Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[O:30][C:29]([CH3:32])([CH3:31])[O:28][C:27](=[O:33])[C:26]=2[CH:34]=1>>[CH3:31][C:29]1([CH3:32])[O:30][C:25]2[CH:24]=[CH:23][C:22]([NH:21][CH2:15][C:14]3[CH:17]=[CH:18][C:11]([C:10]#[C:9][C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:19])[F:1])=[CH:4][CH:5]=4)=[CH:12][CH:13]=3)=[CH:34][C:26]=2[C:27](=[O:33])[O:28]1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Reactant: O=Cc1ccc(C#Cc2ccc(C(F)(F)F)cc2)cc1
Product: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(C(F)(F)F)cc4)cc3)ccc2O1
Yield: 29.5 %

Procedure:
The title compound was prepared following procedure described in example 1, step c) from 4-{[4-(trifluoromethyl)phenyl]ethynyl}benzaldehyde (1.22 g; 4.43 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) and 6-amino-2,2-dimethyl-benzo[1,3]dioxin-4-one (855 mg; 4.43 mmol). Purification of the crude (2.6g) by precipitation in DCM upon addition of pentane gave 590 mg (30%) of the title compound as a brown solid. HPLC, Rt: 4.76 min (purity: 76.2%). LC/MS, M+(ESI): 452, M−(ESI): 450.1, 1H NMR (CDCl3) δ 7.59 (s, 4H), 7.51 (d, J=7.5 Hz, 2H), 7.34 (d, J=7.7 Hz, 2H), 7.15 (s, 1H), 6.80 (m, 2H), 4.34 (s, 2H), 1.68 (s, 6H). Purification of the filtrate by flash chromatography on silicagel (EtOAc/c-Hex 10:90 then 20:80) gave another 420 mg of the title compound (21%) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4](=[O:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>>[CH3:1][O:2][C:3](=[O:22])[C@@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Product: COC(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the thus-prepared reducing agent was added 81.0 mg (0.26 mmol) of (3S)-[(t-butoxycarbonyl)amino]-2-oxo-4-phenylbutyric acid methyl ester, and the mixture was stirred at room temperature for 5 hours. After hydrolysis with 1 N hydrochloric acid, the reaction mixture was extracted with ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:35]=[CH:34][C:16]([O:17][CH:18]([CH3:33])[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=O)=[CH:15][CH:14]=1)[CH:6]=[N:5]2.C1COCC1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:42]>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:35]=[CH:34][C:16]([O:17][CH:18]([CH3:33])[C:19](=[S:42])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[CH:15][CH:14]=1)[CH:6]=[N:5]2
Reactant: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: C1CCOC1
Product: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=S)Nc1ccc(OC(F)(F)F)cc1
Reaction time: 2 h

Procedure:
A mixture of 2.0 g (4.1 mmol) of 2-(4-((6-fluoro-2-quinoxalinyl)oxy)phenoxy)-N-(4-(trifluoromethoxy)phenyl)propanamide and 40 ml of dry THF in a 100 ml flask was placed in a water-filled ultrasonic bath. Phosphorous pentasulfide (0.22 g) was added and the mixture sonicated while maintaining the reaction temperature below 40° C. by occasional addition of ice to the water bath. Additional P2S5 (1.76 g) was added in portions at 20 minute intervals over the next hour. Sonication was continued for an additional 2 hours and the mixture then filtered and the solid washed well with methylene chloride. The combined filtrates were treated with charcoal, filtered and evaporated to dryness. The residue was purified first by chromatography over silica gel, eluting with CH2Cl2, and then by preparative scale HPLC, eluting with 85:15 hexane: acetone. This left 1.1 g (53 percent of theoretical) of the above-named product as a yellow glassy solid. (Compound 34)
Reaction SMILES: [CH:1]1(C2(C3C=CC(OC)=C(OC)C=3)CC(=O)C3C(=CC(O)=CC=3)O2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(OCC)(=[O:36])C>CO>[OH:36][C@@H:1]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: COc1ccc(C2(C3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)CC(=O)c3ccc(O)cc3O2)cc1OC
Reactant: CCOC(C)=O
Solvent: CO
Product: OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Compound (3), was obtained as a pale yellow crystalline mass from (ethyl acetate:methanol; 9:1) eluants. It responded to positive tests of flavonoid glycosides. Its IR spectrum showed characteristic absorption suggested that a flavanone was an aglycone moiety possessing one hydroxyl group in ring A and two methoxy groups in ring B. Further analysis indicated that (3) was an acyclic sesquiterpenic acid possessing three vinylic linkages at carbons C3″, C7″ (14″) and C-10″ was esterified with the sugar moiety. The 1H NMR spectrum of (3) exhibited the presence of aromatic carbons and sugar carbons. Acid hydrolysis of (3) yielded β-D-glucose as a glycone moiety (TLC comparable). On the basis spectral data analysis of (3), the structure has been established as 6″-(3′″,11′″-dimethyl-dodec-3′″,7′″(14′″) 10′″-trienyl glucopyranosyl-7-hydroxy-3′,4′-dimethoxyflavanone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:13][CH2:14][CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[ClH:13].[C:18]1([CH2:17][NH:16][CH2:15][CH2:14][NH:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCCNCc1ccccc1
Reactant: CC(=O)Nc1cccc(N)c1
Agent: Cl
Solvent: CC(C)O
Product: CC(=O)Nc1cccc(NCCNCc2ccccc2)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Combine N-(3-aminophenyl)acetamide (31 g, 0.206 mol) and N-(2-chloroethyl)benzenemethanamine hydrochloride (17.0 g, 0.083 mol) and heat to 180° C. for 1 h. After this time, allow to cool to approximately 85° C. and add isopropanol (100 mL) to precipitate a solid. Decant the solvent and dissolve the white residue in refluxing methanol (800 mL). Filter hot and allow the solution to cool to room temperature. After 2 h, filter the resulting white solid and wash with methanol (50 mL) to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.O1CCOCC1>[C:10]([N:4]1[C:3](=[O:9])[C:2]([F:1])=[CH:7][NH:6][C:5]1=[O:8])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1c(=O)[nH]cc(F)c1=O
Temperature: 0 °C
Yield: 32 %

Procedure:
2.6 g (0.02 mole) of 5-fluorouracil was suspended in 10 ml of absolute pyridine and 10 ml of absolute dioxane, and the suspension was warmed to 80° C and stirred. 5.6 g (0.04 mole) of benzoyl chloride was then added dropwise thereto followed by stirring at 80° C for 1.5 hours to allow the mixture to react. After completion of the reaction, the reaction mixture was poured into ice-water followed by stirring, and the thus precipitated solid was filtered, washed with water and then dissolved in benzene while hot (80° C). Any insoluble matter was removed by filtration, and the filtrate allowed to cool to precipitate crystals, which were recovered by filtration to obtain 1.5 g of 3-N-benzoyl-5-fluorouracil in a yield of 32% (the filtrate was set aside). Melting Point: 170° C.
Reaction SMILES: C(N(CC)CC)C.[Br:8][CH:9]([CH:12](Br)[C:13]([F:16])([F:15])[F:14])[C:10]#[N:11]>O1CCCC1>[Br:8]/[C:9](=[CH:12]\[C:13]([F:16])([F:15])[F:14])/[C:10]#[N:11]
Reactant: N#CC(Br)C(Br)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#C/C(Br)=C/C(F)(F)F
Reaction time: 1 h
Yield: 67.4 %

Procedure:
Triethylamine (3.7 g, 0.037 mol) is added dropwise to a solution of 2,3-dibromo-4,4,4-trifluorobutyronitrile (5.32 g, 0.023 mol) and tetrahydrofuran (100 mL). A voluminous white precipitate forms during the addition. Stirring is continued for 1 hour, then the solid is filtered off and washed with tetrahydrofuran. The tetrahydrofuran is distilled off to give a dark brown oil. Bulb to bulb distillation (15 mm, 24° C.) of the oil yields the title product as a clear colorless liquid (3.1 g, 82%). NMR spectral analyses identifies a 6:1 mixture of E:Z.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:17]([Sn](CCCC)(CCCC)C#CC)[CH2:18][CH2:19]C>C1(C)C=CC=CC=1.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>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]([C:7]1[C:2]([C:17]#[C:18][CH3:19])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:9]
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(c1ccccc1Cl)c1cccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC#Cc1ncccc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dissolve (2-bromo-pyridin-3-yl)-(2-chloro-phenyl)-methanone (18.0 g, 60.8 mmol) in toluene (600 mL) and purge the solution with nitrogen. After 10 minutes., add tributyl(1-propynyl)tin (22.2 mL, 72.9 mmol) followed by tetrakis(triphenylphosphine)palladium (2.10 g, 1.82 mmol) and heat the mixture to reflux temperature. After 2 hours, cool the mixture to room temperature and concentrate. Purification by flash chromatography on silica gel eluting with hexanes:ethyl acetate (5:1 to 2:1) gives the title compound: m.p.=45-49° C.; mass spectrum (m/e): 256 (M+H+); 1H NMR (CDCl3) δ 8.67-8.68 (m, 1H), 7.95-7.98 (m, 1H), 7.32-7.55 (m, 5H), 1.74 (s, 3H); HPLC 98.4%; TLC (Silica, 2:1 Hexanes:Ethyl Acetate) Rf 0.20.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].C(N(CC)CC)C.[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([NH2:24])=[C:19]([Cl:25])[CH:18]=1.O>C(#N)C>[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([NH:24][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:19]([Cl:25])[CH:18]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1cc(Br)cc(Cl)c1N
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: Cc1cc(Br)cc(Cl)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of 4-bromo-2-chloro-6-methyl-phenylamine (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture, and the precipitate that formed was collected to give the title compound as a powder (7.46 g, 100% yield).
Reaction SMILES: [C:1]([CH:3](P(=O)(OCC)OCC)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[H-].[Na+].[C:20]12([CH:30]=O)[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2.O>C1COCC1>[C:20]12([CH:30]=[C:3]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:1]#[N:2])[CH2:21][CH:22]3[CH2:28][CH:26]([CH2:25][CH:24]([CH2:23]3)[CH2:29]1)[CH2:27]2
Reactant: O=CC12CC3CC(CC(C3)C1)C2
Reactant: CCOP(=O)(OCC)C(C#N)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(=CC12CC3CC(CC(C3)C1)C2)c1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 28.3 %

Procedure:
A solution of diethyl 1-cyano-1-phenylmethylphosphonate (10.97 g, 43.3 mmol) in dry THF (60 mL) at 0° C. was treated with NaH (60% dispersion in oil, 1.7 g, 43.3 mmol), stirred at 0° C. for 40 min, warmed to room temperature for 20 min, treated with a solution of 1-adamantanecarboxaldehyde (3.56 g, 21.7 mmol) in dry THF (10 mL) and heated at 60° C. for 16 h. The reaction mixture was cooled, treated with water (50 mL), extracted with EtOAc (3×20 mL), the extracts washed with brine (40 mL), dried (MgSO4) and concentrated in vacuo. The resulting brown oil was purified by chromatography [SiO2, heptane-EtOAc (9:1)] and recrystallised (heptane) to give the product (1.62 g, 28%) as a white solid: mp 107-108° C; IR νmax (Nujol)/cm−1 2924, 2852, 2218, 1497, 1448, 1377, 1343, 1101, 910, 762, 750 and 689; NMR δH (400 MHz, CDCl3) 1.76 (6H, m), 1.99 (6H, m), 2.07 (3H, m), 6.50 (1H, s), 7.37 (3H, m) and 7.51 (2H, m); Anal. Calcd for C19H21N: C, 86.65; H, 8.04; N, 5.32. Found: C, 86.58; H, 8.09; N, 5.33.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:8]([CH3:22])[CH2:7]1.[N:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[N:34][CH:35]=1)=[C:28]=[O:29]>C1COCC1>[F:26][C:3]1[C:2]([NH:1][C:28]([NH:27][C:30]2[CH:35]=[N:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[O:29])=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:8]([CH3:22])[CH2:7]1
Reactant: Cc1ccc(N=C=O)cn1
Reactant: C[C@@H]1CN(Cc2cccc(N)c2F)CCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2cccc(CN3CCN(C(=O)OCc4ccccc4)[C@H](C)C3)c2F)cn1
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a room temperature solution of (R)-benzyl 4-(3-amino-2-fluorobenzyl)-2-methylpiperazine-1-carboxylate (250 mg, 0.70 mmol, 1.0 equiv) in dry THF (3 mL) was added 5-isocyanato-2-methylpyridine (94 mg, 0.70 mmol, 1.0 equiv). After 1 h, the reaction was complete, as determined by LCMS. The reaction was washed with aq. satd. NaHCO3 and brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (2%-10% MeOH/DCM) provided (R)-benzyl 4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)-2-methylpiperazine-1-carboxylate (244 mg, 71%). LCMS m/z (APCI)=492.2 (M+H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[C@H:13](O)[CH2:12][N:11]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:29]([O:32][NH:33][S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N+:43]([O-:45])=[O:44])(=[O:36])=[O:35])[CH:30]=[CH2:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:29]([O:32][N:33]([C@H:13]1[CH2:12][N:11]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH:15]=[C:14]1[C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N+:43]([O-:45])=[O:44])(=[O:36])=[O:35])[CH:30]=[CH2:31]
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CN(C)C(=O)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(=O)N(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A stirred suspension of (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-(dimethylcarbamoyl)-5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 137, 3.09 g, 7.45 mmol), N-(allyloxy)-2-nitrobenzenesulfonamide (2.348 g, 9.09 mmol) and triphenylphosphine (2.150 g, 8.20 mmol) in toluene (65 mL) was cooled in a salt-ice-bath and then (E)-diisopropyl diazene-1,2-dicarboxylate (1.588 mL, 8.20 mmol) was added dropwise. The reaction was let warm up to rt and was stirred for an additional 2 h. The solvent was removed and the crude product was loaded onto silica gel, purified via flash chromatography (25-75% EA/Hex) to obtain the desired product (4.0 g, 82%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]#[N:7].[CH2:9]([NH:11][NH2:12])[CH3:10].Cl>C(O)C>[CH2:9]([N:11]1[C:6]([NH2:7])=[CH:5][C:4]([CH2:3][O:2][CH3:1])=[N:12]1)[CH3:10]
Reactant: CCNN
Reactant: COCC(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CCn1nc(COC)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a 25 mL round bottom was added 4-(methyloxy)-3-oxobutanenitrile (500 mg, 4.42 mmol), ethyl hydrazine (655 mg, 4.42 mmol), and 2 M HCl (2.210 mL, 4.42 mmol) in ethanol (10 mL). The reaction mixture was stirred at the room temperature overnight. The reaction mixture was then evaporated and pardoned between 20 mL of ethyl acetate and 20 mL of 1 M Na2CO3. The organic layer was washed with brine, filtered and evaporated to obtain 1-ethyl-3-[(methyloxy)methyl]-1H-pyrazol-5-amine (450 mg, 2.465 mmol, 55.8% yield) as a yellow oil. The product was used in the next step without further purification. LCMS (M+H)+=156.1; 1H NMR (400 MHz, DMSO-d6) ppm 1.20 (t, J=7.20 Hz, 3 H) 3.19 (s, 3 H) 3.82 (q, J=7.33 Hz, 2 H) 4.11 (s, 2 H) 5.11 (s, 2 H) 5.22 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[NH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1>>[N:20]1([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: c1ccc2c(c1)CCCN2
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCc4ccccc43)n2)c1

Procedure:
B42 was prepared following the general procedure reported for B10 using A1 and 1,2,3,4-tetrahydroquinoline; yield: 11.9 mg (3%), colorless amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.91 (quint, J=6.3 Hz, 2H), 2.73 (t, J=6.6 Hz, 2H), 3.98 (t, J=6.2 Hz, 2H), 4.16 (s, 2H), 6.82 (s, 2H), 6.99 (d, J=7.6 Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 7.13-7.19 (m, 2H), 7.23 (t, J=7.8 Hz, 1H), 7.62-7.69 (m, 2H), 7.72 (d, J=7.8 Hz, 1H), 8.32 (s, 1H), 9.81 (s, 1H). MS (ES) C19H20N6O2S requires: 396. found: 397 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=1[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Cc2ccccc2OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(Cc2ccccc2OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 75.2 %

Procedure:
To a solution of methyl 4-(2-benzyloxybenzyl)benzoate (1.0 g) in methanol (20 mL) was added 2 mol/L aqueous sodium hydroxide solution (7.5 mL), and the mixture was stirred at 60° C. for 5 hours. After dilute hydrochloric acid was added to the residue to acidify, the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 4-(2-benzyloxybenzyl)benzoic acid (0.72 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6](Cl)[N:5]=[C:4]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.Cl.[F:25][C:26]([F:31])([F:30])[C@@H:27]([NH2:29])[CH3:28].C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:5]=[C:6]([NH:29][C@@H:27]([CH3:28])[C:26]([F:31])([F:30])[F:25])[C:7]=1[C:8]1[C:9]([F:16])=[CH:10][C:11]([F:15])=[CH:12][C:13]=1[F:14]
Reactant: Fc1cc(F)c(-c2c(Cl)nc(-c3cnccn3)nc2Cl)c(F)c1
Reactant: C[C@H](N)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(-c2cnccn2)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Temperature: 90 °C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
A mixture of 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluorophenyl)pyrimidine (205 mg, 0.57 mmol), (1S)-2,2,2-trifluoro-1-methylethylamine hydrogen chloride (298 mg, 2 mmol), and N,N-diisopropylethylamine (258 mg, 2 mmol) in 5 mL of N,N-dimethylformamide is stirred at 90° C. in a sealed tube for 18 h. The reaction mixture is partitioned between ethyl acetate and saturated sodium chloride. The organic layer is washed with saturated sodium chloride (×3), dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of 20% ethyl acetate in hexanes to 50% ethyl acetate in hexanes. Concentration provides 6-chloro-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine as a light yellow solid (111 mg). MS: m/z 434.1 (M+H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][O:14][C:15]([CH3:17])=[CH2:16]>CC#N.C([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:13][O:14][C:15]([CH3:17])([O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7])[CH3:16]
Reactant: C=C(C)OC
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(C)(C)ON1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a solution of 20 g (123 mmol) of N-hydroxyphthalimide in 360 ml of CH3CN, 26.42 ml (276 mmol) of 2-methoxypropene and 42.36 mg (0.246 mmol) of anhydrous p-toluenesulfonic acid are added in portions at r.t. After stirring for 1 h, the mixture is diluted with 25 ml of sat. NaHCO3 and concentrated under reduced pressure. The residue is extracted with EtOAc and the organic layer is washed with H2O and brine, dried over MgSO4 and concentrated under reduced pressure to give 21.84 g of 2-(1-methoxy-1-methyl-ethoxy)isoindole-1,3-dione as a white solid; NMR (CDCl3): 1.57 (s, 6H), 3.61 (s, 3H), 7.75 (dd, 2H, J=5.56 Hz, J=3.0 Hz), 7.83 (dd, 2H, J=5.56 Hz, J=3.0 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][CH2:22]O.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:22][CH2:21][C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: OCCc1cccs1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OCCc2cccs2)cc1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of ethyl(4-hydroxy-2-methylphenoxy)acetate (intermediate 7, 1.05 g) and 2-(2-thienyl)ethanol (0.64 g) in dry tetrahydrofuran was treated with tri-n-butyl phosphine (1.2 g) and azodicarbonyldimorpholide (1.53 g) and the mixture stirred at ambient temperature for 3 days. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, concentrated and the residue purified by SPE (Si cartridge) eluting with cyclohexane:ethyl acetate (20:1) to give the title compound as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N:22]=[N+]=[N-])=[C:8]([C:20]#[N:21])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1C(C)(C)C)=[O:4]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([NH2:22])=[C:8]([C:20]#[N:21])[C:9]=1[C:10]1[CH:11]=[CH:12][C:13]([C:8]([CH3:20])([CH3:9])[CH3:7])=[CH:14][CH:15]=1)=[O:4]
Reactant: COC(=O)c1sc(N=[N+]=[N-])c(C#N)c1-c1ccccc1C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1sc(N)c(C#N)c1-c1ccc(C(C)(C)C)cc1

Procedure:
Combine 5-azido-3-(tert-butyl-phenyl)-4-cyano-thiophene-2-carboxylic acid methyl ester (0.309 mmol) and THF at room temperature and add a fresh THF solution of 0.1M SmI (0.93 mmol). Stir the reaction for 15 minutes and quench with 2M sodium carbonate solution until pH was greater than 9.0. Dilute the reaction with ethyl acetate and wash successively with 2M sodium carbonate, water, and brine. Separate the organics, dry over sodium sulfate, filter, and concentrate to give the title compound as a dark solid: 1H NMR (400 MHz, CDCl3) δ 7.46-7.36 (m, 4H), 5.23 (s, 2H), 3.71 (s, 3H), 1.36 (s, 9H), MS found (M+1) 315.1.