Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:44][C@H:45]1[CH2:50][CH2:49][C@H:48]([CH2:51][N:52]([CH:54]2[CH2:59][CH2:58][N:57]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:56][CH2:55]2)[CH3:53])[CH2:47][CH2:46]1>C(#N)C.C(N(CC)CC)C>[C:63]([O:62][C:60]([N:57]1[CH2:58][CH2:59][CH:54]([N:52]([CH2:51][C@H:48]2[CH2:49][CH2:50][C@H:45]([NH:44][C:18]([C:14]3[CH2:15][CH2:16][O:17][C:11]4[CH:10]=[CH:9][C:8]([C:5]5[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=5)=[CH:21][C:12]=4[CH:13]=3)=[O:19])[CH2:46][CH2:47]2)[CH3:53])[CH2:55][CH2:56]1)=[O:61])([CH3:66])([CH3:65])[CH3:64]
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)N[C@H]2CC[C@H](CN(C)C4CCN(C(=O)OC(C)(C)C)CC4)CC2)CCO3)cc1
Reaction time: 2 h

Procedure:
Into a suspension of 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (400 mg) and 1-hydroxybenzotriazole (289 mg) in acetonitrile (20 ml) was added at room temperature 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.41 g), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of tert-butyl trans-4-[N-(4-aminocyclohexylmethyl)-N-methylamino]piperidine-1-carboxylate (698 mg) and triethylamine (0.4 ml) in acetonitrile (30 ml), and the resulting mixture was stirred for 20 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the residue was subjected to purification using column chromatography (ethanol/ethyl acetate 1:3→1:2) and to recrystallization (ethyl acetate/hexane) to obtain trans-N-[4-[N-(1-tert-butoxycarbonylpiperidin-4-yl)-N-methylaminomethyl]cyclohexyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 65) (560 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5](=[CH:10][CH3:11])[C:6](=O)[CH2:7]Cl)[CH3:2].C([O-])(=O)C.[Na+].[NH2:18][C:19]([NH2:21])=[S:20]>O1CCCC1.O>[CH2:1]([O:3][C:4]([C:5]([C:6]1[N:18]=[C:19]([NH2:21])[S:20][CH:7]=1)=[CH:10][CH3:11])=[O:12])[CH3:2]
Reactant: NC(N)=S
Reactant: CC=C(C(=O)CCl)C(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC=C(C(=O)OCC)c1csc(N)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
to a solution of 190 g of the product of example 81 in 400 ml tetrahydrofuran were added first a solution of 82 g sodium acetate in 150 ml of water and then 76 g thiourea. The solution was stirred at room temperature for 20 hours, then the THF was distilled off and acetic acid ethyl ester was added to the residue.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][O:19]1>N1CCCCC1.C(O)C>[O:16]=[C:10]1[C:9](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:18](=[O:17])[O:19][CH2:20][CH2:21][C:22]=23)[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11]1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cccc(-c3ccncc3)c2C1=Cc1[nH]cc2c1CCOC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.5 %

Procedure:
A mixture of 4-pyridin-4-yl-1,3-dihydroindol-2-one (50 mg, 0.24 mmol), 4-oxo-2,4,6,7-tetrahydropyrano[3,4-c]pyrrole-1-carbaldehyde (39.2 mg, 0.24 mmol) and piperidine (1 drop) in ethanol (2 mL) was stirred at room temperature for 48 hours. The precipitate which formed was collected by vacuum filtration, washed with ethanol and dried to give 15 mg (17%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH:12]=[C:11]2[NH2:25])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]([C:13]2[CH:12]=[C:11]([NH2:25])[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([NH2:7])[CH:9]=3)[N:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2nc(-c3cccc(Cl)c3)cc(N)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc2nc(-c3cccc(Cl)c3)cc(N)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
The BOC protecting group was removed by the following procedure. Into a 200 mL round bottom flask equipped with a magnetic stir bar and nitrogen inlet was placed 1.0 g (2.71 mmoles, 1 equiv) of [4-amino-2-(3-chlorophenyl)-quinolin-6-yl]-carbamic acid tert-butyl ester and 60 mL of a 1:2 mixture of trifluoroacetic acid and methylene chloride. The mixture was stirred at room temperature for 3 hrs., then concentrated. The residue was made basic with dilute NaOH solution then extracted with ethyl acetate. The organic layer was washed with NaHO solution, dried over Na2SO4, filtered and concentrated. The residue was crystallized from methylene chloride and hexanes to give 700 mg (95%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH3:13])[C:7]2=[O:12].[CH:14]1([CH2:21][C:22](O)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[CH:14]1([CH2:21][C:22]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([CH3:13])[C:7]3=[O:12])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)CC1CCCCCC1
Reactant: Cn1ccc2c(N)cccc2c1=O
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc2c(NC(=O)CC3CCCCCC3)cccc2c1=O

Procedure:
5-Amino-2-methyl-2H-isoquinolin-1-one (50 mg, 0.0003 mol), 2-cycloheptylacetic acid (90 mg, 0.0006 mol), fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (200 mg, 0.0006 mol), N,N-diisopropylethylamine (100 mg, 0.0009 mol) were stirred in methylene chloride (2 mL, 0.03 mol) at room temperature over 72 hours. The mixture was purified via flash chromatography (12 g of silica gel, 0-50% EtOAc/Hexane) to give a yellow solid. 1H NMR δ (CDCl3) δ: 8.31 (d, J=7.9 Hz, 1H), 7.95-7.92 (m, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.20 (br, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.41 (d, J=7.5 Hz, 1H), 3.60 (s, 3H), 2.37 (d, J=7.3 Hz, 2H), 2.17 (br, 1H), 1.86-1.25 (12H).
Reaction SMILES: [ClH:1].[N:2]1([C:8](=[O:21])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.N1([C:27]2C=CC(CC(O)=O)=C[CH:28]=2)C=NN=N1.C12CCC(NC1)CN2C(OC(C)(C)C)=O>>[ClH:1].[CH:3]12[CH2:28][CH2:27][CH:6]([NH:5][CH2:4]1)[CH2:7][N:2]2[C:8](=[O:21])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)=[CH:14][CH:15]=1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Agent: CC(C)(C)OC(=O)N1CC2CCC1CN2
Agent: Cl
Product: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CCC1CN2

Procedure:
1-(2,5-Diazabicyclo[2.2.2]oct-2-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride was prepared in an analogous fashion as described above in the synthesis of 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride starting from [4-(1H-tetrazol-1-yl)phenyl]acetic acid and commercially available tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate. LC/MS: [(M+1)]+=299
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=2[O:20][CH3:21])[C:9]#[N:10])=[CH:4][CH:3]=1.S1C=CC=C1.[H][H]>CO.[Pt]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]#[N:10])=[C:12]([O:20][CH3:21])[CH:13]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C(C#N)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: c1ccsc1
Product: COc1cc(N)ccc1C(C#N)c1ccc(Cl)cc1

Procedure:
A mixture of 8.1 parts of α-(4-chlorophenyl)-2-methoxy-4-nitrobenzeneacetonitrile, 2 parts of a solution of thiophene in methanol 4% and 200 parts of methanol is hydrogenated at normal pressure and at 50° C. with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is stirred in a small amount of 2-propanol. The product is filtered off and dried, yielding 4-amino-α-(4-chlorophenyl)-2-methoxybenzeneacetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15]CC)=O)=[C:11]([CH3:18])[N:10]=[C:9]2[SH:19])=[CH:4][CH:3]=1.F[C:21]1C=CC(N)=CC=1.ClC(C(=O)C)C(=O)C.[S-]C#N.[K+]>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13](=[O:15])[CH3:21])=[C:11]([CH3:18])[N:10]=[C:9]2[SH:19])=[CH:6][CH:7]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)c1c(C)nc(S)n1-c1ccc(F)cc1
Agent: CC(=O)C(Cl)C(C)=O
Agent: N#C[S-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(=O)c1c(C)nc(S)n1-c1ccc(F)cc1

Procedure:
1-(1-(4-Fluorophenyl)-2-mercapto-4-methyl-1H-imidazol-5-yl)ethanone (60) was prepared in a similar manner as that described for the synthesis of compound 57 using 4-fluoroaniline (2 g, 18 mmol), 3-chloropentane-2,4-dione (2.7 g, 19.8 mmol), potassium thiocyanate (3.5 g, 36 mmol) and acetic acid (10 mL) in acetonitrile (100 mL).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][O:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1>ClCCl>[N:25]([C:21]1[CH:20]=[C:19]([O:18][CH3:17])[N:24]=[CH:23][N:22]=1)=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc(N)ncn1
Solvent: ClCCl
Product: COc1cc(N=C=S)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a bright orange solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (1.86 g, 7.99 mmol) in dichloromethane at room temperature was added 6-methoxypyrimidin-4-amine (1 g, 8 mmol). The orange solution was stirred at room temperature for 18 hours. The LC/MS showed the desired product as one of the major peaks. The deep orange solution was concentrated and the remaining residue was filtered. The filtrate was purified by silica gel chromatography (10-50% ethyl acetate/hexanes) to afford 4-isothiocyanato-6-methoxypyrimidine (0.72 g, 4.3 mmol, 54% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (1 H, d, J=5.79 Hz), 6.95 (1 H, d, J=5.79 Hz), 3.92 (3 H, s). MS (LC/MS) R.T.=3.15; [M+H]+=168.1.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1)#[N:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:20])[CH:14]=1>>[NH2:2][CH2:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][C:15]=2[NH2:20])=[O:9])=[CH:5][N:4]=1
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: Nc1ccc(F)cc1N
Product: NCc1ccc(C(=O)Nc2ccc(F)cc2N)cn1
Yield: 25.9 %

Procedure:
The title compound (135 mg, 52% yield) was prepared as a grey solid from 6-cyano-nicotinic acid (296 mg, 2 mmol) and 4-fluoro-o-phenylenediamine (302 mg, 2.4 mmol) by an analogous procedure to that described in example 8. LC-MS (m/z) 261 (M+1).
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][CH:12]([CH3:20])[C:13](=O)[C:14](OCC)=[O:15]>C(O)C(F)(F)F>[CH:12]([C:13]1[C:14](=[O:15])[O:10][CH2:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)([CH3:20])[CH3:11]
Reactant: CCOC(=O)C(=O)C(C)C
Reactant: N[C@@H](CO)c1ccccc1
Solvent: OCC(F)(F)F
Product: CC(C)C1=N[C@H](c2ccccc2)COC1=O
Yield: 35.6 %

Procedure:
(R)-2-phenylglycinol (4) (2.00 g, 14.6 mmol, 1.0 equiv.) and ethyl 3-methyl-2-oxobutyrate (2.20 mL, 14.6 mmol. 1.0 equiv.) were refluxed in trifluoroethanol (30 mL) over activated 4 molecular sieves (7.0 g) for 24 hours. Filtration through a short pad of Celite® CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo generated the crude product which was purified by flash column chromatography on silica, eluting with petrol and diethyl ether (4:1) to furnish the title compound as a colourless oil (1.13 g, 36%); v(max)(film) 2965 (C—H), 1740 (C═O), 1638 (C═N) cm−1; δH (250 MHz, CDCl3) 7.45-7.32 (5H, m, Ph), 4.90-4.83 (1H, m, PhCH), 4.55 (1H, dd, J 4.4 Hz, T 11.5 Hz, 6β-H), 4.13 (1H, dd/10.9 Hz, T 11.4 Hz, 6α-H), 3.32 (1H, m, CH(CH3)2), 1.25 (3H, d, J 5.0 Hz, CH(CH3)2×3), 1.22 (3H, d, /5.0 Hz, CH(CH3)2×3); δc (62.5 MHz, CDCl3) 167.7, 155.7, 137.5, 129.3, 128.6, 127.4, 71.7, 59.7, 32.7, 20.7, 19.9: m/z (CL, NH3), 220 (100%), 218 (MH+, 17%), 217 (27%), and 216 (25%); HRMS for C13H16NO2 requires 218.1177 found 218.1181. [α]D20-207.5 (c 1.17 CHCl3).
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6].ClC(OCC)=O.C(N(CC)CC)C.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.[Cl-].[Na+]>C1COCC1>[CH:22]1([NH:25][C:1](=[O:8])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6])[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: CCC/C=C\C(=O)O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC/C=C\C(=O)NC1CC1
Yield: 77 %

Procedure:
3Z-Hexenoic acid 1 eq, ethyl chloroformate 1.1 eq, triethylamine 1.2 eq, cyclopropylamine 1.5 eq as a 2.0M solution in THF, quench with 10% sodium chloride solution, yield=77%. 0.49 ppm (m, 2H), 0.75 ppm (m, 2H), 0.98 ppm (t, 3H, J=7.48 Hz), 2.05 ppm (d, 2H, J=0.97 Hz, of pentet, J=7.46 Hz), 2.70 ppm (octet, 1H, J=3.59 Hz), 2.98 ppm (d, 2H, J=7.46 Hz), 5.46-5.52 ppm (m, 1H), 5.58-5.66 ppm (m, 1H), 6.19 ppm (br. s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]#[N:15])=[CH:5][CH:4]=1.[O:16]=[C:17]([CH2:24][CH2:25][CH3:26])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(C(C)C)CC)(C)C.[Li+].[Br-]>C1COCC1>[C:14]([C:13]1[CH:12]=[CH:11][S:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH:18]([C:17](=[O:16])[CH2:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:5]=1)#[N:15]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N#Cc1ccsc1-c1ccc(CBr)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)C(Cc1ccc(-c2sccc2C#N)cc1)C(=O)OCC
Yield: 97.7 %

Procedure:
A mixture of 50 g of 2-(4-bromomethylphenyl)-3-cyanothiophene, prepared above, 40 g of ethyl 3-oxohexanoate, prepared in Example 1, 300 ml of THF, 62 ml of diisopropylethylamine and 15.6 g of LiBr is refluxed for 15 h. It is concentrated under vacuum, a dilute solution of hydrochloric acid is added and the mixture is extracted with ethyl acetate. The organic phases are combined, washed with water, dried and evaporated to give 62.4 g of ethyl 2-[4-(3-cyano-2-thienyl)benzyl]-3-oxohexanoate in the form of an oil, which is used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16](OS(C)(=O)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OS(C)(=O)=O
Reactant: Nc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Nc1ccccc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture of 4.00 g of ethyl 3-(4-benzyloxyphenyl)-2-methanesulfonyloxypropionate and 5 ml of aniline was stirred at 110° C. for 24 hours. The reaction mixture was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 3.94 g of the desired compound as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=O)[C:7]2=[O:12].[C:13]12[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:18]C(=O)O[C:14]2=[O:15].CN(C1C=CC=CN=1)C.Cl>N1C=CC=CC=1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[C:8](=[N:18][C:19]3[C:13]([C:14]1=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]2=[O:12]
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1c2cccc(F)c2-n2c1nc1ccccc1c2=O
Yield: 14 %

Procedure:
A solution of 7-fluoroisatin (300 mg, 1.8 mmol), isatoic anhydride (1.2 g, 7.3 mmol), and dimethylaminopyridine (222 mg, 2 mmol) in 5 mL of pyridine were heated at reflux temperature for 64 h. 50 mL of 0.2N HCl and 100 mL of chloroform were added and the chloroform layer was separated. The water layer was extracted with chloroform and the combined organic extracts were concentrated. Chromatography on silica gel eluting with chloroform gave the title compound in 14% yield: mp 264-267° C.; 1H NMR (300 MHz, CDCl3) δ 8.46 (d, 1H) 8.02 (d, 1H) 7.82-7.92 (m, 1H) 7.79 (d, 1H) 7.64-7.74 (m, 1H) 7.52-7.64 (m, 1H) 7.40-7.49 (m, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4].Cl[C:21]([O:23][CH2:24][Cl:25])=[O:22]>N1C=CC=CC=1>[CH2:1]([N:5]1[C:10](=[O:11])[CH2:9][N:8]([C:21]([O:23][CH2:24][Cl:25])=[O:22])[C:7]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1N=C(c2cc(Cl)cc(Cl)c2)NCC1=O
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Product: CCCCN1N=C(c2cc(Cl)cc(Cl)c2)N(C(=O)OCCl)CC1=O
Yield: 51 %

Procedure:
1-(n-Butyl)-3-(3,5-dichlorophenyl)-4,5-dihydro-1,2,4-triazin-6-one was acylated with chloromethyl chloroformate in a similar manner to the reaction described to make compound 14 except that pyridine was used as a base. The product 1-(n-butyl)-3-(3,5-dichlorophenyl)-4-(chloromethyloxycarbonyl)-4,5-dihydro-1,2,4-triazin-6-one was isolated in 51% yield.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[C:16]([O:19][C:20]([CH3:26])([CH2:22][CH2:23][CH:24]=O)[CH3:21])(=[O:18])[CH3:17].C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Ti](Cl)(Cl)(Cl)Cl>[C:16]([O:19][C:20]([CH3:26])([CH2:22][CH2:23][CH2:24][N:8]1[CH2:7][C@@H:6]2[CH2:12][O:13][CH2:14][CH2:15][N:5]2[C:4]2[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]1=2)[CH3:21])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)(C)CCC=O
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC(C)(C)CCCN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x3, 200 mg, 0.882 mmol) and 2-methyl-5-oxopentan-2-yl acetate (55.8 mg, 0.353 mmol) were combined in a 25 mL pear flask to give an orange suspension. Titanium(IV) chloride in DCM (1M, 0.971 mL, 0.971 mmol) was added at room temperature to give a deep-red suspension, which was stirred at room temperature for 1 hour before being cooled to 0° C. Sodium triacetoxyborohydride (281 mg, 1.324 mmol) was added at 0° C. in portions. The thick suspension slowly turned into a thinner, orange one with gas evolution. UPLC showed the reaction proceeded more than half-way after about 20 minutes. The reaction mixture was carefully quenched with brine, and was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted a second time with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C17H25ClN4O3, 369.17; found 396.2.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)c1ccnc(I)c1
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)c1ccnc(-c2ccc(F)cc2F)c1
Temperature: 90 °C
Yield: 78.3 %

Procedure:
A mixture of 2-iodo-4-dimethylaminopyridine (3 g, 12 mmol), 2,4-difluorophenylboronic acid (2.3 g, 14.5 mmol) and K2CO3 (6 g 43.5 mmol) in toluene (60 ml) and water (10 ml) were degassed with nitrogen for 15 minutes. Pd(PPh3)4 (800 mg, 0.66 mmol) was added and the resulting mixture was heated to 90° C. for 48 hours under nitrogen. After being cooled to room temperature, the aqueous phase was separated and extracted with EtOAc (3×100 ml). The combined organic fractions were washed with brine, dried over MgSO4, filtered and evaporated. To further purify the compound the so-obtained oil was dissolved in Et2O and extracted with 10% HCl solution (3×50 ml). The combined aqueous fractions were washed with Et2O (2×100 ml) and neutralized with concentrated NaOH aqueous solution. The resulting mixture was extracted with EtOAc (4×100 ml), the combined organic fractions were washed with brine (50 ml), dried over MgSO4, filtered and evaporated to dryness. The crude compound was purified by column chromatography (SiO2, CHCl3 then CHCl3/MeOH, 97/3) to afford 2.2 g (78%) of the titled compound as slightly yellow oil which solidified upon standing.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][CH2:10][O:11][CH3:12].C([Mg]Br)(C)C.[N+:18]([CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O-:20])=[O:19]>C1COCC1>[CH3:12][O:11][CH2:10][O:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][N+:18]([O-:20])=[O:19]
Reactant: COCOCc1ccccc1I
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: COCOCc1ccccc1C(C[N+](=O)[O-])c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirring solution of 1-iodo-2-((methoxymethoxy)methyl)benzene (4.51 g, 16.22 mmol) in THF (40 mL) under argon was added dropwise a solution of i-PrMgBr (9.5 mL, 2.12M in Et2O, 20.14 mmol) via syringe. The stirring was maintained at 0° C. After 1 hour, a solution of nitrostyrene (2.014 g, 13.50 mmol) in THF (40 mL) was added via cannula over 10 minutes and the stirring was maintained at 0° C. After 30 minutes, the reaction was quenched with saturated NH4Cl and extracted with EtOAc (2×). The combined extracts were dried (MgSO4), filtered and concentrated to an oil which was purified on Biotage Horizon (10-50% EtOAc:hexane, SiO2, 40+M) to afford the product (2.93 g) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.35-7.39 (m, 1H), 7.27-7.34 (m, 3H), 7.22-7.27 (m, 5H), 5.34 (t, J=8.08 Hz, 1H), 4.94-5.03 (m, 2H), 4.73 (d, J=11.87 Hz, 1H), 4.68 (q, J=6.57 Hz, 2H), 4.57 (d, J=11.87 Hz, 1H), 3.42 (s, 3H).