Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].C(=O)([O-])[O-].[Na+].[Na+].[CH2:29]([O:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C.CC(C)=O>[CH2:29]([O:36][C:37]([N:7]([CH2:18][CH2:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])[CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CN
Reactant: C=CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a suspension of glycine ethyl ester hydrochloride (41.9 g, 0.3 mol) in ethanol (300 mL) was added triethylamine (41.8 mL, 0.3 mol) and ethyl acrylate (10.8 mL, 0.1 mol) in an ice bath, and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and water (400 mL) was added to the residue, and the mixture was extracted with ethyl acetate (200 mL×3). The extract was washed with water (200 mL×2) and saturated aqueous solution of sodium chloride (200 mL) in this order, an the dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in acetone (150 mL). To this solution were added aqueous solution of sodium carbonate (11.5 g, 108 mmol) (50 mL) and a solution of benzyloxycarbonyl chloride (18.4 g, 108 mmol) in acetone (50 mL) in an ice bath, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and water (400 mL) was added to the residue. The mixture was extracted with ethyl acetate (200 mL×3), and the extract was washed with saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 5:1) to obtain 31.1 g (92%) of the title compound as a colorless oily product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:54][O:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([NH2:62])[CH:57]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:62][C:58]3[CH:59]=[CH:60][CH:61]=[C:56]([O:55][CH3:54])[CH:57]=3)=[O:17])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: COc1cccc(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (41 mg, 0.15 mmol), N,N-diisopropylethylamine (0.105 mL, 0.60 mmol), and HBTU (63 mg, 0.165 mmol) in 1.5 mL DMF was briefly warmed to approx. 50° C. to dissolve solids, then continued stirring at room temperature. After 10 minutes meta-anisidine (0.025 mL, 0.225 mmol) was added and the reaction continued at room temperature for 4 hours. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with an acetone/hexane mixture to give the title compound as a light beige solid (41 mg, 73%). 1H NMR (DMSO-d6) δ: 10.13 (s, 1H), 8.13 (s, 1H), 7.46-7.51 (m, 2H), 7.31-7.41 (m, 3H), 7.19-7.28 (m, 2H), 6.68 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 6.41 (s, 2H), 4.29 (s, 2H), 3.75 (s, 3H), 3.65 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.C(OCC)(=O)C>[CH2:13]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: Oc1ccc2ccccc2c1OCc1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
1,2-Dihydroxynaphthalene (70 mg) was dissolved in acetone (1 ml), the solution was added with benzyl bromide (74.7 mg) and potassium carbonate (72.5 mg), and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was added with distilled water and ethyl acetate, the layers were separated, and the organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:acetone:triethylamine=50:10:0.2) to obtain the title compound (20.7 mg).
Reaction SMILES: [C:1]([O:11]CC(N)CC)(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C(OCC(N)CC)(=O)[C@@H](C1C=CC=CC=1)O.[OH-].[K+]>>[C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: CCC(N)COC(=O)[C@@H](O)c1ccccc1
Agent: CCC(N)COC(=O)[C@H](O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C(O)c1ccccc1

Procedure:
To a portion (1100 mls out of a total of 4800 mls) of the mother liquor plus methanol wash liquor obtained from resolution B, containing about 2.4 moles of a mixture of diastereomers, consisting of about 2.25 moles of (-)-2-amino-1-butanol L-(+)-mandelate and about 0.15 mole of (-)-2-amino-1-butanol D-(-)-mandelate, is added 180 grams of potassium hydroxide (88.8% real; 2.85 moles) to obtain a solution having an initial αD25° C of +24.7° ("as is", 10 cm cell). The solution is then heated at 115°-116° C. under pressure (40 psi) for 4 hours to obtain a mandelic acid solution having an αD25° C. of -3.0° ("as is", 10 cm cell). The resulting solution is essentially racemized, the negative rotation being due to the presence of the (-)-2-amino-1-butanol.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.C([N:18](CC)[CH2:19][CH3:20])C.CC[N:25]=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[O:12][N:25]=[C:19]([CH3:20])[N:18]=2)=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCN(CC)CC
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1noc(COc2ccc([N+](=O)[O-])cc2)n1
Yield: 60.4 %

Procedure:
A mixture of 4-nitrophenoxy acetic acid (2.25 g, 11.4 mmole), acetamideoxime, triethylamine hydrochloride (3.85 g, 27.62 mmole), EDCI.HCl (4.37 g, 22.79 mmole) and diisopropylethylamine (7.42 g, 57.40 mmole) in anhydrous THF (250 ml) was refluxed for 18 h. The unhomogenous brown colored reaction mixture was quenched with water and extracted with EtOAc (3×300 mL). The combined organic layers washed successively with aqueous NaHCO3, brine and dried over anhydrous Na2SO4. Removal of solvent and purified by chromatographic purification provided 5-[(4-nitrophenoxy)methyl]-3-methyl-1,2,4-oxadiazole (1.62 g, 60%). 1H NMR (CDCl3): δ 8.24 (d, 2H, J=8.8 Hz), 7.08 (d, 2H, J=8.8 Hz), 5.36 (s, 2H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:5][C:4]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)([C:6](O)=[O:7])[CH2:3]1.C1C=C2[N:21]=[N:22]N(O)C2=CC=1.O.O.NN>C(#N)C>[CH3:1][C:2]1([CH3:14])[CH2:5][C:4]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)([C:6]([NH:21][NH2:22])=[O:7])[CH2:3]1
Reactant: On1nnc2ccccc21
Reactant: CC1(C)CC(C(=O)O)(c2cccs2)C1
Agent: NN
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(C(=O)NN)(c2cccs2)C1

Procedure:
3,3-Dimethyl-1-(2-thienyl)cyclobutanecarboxylic acid was reacted with HOBt monohydrate and WSC monohydrochloride in acetonitrile at room temperature. The above reaction solution was added dropwise to an acetonitrile solution of hydrazine monohydrate and the whole was reacted at 0° C. to obtain 3,3-dimethyl-1-(2-thienyl)cyclobutanecarbohydrazide.
Reaction SMILES: [C:1]([C:3]1([NH:11][C:12](=[O:14])[O-:13])[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][CH2:4]1)#[N:2].[NH2:15][OH:16].[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])#[C:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CCO>[CH2:1]([O:14][C:12]([NH:11][C:3]1([C:1]([NH:15][O:16]/[C:18](=[CH:17]\[C:24]([O:26][CH2:27][CH3:28])=[O:25])/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[NH:2])[CH2:4][CH2:5][CH:6]([CH2:9][OH:10])[CH2:7][CH2:8]1)=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CC1(NC(=O)[O-])CCC(CO)CC1
Reactant: NO
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)/C=C(\ONC(=N)C1(NC(=O)OCc2ccccc2)CCC(CO)CC1)C(=O)OCC
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of 1-cyano-4-(hydroxymethyl)cyclohexylcarbamate (6.5 g, 22.54 mmol), 50% aq. hydroxylamine (1.66 mL, 27.05 mmol) in EtOH (150 mL) was heated at 70° C. for 18 h. The mixture was then cooled to room temperature and treated with diethyl acetylenedicarboxylate (4.33 mL, 27.1 mmol). After 18 h at room temperature, the reaction mixture was concentrated and the resulting yellow residue was taken up in ethyl acetate (250 mL), washed with water (2×100 mL) followed by brine (100 mL), then dried (Na2SO4), filtered and concentrated to give yellow oil. Flash column chromatography on silica gel (using 5% to 50% ethyl acetate-hexane gradient) afforded the title compound as a mixture of isomers and as a yellow oil (8 g, 72% yield). 1H NMR (500 MHz, CDCl3) δ: 7.30-7.36 (m, 6H), 5.59 (s, 0.5 H), 5.75 (s, 0.5 H), 5.13 (s, 1H), 5.04 (s, 2H), 4.32-4.36 (m, 1H), 4.24-4.29 (m, 1H), 4.09-4.17 (m, 4H), 3.46-3.51 (m, 2H), 2.54-2.58 (m, 2H), 1.45-1.57 (m, 5H), 1.23-1.26 (m, 6H). LCMS (M+H)=492.36.
Reaction SMILES: C(O/[CH:4]=[C:5](\[CH3:12])/[C:6](=O)[C:7]([F:10])([F:9])[F:8])C.O.[NH2:14][NH2:15]>CCO>[CH3:12][C:5]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:14][NH:15][CH:4]=1
Reactant: CCO/C=C(\C)C(=O)C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1c[nH]nc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Into a 100-mL round-bottom flask, was placed (E)-4-ethoxy-1,1,1-trifluoro-3-methylbut-3-en-2-one (compound 261.1, 2.6 g, 14.3 mmol) in EtOH (20 mL). Hydrazine hydrate (1.8 mL, 38 mmol) was added and the resulting solution was stirred for 2 h at 80° C. The reaction was concentrated under reduced pressure to obtain the title compound as a yellow oil (2 g, crude).
Reaction SMILES: CN(C)C(=O)O[C:5]1[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1.[Li][CH2:25]CCC.CCCCCC.Br[C:36]1([CH:43]=[CH:42][CH:41]=[CH:40][CH2:39]1)[CH:37]=[CH2:38].Cl>CCOCC>[C:10]1([C:7]2[S:8][C:9]3[CH2:38][C:37]([C:36]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:25][C:5]=3[C:6]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)C(=O)Oc1csc(-c2ccccc2)c1-c1ccccc1
Reactant: [Li]CCCC
Reactant: C=CC1(Br)C=CC=CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: C1=C(c2ccccc2)Cc2sc(-c3ccccc3)c(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
30.7 g (100 mmol) of 2,3-diphenyl-thienylcarbonic acid dimethylamide was mixed with 100 ml ether and the resulting suspension was added in some portions at 0° C. to solution of 1-stiryllitium prepared from 62 ml 1.6M BuLi in hexane (100 mmol) and 27 g 1-bromostyrene (150 mmol) in 200 ml ether. The mixture warmed to room temperature (r.t.) and was stirred for 1 h. The resulting solution was poured into 500 ml of 5% aqueous HCl. The organic phase was collected, separated from insoluble impurities, washed with water, dried over MgSO4 and evaporated to give 20.9 g (57%) of crystalline solid. The product can be contaminated with 5-10% of starting amide (by NMR) and can be used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][O:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][Br:20])=[CH:11][CH:10]=1)=[O:7].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[O:7]=[C:6]1[CH2:5][CH2:4][CH2:3][CH2:2][N:8]1[C:9]1[CH:23]=[CH:22][C:12]([CH2:13][O:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][Br:20])=[CH:11][CH:10]=1
Reactant: O=C(CCCCBr)Nc1ccc(COC(=O)CCCCBr)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCCCBr)OCc1ccc(N2CCCCC2=O)cc1

Procedure:
The ester from Step 1 (1 g, 2.22 mmol) was dissolved in DMF. Cs2CO3 (725 mg , 2.22 mmol) was added and the reaction mixture was heated to 50° for 18 hours. TLC shows ~50% starting material remaining. Additional Cs2CO3 (2.22 mmol) was added the reaction mixture was heated at 50° for and additional 8 hours. The mixture was dissolved in 10% citric acid and extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried (MgSO4) filtered and concentrated to yield a yellow oil. Flash chromatography (EtOAc) yielded the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].[CH3:12][C:13]1[CH:14]=CC(S(O)(=O)=O)=CC=1.[OH2:23]>C1(C)C(C)=CC=CC=1>[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])(=[O:23])[CH:13]=[CH2:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Reactant: CC(C)CCCCCCCO
Solvent: Cc1ccccc1C
Product: C=CC(=O)OCCCCCCCC(C)C
Temperature: 140 °C

Procedure:
To 157 g isodecyl alcohol in 200 ml xylene is added 117 g AA, 1.0 g HQ and 2.0Q PTSA. The reaction mixture is heated for 2 hrs. at reflux (140° C) while the water of reaction is collected (17 ml). The reaction mixture is cooled and the xylene removed under reduced pressure to give 250 g isodecyl acrylate. The analytical data for this acrylate is shown below.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]1[CH2:12][CH2:11]1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:14](OCC#N)=[O:15]>ClCCl>[C:1]([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]1[CH2:12][CH2:11]1)[NH:8][CH:14]=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CC1CC1
Reactant: N#CCOC=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](CC1CC1)NC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 10 g (54 mmol) of (S)-β-cyclopropylalanine tert-butyl ester and 4.7 g (55.2 mmol) of cyanomethyl formate in 100 mL of dichloromethane was stirred at room temperature overnight. The residue obtained after removal of the solvent in vacuo was distilled in vacuo. Yield: 8.8 g (76%). Boiling point 120° C./40 Pa (0.3 torr).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.Br[CH2:27][CH2:28][OH:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:27][CH2:28][OH:29])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(O)ccc3n2)Cc2ccccc21
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=S1(=O)CCN(c2cc(Cl)c3cc(OCCO)ccc3n2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin-6-ol (250 mg, 0.67 mmol, prepared in analogy to the one in Example 29), 2-bromo-ethanol (166.7 mg, 1.33 mmol), and potassium carbonate (277 mg, 2.01 mmol) in acetone (30 mL) was stirred at room temperature overnight and then refluxed for 12 hours. The reacting mixture was filtered and concentrated in vacuo. The residue was purified by preparative TLC to afford 230 mg of the desired product (yield was 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](SC)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:34].O[O:36][S:37]([O-:39])=O.[K+].[C:41](#N)C>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:37]([CH3:41])(=[O:39])=[O:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:34]
Reactant: O=S([O-])OO
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(SC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Reactant: CC#N
Agent: [K+]
Solvent: O
Product: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)(=O)=O)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
3-[8-(2,6-Difluoro-phenyl)-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-propyl-benzamide (204 mg, 0.426 mmol, 1 eq) was suspended in acetonitrile (6 mL). The suspension was added to a stirring suspension of Oxone® (786 mg, 1.28 mmol, 3 eq) in water (3 mL). The resulting mixture was stirred overnight at about 40° C. The reaction mixture was then partitioned between dichloromethane and sodium metabisulfite (10% aq solution). The layers were separated then the organic was dried over magnesium sulfate, filtered then evaporated to furnish the title compound: LC-MS m/z 513 (M+H)+, 2.9 min (ret time).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH2:30]([O:37][C:38]1[CH:39]=[C:40]([Cl:47])[C:41]([CH2:45]Br)=[C:42]([Cl:44])[CH:43]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([CH2:45][C:41]1[C:40]([Cl:47])=[CH:39][C:38]([O:37][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:43][C:42]=1[Cl:44])[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Reactant: C=CCCC(=O)N1C(=O)OCC1Cc1ccccc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: C=CC[C@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve 4-Benzyl-3-pent-4-enoyl-oxazolidin-2-one (2.21 g, 8.52 mmol) in 25 ml of dry THF. Chilled to −78° C. Add LiN(TMS)2 (10.23 ml, 10.23 mmol). Stir for 30 min at same temperature. Add 5-Benzyloxy-2-bromomethyl-1,3-dichloro-benzene (3.10 g, 8.95 mmol) in 5 ml of THF. Let the reaction slowly warm to room temperature.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1([CH3:17])[C:8]2[O:9][C:10]3[CH:15]=[C:14](I)[CH:13]=[CH:12][C:11]=3[C:7]=2[CH2:6][CH2:5][NH:4]1.[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[S:27][Si](C(C)C)(C(C)C)C(C)C.[F-].[Cs+].C(O)CO.CN(C=O)C>[Cu]I>[F:1][CH:2]([F:18])[C:3]1([CH3:17])[C:8]2[O:9][C:10]3[CH:15]=[C:14]([S:27][C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=4[F:19])[CH:13]=[CH:12][C:11]=3[C:7]=2[CH2:6][CH2:5][NH:4]1
Reactant: CC(C)[Si](Sc1cccc(F)c1F)(C(C)C)C(C)C
Reactant: CC1(C(F)F)NCCc2c1oc1cc(I)ccc21
Agent: [Cu]I
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: OCCO
Product: CC1(C(F)F)NCCc2c1oc1cc(Sc3cccc(F)c3F)ccc21
Temperature: 105 °C
Yield: 135.5 %

Procedure:
Into a Schlenk flask equipped with a magnetic stir bar was added 1-difluoromethyl-7-iodo-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-C]pyridine (enantiomer 1, 100 mg, 0.30 mmol), (2,3-difluorophenylsulfanyl)-triisopropylsilane (125 mg, 0.43 mmol), CsF (189 mg, 1.24 mmol), CuI (25 mg, 0.13 mmol), ethylene glycol (85 μL, 1.5 mmol) and anhydrous DMF (3 mL, 0.30 mmol). The Schlenck flask was evacuated and flushed with argon three times. The reaction mixture was heated at 105° C. under argon for 17 h. Upon cooling, the reaction was diluted with DCM, filtered through celite and solvent was evaporated. Purification using preparative TLC (2000 micron silica gfel plate; elution with 15% EtOAc in dichloromethane) afforded 155 mg of product as a viscous, pale oil. MS m/z: 382 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14]CC(=O)NCCCCCCCC)[N:10]=[C:9]1[NH2:27])=O)(C)(C)C.[N:28]#CN.C(O)C.[ClH:34]>O.CO>[ClH:34].[ClH:34].[NH2:28][CH2:14][CH2:13][C:11]1[N:10]=[C:9]([NH2:27])[NH:8][CH:12]=1
Reactant: N#CN
Reactant: CCCCCCCCNC(=O)CCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCO
Product: NCCc1c[nH]c(N)n1
Yield: 62 %

Procedure:
1,4-diamino-2-butanone dihydrochloride 25 (0.300 g, 1.71 mmol) and cyanamide (0.753 g, 17.9 mmol) were dissolved in water (10 mL). The pH of the solution was adjusted to pH=4.3 before heating the reaction at 95° C. for 3.5 h while open to the atmosphere. After cooling to ambient temperature ethanol (10 mL) was added to the flask and the solution was evaporated to dryness. Purification of the residue by column chromatography (MeOH sat. with NH3/CH2Cl2 90:10) yielded the product as its corresponding free base. Addition of methanol (10 mL) and concentrated hydrochloric acid followed by evaporation in vacuo afforded the target compound 26 (0.211 g, 62%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 6.21 (s, 1H), 5.14 (br s, 2H), 2.81 (m, 2H), 2.47 (in, 2H); HRMS (ESI) calcd for C5H11N4 (MH+) 127.0978. found 127.0977.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[CH:41]=2)[C:21](=[O:39])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][C:25]=1[F:38])[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[CH:41]=2)[C:21](=[O:39])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][C:25]=1[F:38])[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(-c2cccc(C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(-c2cccc(C)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.85 g), sodium hydrogen carbonate (2.68 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-1-(3-methylphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (1.35 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.56 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.52 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.94 g, 68%).