under reduced pressure and chromatographed [SiO2; hexane:ethyl acetate (80:20)] to give 3-cyano-8-benzyl-8-azabicyclo[3.2.1]octane (0.87 g).
Reaction SMILES: [O:1]([C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:20][C:21](=[O:40])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33](Br)[CH:32]=2)=[CH:26][C:25]=1[CH3:39]>>[CH3:39][C:25]1[CH:26]=[C:27]([O:30][C:31]2[CH:32]=[C:33]([O:18][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([F:15])([F:16])[F:17])[C:8]=3[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:34]=[C:35]([CH3:37])[CH:36]=2)[CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][C:21]([OH:40])=[O:20]
Reactant: COC(=O)CCc1ccc(Oc2cc(C)cc(Br)c2)cc1C
Reactant: Oc1cccc(C(F)(F)F)c1Oc1ccccc1
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2cccc(C(F)(F)F)c2Oc2ccccc2)c1

Procedure:
The title compound is prepared according to Example 85 by using 2-phenoxy-3-trifluoromethyl-phenol and 3-[4-(3-bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester to afford about 57 mg (10%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H25O5F3 522, found 523 (M+1, 100%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]([CH3:9])[C:7](=[O:10])[N:6]([CH3:11])[C:5](=[O:12])[C:4]=1[NH:13][C:14](=O)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[OH-].[Na+]>CO>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:14]2[NH:13][C:4]3[C:5](=[O:12])[N:6]([CH3:11])[C:7](=[O:10])[N:8]([CH3:9])[C:3]=3[N:2]=2)=[CH:17][CH:18]=1
Reactant: Cn1c(N)c(NC(=O)Cc2ccc(N)cc2)c(=O)n(C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(=O)c2[nH]c(Cc3ccc(N)cc3)nc2n(C)c1=O
Temperature: 50 °C

Procedure:
To a solution of crude N-(6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-2-(4-amino-phenyl)-acetamide hydrochloride salt (0.68 mmol) in methanol (35 mL) was added 10% w/v aqueous sodium hydroxide (3.4 mL) and the mixture heated to 50° C. for 7 hrs. The reaction mixture was concentrated in vacuo to dryness and the residue triturated with warm tetrahydrofuran and filtered to remove insoluble inorganic material. The filtrate was concentrated in vacuo to give crude 8-(4-amino-benzyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione which was of sufficient purity for subsequent use without additional purification (58%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:10])=[N:4][C:5]([CH3:9])=[C:6]([Cl:8])[CH:7]=1.[Li]CCCC.[CH3:16][S:17]SC.O>O1CCCC1>[Cl:8][C:6]1[CH:7]=[C:2]([S:17][CH3:16])[C:3]([NH2:10])=[N:4][C:5]=1[CH3:9]
Reactant: Cc1nc(N)c(Br)cc1Cl
Reactant: CSSC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CSc1cc(Cl)c(C)nc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
3-Bromo-5-chloro-6-methylpyridin-2-amine (300 mg, 1.35 mmol, Eq: 1.00) was dissolved in tetrahydrofuran (5 ml). 1.6M n-BuLi in hexanes (3.39 ml, 5.42 mmol, Eq: 4) was added at −78° C. The mixture was stirred for 10 min. 1,2-Dimethyldisulfane (510 mg, 481 μl, 5.42 mmol, Eq: 4) was added and mixture allowed to warm to room temperature. The mixture was stirred for 30 min. Water was added and the mixture was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to an oil. The product (158 mg, 61.8%) was obtained as a light yellow solid by chromatography (SiO2, ethyl acetate/n-heptane). MS: m/z=230.1 (M+acetonitrile+H+)
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.[F:32][C:33]1[CH:34]=[N:35][C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:37][CH:38]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:27])[NH:42][C:39]2([C:36]3[N:37]=[CH:38][C:33]([F:32])=[CH:34][N:35]=3)[CH2:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: NC1(c2ncc(F)cn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(F)cn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(5-fluoropyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.064 g, 0.12 mmol, 1.3 eq), in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.026 g (50%). 1H NMR (400 MHz, CDCl3): δ 8.46 (s, 2H), 7.99-7.95 (m, 2H), 7.80 (dd, J=2.0, 8.0 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.43-7.39 (m, 2H), 7.23-7.15 (m, 3H), 7.07 (bs, 1H), 6.18 (bs, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.27 (s, 3H), 1.81-1.78 (m, 2H), 1.55-1.53 (m, 2H). 19F NMR (376.47 MHz, CDCl3) δ−75.77 (TFA), −109.62, −119.26, −142.84 LCMS: (ES+) m/z=557.4 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][OH:19])[CH2:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(Cc1cnccn1)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(Cc1cnccn1)c1ccc(Cl)cc1

Procedure:
10 g of 4'-chloro-2-(2-pyrazinyl)-acetophenone, 10 g of hydroxylamine hydrochloride and 12 g of anhydrous sodium carbonate are stirred at 60° in 100 ml of ethanol for 2 hours. The mixture is then treated with water and extracted with ethyl acetate, and the organic phase is dried over sodium sulfate and subsequently concentrated. The residue is crystallized from acetone/n-hexane to yield 4'-chloro-2-(2-pyrazinyl)-acetophenone oxime, m.p. 134°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[O:12]([C:19]([NH:21][C@H:22]([C:26]([OH:28])=[O:27])[CH:23]([CH3:25])[CH3:24])=O)C1C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][N:2]([C:19]([NH:21][C@H:22]([C:26]([OH:28])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:12])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1
Reactant: CNCc1csc(C(C)C)n1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
To a suspension of LiOH monohydrate (1.06 g, 25.2 mmol) in THF (20 mL) at 0° C. to 5° C. was added 3.78 g (22.2 mmol) of N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine, followed by a 5 mL THF rinse. To this solution was added a solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) in 20 mL of THF. Following a 5 mL THF rinse, 0.5 mL of water was added, and the reaction mixture was allowed to warm to 20° C. with stirring. After 6 hours, the reaction was cooled to 10° C. and quenched with water (55 mL). The THF was removed under reduced pressure, MTBE (50 mL) was added, and the biphasic solution was adjusted to pH 9.0 with 4 N HCl. The layers were separated and the aqueous layer was washed with an additional 50 mL of MTBE. The aqueous layer was sitrred with 130 mL of toluene and adjusted to pH 3 with 4 N HCl, and the phases were separated. The aqueous, product-containing layer was stirred with 50 mL of toluene and adjusted to pH=3.0 with 4N HCl. The aqueous layer was separated and extracted once more with 50 mL of toluene. The combined organic extracts were concentrated in vacuo. The residue obtained was redissolved in toluene, filtered and rinsed with toluene (approx. 50 mL total). The combined filtrates were concentrated in vacuo to an oil. Toluene (25 mL) and heptane (25 mL) were added and warmed to 50° C. The clear solution was allowed to cool until cloudy and then was seeded with N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-Valine. The resulting slurry was stirred for at least 12 hours and the product was collected by filtration and washed with heptane (5 mL). The resulting solid was dried in a vacuum oven at 50° C. to yield the desired product as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C1C(=O)N([Br:31])C(=O)C1.Cl>CC#N>[Br:31][C:13]1[C:11]2[CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[O:9][C:10]=2[CH:16]=[CH:15][C:14]=1[OH:17]
Reactant: Oc1ccc(-c2cc3cc(O)ccc3o2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Oc1ccc(-c2cc3c(Br)c(O)ccc3o2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 75 2-(4-Hydroxy-phenyl)-benzofuran-5-ol (0.65 g, 2.9 mmol) in CH3CN (40 mL) was treated with K2CO3 (1 g, 7.1 mmol) followed by portionwise addition of NBS (0.36 g, 2.0 mmol). After stirring for approximately 30 minutes, the reaction was worked up by addition of 2 N HCl followed by 10% Na2SO3aq. and then the CH3CN was stripped off. The aqueous layer was extracted with EtOAc and washed with brine and dried over MgSO4. The reaction mixture was concentrated and chromatographed on silica gel (EtOAc/hexanes; 1:4): Mp 196-198° C.; 1H NMR (DMSO-d6) δ 9.93 (br s, 2 H), 7.76 (d, 2H, J=8.5 Hz), 7.40 (d, 1 H, J=8.7 Hz), 7.04 (s, 1 H), 6.87 (dd, 2 H, J=9.0 Hz, 3.1 Hz); MS 305/307 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[O:31])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15]
Reactant: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccc(C(=O)N(C)C)cc3Cl)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with N1,N1-dimethylethane-1,2-diamine, HATU and DIPEA in THF to give 334 as a colorless solid after reverse phase HPLC. MS: (ESI+) 555.2
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:16]([NH2:28])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:35][C:34]([C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=2)[C:39]#[N:40])=[CH:33][C:32](=O)[O:31]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:16]([NH:28][C:32](=[O:31])[CH2:33][C:34]([C:36]3[CH:43]=[CH:42][CH:41]=[C:38]([C:39]#[N:40])[CH:37]=3)=[O:35])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 92 %

Procedure:
Prepared from 4-(3-amino-4-tert.-butoxycarbonylamino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert.-butyl ester (Example G29) (544 mg, 1.4 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (336 mg, 1.5 mmol) according to the general procedure K. Obtained as an orange solid (722 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:9]([CH3:23])[CH:8]=1)[NH2:5].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28](Cl)=[O:29].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:9]([CH3:23])[CH:8]=1)[NH:5][C:28]([C:27]1[C:26]([Cl:25])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:35])=[O:29]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
To a suspension of 4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester (0.128 mmol, 47 mg) and 2,6-dichlorobenzoyl chloride (0.153 mmol, 32 mg) in dichloromethane (1 mL) was added diisopropylethylamine (0.45 mmol, 77 uL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 15 h at room temperature. The resulting brown solution was diluted with dichloromethane (25 mL). The dichloromethane layer was washed successively with 1N hydrochloric acid (2×25 mL), saturated sodium bicarbonate solution (25 mL), and brine solution (25 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to afford 52 mg (81% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C24H23Cl2N3O5 (M+Na) 526.0907, found 526.0912.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][N:3]=1.[CH3:11][S:12][C:13](SC)=[CH:14][N+:15]([O-:17])=[O:16]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:13]([S:12][CH3:11])=[CH:14][N+:15]([O-:17])=[O:16])[CH3:9])=[CH:4][N:3]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CC(N)c1ccc(Cl)nc1
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])NC(C)c1ccc(Cl)nc1
Yield: 40.2 %

Procedure:
A mixture of 1-(2-chloro-5-pyridyl)ethylamine (4.7 g), 1,1-bis-methylthio-2-nitroethylene (5.0 g) and ethanol (50 ml) was refluxed under heating until the generation of mercaptan ceased. Then, the ethanol was distilled off from the mixture under reduced pressure and the resulting residue was purified on a chromatographic column (the eluent mixture=ethanol+chloroform) to obtain the desired 1-{1-(2-chloro-5-pyridyl)ethylamino}-1-methylthio-2-nitroethylene (3.3 g) having a melting point in the range of from 136° to 140° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=S)=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31].C(Cl)CCl>CC#N>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[NH:18][C:28]([NH:27][C:24]4[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:23]=4)=[N:19][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(N)c2)ccn1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Solvent: CC#N
Solvent: ClCCCl
Product: CNC(=O)c1cc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(C(F)(F)F)c4)nc3c2)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(3,4-diamino-phenoxy)-pyridine-2-carboxylic acid methylamide (Step B) (0.07 g, 0.27 mmol) in 20 mL CH3CN was added dropwise, over 5 min, a solution 1-chloro-4-isothiocyanato-2-trifluoromethyl-benzene (0.055 g, 0.27 mmol) in 10 mL CH3CN. The reaction was stirred 18 h at RT. The reaction was diluted with 10 mL CH3CN, then EDC (0.078 g, 0.41 mmol) was added. The reaction was heated at 80° C. for 3 h. The reaction was cooled to RT and concentrated in vacuo. The crude mix was dissolved in EtOAc and water. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a hexane-EtOAc gradient to yield the title compound. MS (MH+)=461.9; MW Calc'd 461.09 for C21H15ClF3N5O2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[CH:25][CH:24]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>C(#N)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:19]2[CH2:18][CH2:17][N:16]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[CH:27][CH:28]=3)[CH2:21][CH2:20]2)[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CC(=O)NCc1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3nc(Cl)cc(Cl)n3)CC2)cc1
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of 2,4,6-trichloropyrimidine (1.0 g) and potassium carbonate (0.84 g) in acetonitrile (20 ml) was added a solution of N-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide (1.0 g) obtained in Example 78(2) in acetonitrile (20 ml) under ice-cooling over 5 min. The mixture was stirred at the same temperature for 30 min. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-brown oil (1.6g). The obtained pale-brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=50:1) to give a crude purification product (0.28 g) of N-(4-((4-(4,6-dichloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide and a crude purification product (0.9 g) of N-(4-((4-(2,6-dichloropyriinidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide. The crude purification product of N-(4-((4-(4,6-dichloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide was crystallized from ethyl acetate:hexane to give the title compound (0.2 g) as white crystals, m.p.=139-140° C.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3].B#B.[OH-:14].[Na+].OO>O1CCCC1>[CH3:8][CH:7]([CH2:6][CH2:5][CH:4]([OH:14])[CH:2]([CH3:3])[CH3:1])[CH2:9][CH:10]=[O:11]
Reactant: CC(C)=CCCC(C)CC=O
Reactant: [OH-]
Agent: B#B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CC=O)CCC(O)C(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To the dimethyl acetal of citronellal prepared in (a) is added 50 ml. of a 1M solution of diborane in tetrahydrofuran while the temperature of the reaction mixture is maintained at -10° to 0° .C. The reaction mixture is stirred at 0°C for 45 minutes and then at 20°C for 30 minutes. To this mixture is added 12.0 g. sodium hydroxide, as a 50% aqueous solution. Hydrogen peroxide (as a 30% aqueous solution) is added dropwise until residual peroxide is present. Heat evolved during this addition is dissipated by permitting the solvent to distill under reflux. The reaction mixture is shaken with hexane, the hexane layer is separated and washed in turn with 5% aqueous sodium sulfite solution and saturated brine. Solvent is removed from the solution under reduced pressure and the residue is distilled to yield the dimethyl acetal of 3,7-dimethyl-6-hydroxyoctan-1-al.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: Cc1cccc(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)c2cc(Br)ccc2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method B; 200 mg, 0.651 mmol) was added to a stirred suspension of CDI (106 mg, 0.651 mmol) in THF (6 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min and m-toluidine (69.8 mg, 0.65 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated to obtain crude product. The crude product was dissolved in 20 ml of CH2Cl2 and the organic phase was washed with 2M hydrochloric acid (5 ml), water (5×2 ml), dried over sodium sulphate and evaporated in vacuo to give yellow solid. The crude product was further purified by silica gel chromatography eluting with hexane:ethyl acetate (10:1) to yield the title compound. 120 mg.