Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:24]([S:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])[CH2:28][CH2:27]2)=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.C(O)(C(F)(F)F)=[O:38].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[F:1][C:2]1[C:24]([S:25]([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])[CH2:28][CH2:27]2)=[O:38])=[CH:23][C:5]2[C:6]3[N:10]([CH:9]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[N:7]=3)[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)(C)CO)CC4)c(F)cc2OCC3)n(C(C)C)n1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)(C)CO)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To an ice-cooled solution of 2-{4-[8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropan-1-ol from Example 8 (148 mg, 0.287 mmol) in DCM (10 mL) was added TFA (67 μL, 0.863 mmol) followed by a solution of m-CPBA (55 mg, 0.316 mmol) in DCM (2 mL). The resulting mixture was stirred for 30 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 10-40% MeOH in 0.5% TFA/H2O) affording 212 as a white solid (135 mg, 88%). LCMS: RT 2.58 min [M+H]+ 531.1. 1H NMR (DMSO, 400 MHz): δ 8.69 (1H, d, J=7.99 Hz), 7.91 (1H, s), 7.13 (1H, d, J=10.67 Hz), 5.67-5.56 (1H, m), 4.65-4.50 (4H, m), 4.20 (1H, t, J=5.39 Hz), 3.20 (2H, d, J=5.03 Hz), 3.09-2.97 (2H, m), 2.84-2.73 (1H, m), 2.25 (3H, s), 2.21-2.07 (2H, m), 1.90-1.82 (1H, m), 1.56-1.38 (9H, m), 0.88 (6H, s)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([Br:14])[CH:8]=1)Cl.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([Br:14])[CH:8]=1)=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)c(Br)c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(F)c(Br)c1

Procedure:
prepared by reaction of 3-(3-Bromo-4-fluoro-phenyl)-3-chloro-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.95 min; [M+H]+=330.2.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:4]([CH3:5])([CH3:9])[CH3:3])[CH:5]=1
Reactant: Oc1cccc(CCBr)c1
Solvent: ClCCl
Product: CC(C)(C)Oc1cccc(CCBr)c1
Yield: 71 %

Procedure:
3-(2-Bromoethyl)phenol (1.349 g, 6.709 mmol) in DCM (7 ml) was cooled under argon to −78° C. Under stirring, isobutene was bubbled into the mixture until more than 5 ml were added. Trifluoromethanesulphonic acid (50 μl) was dropped in. The mixture was stirred under argon at −78° C. for 4.5 hours. Triethylamine (120 μl) was added. The reaction mixture was allowed up to room temperature and then filtered. The filtrate was evaporated to dryness and petroleum ether (25 ml) was added into the residue. It was then filtered and evaporated. The obtained oil was solved in ethyl acetate, washed with water, dried (sodium sulphate) and evaporated. The residue was dissolved in CDCl3 and then evaporated. 1.223 g desired product was left, yield 71%.
Reaction SMILES: Cl.[F:2][C:3]([F:28])([F:27])[C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[CH:6]([O:18][CH:19]1[CH2:22][NH:21][CH2:20]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[N-:29]=[C:30]=[O:31]>>[F:28][C:3]([F:27])([F:2])[C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[CH:6]([O:18][CH:19]1[CH2:22][N:21]([C:30]([NH:29][CH2:3][C:4]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:5]=2)=[O:31])[CH2:20]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: FC(F)(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: [N-]=C=O
Agent: Cl
Product: O=C(NCc1ccccc1)N1CC(OC(c2ccc(OC(F)(F)F)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-(trifluoro-methoxy)benzyloxy]azetidine hydrochloride (141) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2]>C(N)C1C=CC=CC=1>[CH2:20]([NH:2][C:1]1[N:10]=[CH:9][N:8]=[C:7]2[NH:6][N:5]=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[C:3]=12)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:14][CH:15]=1
Reactant: Cc1cccc(Nc2n[nH]c(N=CN(C)C)c2C#N)c1
Solvent: NCc1ccccc1
Product: Cc1cccc(Nc2n[nH]c3ncnc(NCc4ccccc4)c23)c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, a mixture of 1 g (3.74 mmol) of 4-cyano-5-(dimethylamino-methyleneamino)-3-(3-methyl-phenylamino)-pyrazole and 10 ml of benzylamine is stirred for 4 hours at 120° C. and then concentrated by evaporation under a HV. The crystalline residue is digested in 10 ml of acetonitrile and filtered and the filter residue is recrystallized from 40 ml of acetonitrile, yielding the title compound; m.p. 200-201° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:16])[CH2:6][CH2:5]2
Reactant: NCCCCO
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCCO)O2
Yield: 74.8 %

Procedure:
Following the amide coupling procedure described in protocol A, 507 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.03 mmol), 356 mg CDI (2.20 mmol) and 196 mg 4-aminobutanol (2.20 mmol) produced 488 mg of 6-hydroxy-N-(4-hydroxybutyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a white powder.
Reaction SMILES: [C:1]([O:9][CH:10]([C:14](=[O:16])[CH3:15])[C:11](=[O:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](OCC)=[O:18]>>[C:1]([O:9][CH:10]([C:14](=[O:16])[CH3:15])[C:11](=[O:13])[CH:12]=[CH:17][OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(OC(=O)c1ccccc1)C(C)=O
Reactant: CCOC=O
Product: CC(=O)C(OC(=O)c1ccccc1)C(=O)C=CO

Procedure:
3-benzoyloxy-2,4-pentanedione is reacted with ethyl formate to form 4-benzoyloxy-1-hydroxy-1-hexene-3,5-dione,
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[CH2:14]([O:21][CH2:22][C@H:23]([NH:27]C(OC(C)(C)C)=O)[C:24](O)=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:27][C@@H:23]([CH2:22][O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:24]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:8][CH:9]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: Nc1ccc(Oc2nccs2)cc1
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2nccs2)cc1
Yield: 60 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(thiazol-2-yloxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-thiazol-2-yloxyphenyl)propanamide (200 mg, 60%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[CH2:21]=[C:22]1[O:26][C:24](=[O:25])[CH2:23]1>>[CH2:14]([O:13][CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][O:1][C:24](=[O:25])[CH2:23][C:22]([CH3:21])=[O:26])=[CH:5][CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=C1CC(=O)O1
Reactant: OCCc1ccc(OCCOCc2ccccc2)cc1
Product: CC(=O)CC(=O)OCCc1ccc(OCCOCc2ccccc2)cc1

Procedure:
Diketene (3-buteno-β-lactone, available, e.g., from Aldrich Chemical Co.) is then added to the hydroxyalkylbenzene derivative 4 under basic conditions, e.g., using triethylamine in dimethoxyethane (DME) to form a ω-phenylalkylacetoacetate derivative (5). For example, 1-(2-hydroxyethyl)-4-(2-benzyloxyethoxy)benzene is reacted with diketene to afford 2-[4-(2-benzyloxyethoxy)phenyl]ethylacetoacetate (5) (Step 5).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>ClC1C=CC=CC=1Cl.[Cu]>[C:16]1([N:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: Clc1ccccc1Cl
Product: c1ccc(N2c3ccccc3Sc3ccccc32)cc1

Procedure:
A mixture of phenothiazine (15 g, 0.075 mol), 23 g (0.11 mol) of iodobenzene, 9.6 g (0.150 mol) of copper powder, 35.3 g (0.26 mol) of potassium carbonate, and 1.98 g (0.0075 mol) of 18-crown-6 in 20 ml of 1,2-dichlorobenzene was reflux under nitrogen for 24 hour. The inorganic components were removed by filtering the hot reaction mixture. The crude product formed crystals from the reaction mixture. The product was purified by recrystallization from methanol. The yield of 10-phenylphenothiazine was 12.4 g (60%). The product had a melting point of 93–94° C. (recrystallized from methanol). A 1H NMR spectrum yielded the following results (100 MHz, CDCl3, δ, ppm): 6.0–6.45 (m, 2H, Ar), 6.68–7.20(m, 6H Ar), 7.22–7.68(m, 5H, Ar).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:6][CH:5]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:23][O:22][N:21]([CH3:20])[C:14](=[O:16])[CH2:13][CH2:12][C:11]#[C:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:18])[F:17])=[CH:9][CH:8]=1
Reactant: CNOC
Reactant: O=C(O)CCC#Cc1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)CCC#Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of 1.00 g (3.87 mmol) of 5-(4-trifluoromethoxy-phenyl)-pent-4-ynoic acid (example 29D]) in 50 ml CH2Cl2 was treated with 0.45 g (4.65 mmol) N,O-dimethylhydroxylamine hydrochloride, 0.55 ml (5.03 mmol) N-methylmorpholine and at 0° C. with 0.97 g (5.03 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI). The reaction was naturally warmed to ambient temperature over night and partitioned between aqueous 10% KHSO4/ether (three times). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried (Na2SO4) to give 1.165 g of the title compound as brown oil.
Reaction SMILES: [CH2:1]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[NH:54]([C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[C@H:55]([C:75]([OH:77])=[O:76])[CH2:56][NH:57][C:58]([O:60][CH2:61][CH:62]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[C:68]2[C:63]1=[CH:64][CH:65]=[CH:66][CH:67]=2)=[O:59].CCCCCC.C(OC(=O)C)C>ClCCl>[NH:54]([C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])[C@H:55]([C:75]([OH:77])=[O:76])[CH2:56][NH:57][C:58]([O:60][CH2:61][CH:62]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[C:68]2[C:63]1=[CH:64][CH:65]=[CH:66][CH:67]=2)=[O:59].[CH2:20]([N-:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCC/C=C\CCCCCCCCNCCCCCCCCCCCCCCCC
Agent: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCC[N-]CCCCCCCCCCCCCCCC
Reaction time: 20 h

Procedure:
521 mg (1.06 mmol)N-oleyl-palmitylamine in 10 ml anhydrous dichloromethane are dissolved in a 50 ml round-bottom flask and 289 mg (1.17 mmol) EEDQ are added. Subsequently, 500 mg (1.17 mmol) Boc-Dap(Fmoc)-OH are added under steering and the mixture is steered at room temperature for 20 hours. The solution is transferred with 80 ml dichloromethane into a separating funnel and washed three times with 20 ml 0.1 N HCl each and once with 20 ml saturated NaHCO3 solution. After drying over Na2SO4 the solvent is removed using a rotary evaporator (FIG. 4). A yellowish viscous oil is obtained which is not further purified. In thin layer chromatography using hexane/ethylacetate of 1:1 a Rf of 0.70 was observed.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[C:17](=O)[NH:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:46]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[C:17]([Cl:46])=[N:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc3nc[nH]c(=O)c23)CC1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc3ncnc(Cl)c23)CC1

Procedure:
5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one (0.31 g) was reacted with triphenylphosphine and carbon tetrachloride to give 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chloroquinazoline (0.156 g); NMR Spectrum: (CDCl3) 1.5 (s, 9H), 1.9–2.1 (m, 4H), 3.5–3.8 (m, 4H), 4.8 (m, 1H), 7.05 (d, 1H), 7.65 (d, 1H), 7.82 (m, 1H), 8.95 (s, 1H); Mass Spectrum: M+H+ 364 and 366; and
Reaction SMILES: [C:1]([C:3]1[CH:4]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[O:24][C:23]([CH3:26])=[CH:22][C:21]3=[O:27])[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([CH3:10])[NH:7][C:8]=1[CH3:9])#[N:2].CCCC(C)C.C(O)C.C(NCC)C>>[C:1]([C:3]1[C@@H:4]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[O:24][C:23]([CH3:26])=[CH:22][C:21]3=[O:27])[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([CH3:10])[NH:7][C:8]=1[CH3:9])#[N:2]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C#N)C1c1cccc2c(=O)cc(C)oc12
Solvent: CCCC(C)C
Solvent: CCNCC
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C#N)[C@H]1c1cccc2c(=O)cc(C)oc12

Procedure:
536 mg (1.45 mmol) of racemic ethyl 5-cyano-2,6-dimethyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-1,4-dihydropyridine-3-carboxylate (example 7) are separated into the enantiomers by preparative HPLC on a chiral phase [column: Chiralpak AS-H, 250 mm×4.6 mm; eluent: isohexane/ethanol 3:1 (v/v)+0.2% diethylamine; flow rate: 1 ml/min; W detection: 220 nm]:
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[C:12]([O:18][CH3:19])[CH:11]=1.N1C=CN=C1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(Br)ccc1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1CO[Si](C)(C)C(C)(C)C
Yield: 66.1 %

Procedure:
tert-Butyldimethylsilyl chloride (1.04 g, 6.9 mmol) was added to a mixture of (4-bromo-2-methoxyphenyl)methanol (1.0 g, 4.6 mol) and imidazole (470 mg, 7.0 mmol) in DMF (15 mL) and the resultant mixture was stirred at ambient temperature for 66 h. The mixture was concentrated to about a third of the original volume then diluted with water and extracted with diethyl ether (×3). The combined organic layer was dried over magnesium sulfate, filtered and evaporated. The resultant residue was purified by chromatography (silica, 50 g column, Si-SPE, 5% diethyl ether in pentane) to afford the title compound as a colourless oil (1.51 g, 98%). 1H NMR (CDCl3, 400 MHz): 7.34 (dt, J=8.1, 1.05 Hz, 1H); 7.11 (dd, J=8.1, 1.8 Hz, 1H); 6.95 (d, J=1.8 Hz, 1H); 4.69 (d, J=1.0 Hz, 2H); 3.81 (s, 3H); 0.97-0.94 (m, 9H); 0.13-0.08 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[C:16]([F:24])=[C:17]([C:20]([F:23])=[CH:21][CH:22]=3)[C:18]#[N:19])[S:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].[OH-].[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[C:16]([F:24])=[C:17]([C:20]([F:23])=[CH:21][CH:22]=3)[C:18]([NH:26][OH:27])=[NH:19])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1c(F)ccc(OCc2nc(-c3ccc(Cl)cc3)ns2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(NO)c1c(F)ccc(OCc2nc(-c3ccc(Cl)cc3)ns2)c1F
Yield: 68.7 %

Procedure:
To a solution of 3-[3-(4-chlorophenyl)-[1,2,4]thiadiazol-5-ylmethoxy]-2,6-difluorobenzonitrile (0.10 g, 2.75 mmol) in EtOH (3 ml) was added hydroxylamine hydrochloride (0.48 g, 6.87 mmol) and NaOH (0.27 g, 6.87 mmol). The resulting reaction mixture was refluxed overnight. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added EtOH and filtered. The filtrate was evaporated in vacuum to get the desired product (0.75 g, 69%).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[C:11]([C:16]([OH:18])=[O:17])=[N:12][CH:13]=[CH:14][N:15]=2)=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:40][CH:39]=2)=[CH:33][CH:32]=1.C(OC(=O)C)(=O)C>>[CH2:21]([N:3]([CH2:1][CH3:2])[C:4]1[CH:20]=[CH:19][C:7]([C:8]2([N:37]([C:38]3[CH:39]=[CH:40][C:41]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:42][CH:43]=3)[C:34]3[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])=[CH:36][CH:35]=3)[C:10]3=[N:15][CH:14]=[CH:13][N:12]=[C:11]3[C:16](=[O:18])[O:17]2)=[CH:6][CH:5]=1)[CH3:22]
Reactant: CCCCCCCCc1ccc(Nc2ccc(CCCCCCCC)cc2)cc1
Reactant: CCN(CC)c1ccc(C(=O)c2nccnc2C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCc1ccc(N(c2ccc(CCCCCCCC)cc2)C2(c3ccc(N(CC)CC)cc3)OC(=O)c3nccnc32)cc1
Reaction time: 8 h

Procedure:
A mixture containing 0.15 g. of 3-[4-(diethylamino)benzoyl]-2-pyrazinecarboxylic acid, 0.18 g. of 4,4'-dioctyldiphenylamine and 3 ml. of acetic anhydride was gently heated for 5 hours and then allowed to stand overnight. The product, 7-[4-(diethylamino)phenyl]-7-[bis(4-octylphenyl)amino]furo[3,4-b]pyrazine-5(7H)-one was isolated by column chromatography followed by crystallization from hexane to give a peach solid, m.p. 180°-181° C. A toluene solution of this product contacted with acidic clay or phenolic resin developed a red image.
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[CH2:11]([O:14][C:15]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18])[CH2:12][CH3:13]>O>[C:1]([S:24][C:21]1[CH:22]=[CH:23][C:15]([O:14][CH2:11][CH2:12][CH3:13])=[C:16]([CH:20]=1)[C:17]([NH2:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCOc1ccc(S)cc1C(N)=O
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCOc1ccc(SC(C)(C)C)cc1C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.3 %

Procedure:
t-Butanol (16 g.) was added to an aqueous sulphuric acid solution (200 ml.; containing 75% w/w sulphuric acid) cooled in ice-water. The mixture was stirred until all the t-butanol had dissolved, and then 2-propoxy-5-mercaptobenzamide (20 g.; prepared as described in Reference Example 2) was added in small portions with stirring during 15 minutes. After all the solid had dissolved the mixture was allowed to warm up to room temperature and kept at that temperature for 15 minutes. The solution was diluted with water (600 ml.), and the precipitated solid was filtered off and dissolved in chloroform (200 ml.). The chloroform solution was then washed with aqueous sodium hydroxide solution (2N; 40 ml.) and then with water (3 × 20 ml.), and dried over sodium sulphate. The solvent was removed in vacuo and the residue was recrystallised from aqueous ethanol, to give 5-t-butylthio-2-propoxybenzamide (15 g.), m.p. 135.5° - 137.5° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([N:32]1[CH2:40][CH2:39][CH:35]([C:36]([OH:38])=O)[CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CN1CCOCC1.[NH2:48][C:49]1[N:50]=[CH:51][C:52](/[C:64](=[N:66]/[NH2:67])/[NH2:65])=[N:53][C:54]=1[C:55]1[O:56][C:57]([C:60]([CH3:63])([CH3:62])[CH3:61])=[N:58][N:59]=1>CC(N(C)C)=O>[NH2:65]/[C:64](/[C:52]1[CH:51]=[N:50][C:49]([NH2:48])=[C:54]([C:55]2[O:56][C:57]([C:60]([CH3:63])([CH3:62])[CH3:61])=[N:58][N:59]=2)[N:53]=1)=[N:66]\[NH:67][C:36]([CH:35]1[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:40][CH2:39]1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(C)(C)c1nnc(-c2nc(/C(N)=N/N)cnc2N)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N/N=C(\N)c2cnc(N)c(-c3nnc(C(C)(C)C)o3)n2)CC1
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (74.3 g, 195.44 mmol) was added to a solution of N-Boc-isonipecotic acid (41.1 g, 179.15 mmol) and 4-methylmorpholine (35.9 mL, 325.74 mmol) in DMA (800 mL). The mixture was stirred for 10 minutes then (Z)-5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbohydrazonamide (45 g, 162.87 mmol) was added to the solution in one portion (exotherm observed from 22° C. to 27° C.). After a few minutes the product crystallised from the reaction mixture. The reaction mixture was removed from the vessel and filtered through a sinter. Additional DMA was added to wash product from the sides of the vessel (150 mL) and this was poured onto the filter cake. Isopropanol (600 mL) was added to the vessel and the remainder of the product in the vessel was suspended in this solvent using vigorous agitation. The isopropanol suspension was used to wash the filter cake once the DMA had been removed by suction. The filter cake was sucked dry then washed with MTBE and sucked dry once again. The filter cake was dried in vacuo to afford (Z)-tert-butyl 4-(2-(amino(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)methylene)hydrazinecarbonyl)piperidine-1-carboxylate (76 g, 95%) as a yellow solid: 1H NMR Spectrum: (DMSO-d6) 1.40 (9H, s), 1.46 (9H, s), 1.63-1.9 (2H, m), 2.33-2.6 (2H, m, obscured by DMSO signal), 2.63-3.03 (2H, m), 3.18-3.48 (4H, m, obscured by water signal), 3.88-4.11 (2H, m), 6.43 (2H, s), 7.76 (2H, br), 8.84 (0.5H, s), 8.87 (0.5H, s), 9.85 (1H, s); Mass Spectrum [M+H]+=488