Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1I.[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13]>C(N(CC)CC)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:13]#[C:12][CH2:11][CH2:10][OH:14]
Reactant: Clc1ccc(I)c(Cl)c1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCCC#Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere 97.2 g (0.356 mole) of 2,4-dichloroiodobenzene, 3.21 g (0.0046 mole) of bis(triphenylphosphine)palladium(II) chloride, and 0.8 g (0.0042 mole) of copper(I) iodide were suspended in 50 mL of triethylamine and 100 mL of acetonitrile. This mixture was cooled in an ice/water bath to 0°-5° C., and 24.6 g (0.356 mole) of 3-butyn-1-ol dispersed in 25 mL of acetonitrile was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature at which it was stirred for approximately 16 hours. The solvent was evaporated from the reaction mixture under reduced pressure, leaving a brown oil as the residue. This oil was passed through a column of silica gel, eluting first with hexane and then with methylene chloride. Product-containing factions were combined, and the solvent was evaporated under reduced pressure, leaving 4-(2,4-dichlorophenyl)-3-butyn-1-ol as the residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CO.[BH4-].[Na+].[N+:5]([N:8]1[C:12]2=[C:13]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:14]3[CH:15]=[CH:16][C:17]([N:52]=3)=[C:18]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:19]3[N:23]([N+:24]([O-])=O)[C:22]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[C:28]4[N:39]=[C:31]([C:32]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[C:9]1[CH:10]=[CH:11]2)[CH:30]=[CH:29]4)=[CH:21][CH:20]=3)([O-])=O>[Pd].ClCCl>[NH2:24][N:23]1[C:19]2=[C:18]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:17]3[CH:16]=[CH:15][C:14]([N:52]=3)=[C:13]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:12]3[N:8]([NH2:5])[C:9]([C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:31]4[N:39]=[C:28]([C:27]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)=[C:22]1[CH:21]=[CH:20]2)[CH:29]=[CH:30]4)=[CH:10][CH:11]=3
Reactant: O=[N+]([O-])n1c2ccc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc(c(-c4ccccc4)c4nc(c2-c2ccccc2)C=C4)n3[N+](=O)[O-])C=C1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nn1c2ccc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc(c(-c4ccccc4)c4nc(c2-c2ccccc2)C=C4)n3N)C=C1
Yield: 96.2 %

Procedure:
A 2-1 three-necked round bottomed flask was fitted with a condenser and a dropping funnel to add solid material. To this flask was added anhydrous dichloromethane (850-ml) and methanol (420-ml). To this organic solution was added 10% palladium on carbon (14.0 g), the mixture was stirred under an argon blanket, and then cooled in an ice bath. Sodium borohydride (4.0 g, mol) was added in small portions over about 30-min. Next the dinitrotetraphenylporphyrin (7.0 g, 0.01 mol) and solid sodium borohydride (14.0 g) were added in small portions over about 60-min. The reaction mixture was stirred under argon for 30 min. The reaction mixture was filtered through a layer of CELITE® (diatomateous earth of Johns Manville, Denver, Colo.) in a Buchner funnel and washed repeatedly with dichloromethane. The solvent was completely removed under reduced pressure to produce a crude residue. The residue was redissolved in dry dichloromethane to separate insoluble CELITE®, and filtered. The solvent was removed under reduced pressure and dried to produce a purified residue (6.2 g). This residue was flash chromatographed over silica using dichloromethane as eluent. The product obtained (0.6 g, 9.6% yield) was free of impurities. See FIG. 4.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:15])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[CH3:14])[CH2:2][CH3:3].[CH3:16][N:17]([CH3:30])[C:18]1[CH:29]=[CH:28][C:21]2[S:22][C:23]([CH:26]=O)=[C:24]([CH3:25])[C:20]=2[CH:19]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C.CO>[CH2:1]([O:4][C:5](=[O:15])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:26][C:23]2[S:22][C:21]3[CH:28]=[CH:29][C:18]([N:17]([CH3:16])[CH3:30])=[CH:19][C:20]=3[C:24]=2[CH3:25])=[CH:9][C:8]=1[CH3:14])[CH2:2][CH3:3]
Reactant: Cc1c(C=O)sc2ccc(N(C)C)cc12
Reactant: CCCOC(=O)Nc1ccc(N)cc1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCOC(=O)Nc1ccc(NCc2sc3ccc(N(C)C)cc3c2C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
A solution of (4-amino-2-methylphenyl)-carbamic acid propyl ester (21 mg, 0.10 mmol) and 5-dimethylamino-3-methyl-benzo[b]thiophene-2-carbaldehyde (26 mg, 0.12 mmol) in acetonitrile (0.5 mL) was heated at 170° C. for 2 minutes using a Personal Chemistry Smith Synthesizer microwave device. After cooling to room temperature, a solution of sodium cyanoborohydride (25 mg, 0.40 mmol) in methanol (0.1 mL) was added followed by acetic acid (50 μL), and the mixture was stirred for 30 minutes. It was partitioned between saturated aqueous sodium bicarbonate (10 mL) and ethyl acetate (10 mL), and the organic layer was dried over sodium sulfate and evaporated. Preparative LC-MS afforded the title compound (32 mg, 77% yield).
Reaction SMILES: C([Li:5])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10](Br)[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15]>CCOCC>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([Li:5])[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15]
Reactant: [Li]CCCC
Reactant: COc1cc(Br)cc(OC)c1OC
Solvent: CCOCC
Product: [Li]c1cc(OC)c(OC)c(OC)c1
Reaction time: 1 h

Procedure:
To a stirred solution of n-butyllithium (0.5 mL, 1.6 M in hexane solution, 0.80 mmol) in dry ether (20 mL), a solution of 3,4,5-trimethoxyphenylbromide (98.8 mg, 0.40 mmol) in ether (10 mL) was added under dry nitrogen at −78° C. The solution was stirred for 1 h in order to form 3,4,5-trimethoxyphenyllithum. 7-[(tertButyldimethylsilyl)oxy]-6-methoxy-1-tetralone (122 mg, 0.40 mmol) was added at −20° C, and stirring was continued for 2 h (−20° C.-rt). The mixture was partitioned between CH2Cl2 and water, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated in vacuo to provide a yellow oil. 7-[(tertbutyldimethylsilyl)oxy]-1-hydroxy-6-methoxy-1-(3′,4′,5′-trimethoxyphenyl)-tetralin (137 mg, 0.29 mmol, 73%) was obtained following purification by column chromatography. 1H-NMR (CDCl3, 300 MHz) 0.04 (s, 6H), 0.89 (s, 9H), 1.80 (b, 1H), 2.11 (m, 4H), 2.81 (t, J=6.5, 2H), 3.79 (s, 6H), 3.81 (s, 3H), 3.84 (s, 3H), 6.49 (s, 1H), 6.56 (s, 2H), 6.59 (s, 1H). 13C-NMR (CDCl3, 75 MHz) −4.3, 18.8, 20.2, 26.1, 29.9, 41.5, 55.8, 56.5, 61.2, 75.6, 104.2, 111.9, 121.2, 131.4, 134.2, 136.8, 143.8, 145.3, 150.9, 152.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:29][CH2:28][N:11]2[C:12](=[O:27])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][C:16]([C:19]([CH3:21])=[CH2:20])=[CH:15][C:14]=3[O:22][C:23]([F:26])([F:25])[F:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:29][CH2:28][N:11]2[C:12](=[O:27])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=3[O:22][C:23]([F:25])([F:26])[F:24])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: C=C(C)c1cc(OC(F)(F)F)c2c(c1)C1CN(C(=O)OC(C)(C)C)CCN1C2=O
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cc(OC(F)(F)F)c2c(c1)C1CN(C(=O)OC(C)(C)C)CCN1C2=O
Reaction time: 2 h
Yield: 101 %

Procedure:
To a stirring degassed solution of N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-isopropenyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one (67 mg, 0.16 mmol) and 10% palladium on carbon (5 mg) in MeOH (3 mL) was added hydrogen (1 atm). The reaction was stirred for 2 h and then filtered. The filtrate was conc in vacuo to a colorless oil. The oil was purified by flash chromatography (SiO2, 0-50% EtOAc in hexanes) to yield 67 mg of the desired product as a colorless oil. MS (ESI) 415 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:12]([O-])=O)=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[C:15](O)([C:17](F)(F)F)=O>O.CC#N>[NH2:12][C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([C:11]1[CH:10]=[C:15]([CH3:17])[CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: COc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: COc1cccc(C(=O)c2cccc(C)c2)c1N

Procedure:
Intermediate A-19 was prepared from 3-methoxy-2-nitrobenzoic acid according to the general synthetic procedure described for Intermediate A-18. HPLC RT=2.21 min (H2O/CH3CN with TFA, Sunfire C18 3.5 μm, 2.1×30 mm, gradient=2 min, wavelength=220 nm). [M+H+]=246.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C.O>CN(C=O)C>[C:7]1([C:5]2[N:4]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)[N:3]=[C:2]([NH:1][C:32]([NH:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=3)=[O:33])[CH:6]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(-n2nc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of amine 6 (0.1 g, 0.32 mmol) in 5 mL of DMF was added 3-(trifluoromethyl)phenyl isocyanate (0.12 g, 0.62 mmol) followed by triethylamine (0.05 mL, 0.32 mmol) at 0° C. The reaction mixture was warmed up to room temperature and stirred overnight. The reaction mixture was poured into water, and the resulting precipitates were collected and washed with water. The crude product was purified by column chromatography by dry loading method to give the titled compound (0.13 g, 81% yield). mp 195.1-197.0° C. 1H NMR (300 MHz, DMSO-d6): δ 9.48 (s, 1H), 9.21 (s, 1H), 8.07 (s, 1H), 7.80 (d, J=9 Hz, 2H), 7.61-7.26 (m, 12H), 6.81 (s, 1H). MS (ESI) m/z: 502.12 (M+H+). Anal. Calcd for C23H18F3N5O3S.0.36CH4O: C, 54.69; H, 3.82; N, 13.65. Found: C, 54.69; H, 3.70; N, 13.44.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][C:8]([O:10]CC)=[O:9])[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[OH-].[Na+].Cl>O1CCCC1.O>[Cl:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:13]([F:16])([F:14])[F:15])[CH:3]=1
Reactant: CCOC(=O)Cn1nc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1nc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of ethyl 5-chloro-3-(trifluoromethyl)-1H-pyrazole-1-acetate (i.e. the product of Example 10, Step D or D1) (218 mg, 0.85 mmol) in tetrahydrofuran (1 mL) was treated with a 50 wt. % aqueous solution of sodium hydroxide (0.2 mL) in water (0.6 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was treated with concentrated aqueous hydrochloric acid to lower the pH to 1, and then extracted with ethyl acetate. The extract was dried (MgSO4) and concentrated under pressure to give 140 mg of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: C([Mg]Br)C.[O:5]([CH2:12][C:13]#[CH:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:16][C:17]#[C:18][CH2:19][C:20]#[CH:21].S(=O)(=O)(O)O>CCOCC.O1CCCC1>[O:5]([CH2:12][C:13]#[C:14][CH2:16][C:17]#[C:18][CH2:19][C:20]#[CH:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCC#CCBr
Reactant: C#CCOc1ccccc1
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CCC#CCC#CCOc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.81 ml (1.92 g, 14.4 mmol) of a 3N solution of ethylmagnesium bromide in ether was added dropwise under argon to a solution of 2 g (15.15 mmol) of 3-phenoxy-1-propyne (G. Pourcelot, et al., Bull. Soc. Chim., France, (1966), pp 3016-24, in 15 ml of anhydrous tetrahydrofuran. The rate of addition was adjusted to maintain the temperature at 0° C. Thereafter, the reaction mixture was stirred for 1 hour further at 0°-5° C. Then, 77 mg of cuprous cyanide was added. After stirring 20 minutes more, a solution of 1.13 g (7.22 mmol) of 1-bromo-2,5-hexadiyne in 10 ml of anhydrous tetrahydrofuran was added dropwise. The temperature was maintained at between 0°-5° C.The resulting mixture was stirred at room temperature for 3 additional hours, then poured into 60 ml of 1N sulfuric acid and ice, and the resulting solution extracted with ether (3×100 ml). The combined organic extracts were concentrated in vacuo to a small volume, and washed several times with EDTA and water, dried over sodium sulfate and evaporated. The crude material was purified by TLC using hexane:methylene chloride (80:20) as the eluant, and the product crystallized from methylene chloride-hexane, to yield 9-phenoxy-1,4,7-nonatriyne, as an oil.The product was stored in dry ice.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)(=O)=O)=CC=1.[C:20]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([N+:33]([O-:35])=[O:34])=[CH:28][CH:27]=2)([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:20]([C:24]1[N:25]([CH2:12][C@@H:13]2[CH2:17][O:16][C:15]([CH3:18])([CH3:19])[O:14]2)[C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([N+:33]([O-:35])=[O:34])=[CH:28][CH:27]=2)([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](Cn2c(C(C)(C)C)cc3cc([N+](=O)[O-])ccc32)O1
Temperature: 80 °C
Reaction time: 20 h
Yield: 65.7 %

Procedure:
To a stirred solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (1.58 g, 5.50 mmol) in anhydrous DMF (10 mL) under nitrogen gas was added 2-tert-butyl-5-nitro-1H-indole (1.00 g, 4.58 mmol) followed by Cs2CO3 (2.99 g, 9.16 mol). The mixture was stirred and heated at 80° C. under nitrogen gas. After 20 hours, 50% conversion was observed by LCMS. The reaction mixture was re-treated with Cs2CO3 (2.99 g, 9.16 mol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (1.58 g, 5.50 mmol) and heated at 80° C. for 24 hours. The reaction mixture was cooled to room temperature. The solids were filtered and washed with ethyl acetate and hexane (1:1). The layers were separated and the organic layer was washed with water (2×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/hexane=1.5/1) to give (R)-2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-nitro-1H-indole (1.0 g, 66%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=2.2 Hz, 1H), 8.08 (dd, J=2.2, 9.1 Hz, 1H), 7.49 (d, J=9.1 Hz, 1H), 6.00 (s, 1H), 4.52-4.45 (m, 3H), 4.12 (dd, J=6.0, 8.6 Hz, 1H), 3.78 (dd, J=6.0, 8.6 Hz, 1H), 1.53 (s, 3H), 1.51 (s, 9H), 1.33 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:18])[N:23]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(c1ccc(C#N)cc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.3 g, 1.0 mmol) was treated with 4-aminobenzonitrile (0.47 g, 4.0 mmol). Purification on silica gel, eluting with 3:1 hexane/acetone, afforded a solid that was converted to an HCl salt and recrystallized from EtOAc/ethanol to give 123 as a white solid (m.p. 250-251° C.).
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:18][CH2:17][C:8]2[N:9]=[C:10]([N:12]=CN(C)C)[S:11][C:7]=2[C:6]1=O)C.[N+]([O-])(O)=O.[C:24]1([NH:30][C:31]([NH2:33])=[NH:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[Na+]>COCCO>[C:24]1([NH:30][C:31]2[N:33]=[CH:4][C:5]3[CH2:18][CH2:17][C:8]4[N:9]=[C:10]([NH2:12])[S:11][C:7]=4[C:6]=3[N:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: CN(C)C=Nc1nc2c(s1)C(=O)C(=CN(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Nc1nc2c(s1)-c1nc(Nc3ccccc3)ncc1CC2
Temperature: 100 °C
Yield: 7.5 %

Procedure:
A mixture of N′-(6-dimethylaminomethylene-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-N,N-dimethyl-formamidine (200 mg, 0.72 mmol), N-phenyl-guanidine nitrate (142 mg, 0.72 mmol), NaOH (57 mg, 1.44 mmol) and 2-methoxyethanol (4 mL) was heated under microwave irradiation (300 W, 100° C.) for 30 min. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) afforded the title product as a dark yellow solid (16 mg, 8%): mp 240° C. (dec). 1H-NMR (DMSO-d6): δ 9.42 (s, 1H, NH), 8.23 (s, 1H, Py-H), 7.77 (d, 2H, J 7.7, Ph-H), 7.26 (t, 2H, J 7.7, Ph-H), 6.91 (t, 1H, J 7.2, Ph-H), 2.93 (s, 4H, CH2—CH2). MS (ESI+): m/z 296.07 (M+H)+.
Reaction SMILES: C[Si](C)(C)[I:3].[OH:6][CH2:7][C@@H:8]1[CH:23]=[C:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[NH:16][CH:15]=3)[N:10]([CH3:11])[CH2:9]1.O.N>CS(C)=O>[I:3][C:15]1[NH:16][C:17]2[C:24]3[C:14]=1[CH2:13][C@@H:12]1[C:22]([C:21]=3[CH:20]=[CH:19][CH:18]=2)=[CH:23][C@@H:8]([CH2:7][OH:6])[CH2:9][N:10]1[CH3:11]
Reactant: CN1C[C@H](CO)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: C[Si](C)(C)I
Agent: N
Solvent: O
Solvent: CS(C)=O
Product: CN1C[C@H](CO)C=C2c3cccc4[nH]c(I)c(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2.3 g of trimethyliodosilane are portionwise added to 20 ml of dimethylsulfoxide and the mixture is stirred at room temperature for 5 minutes. Then, a solution of 1 g of lysergol in 15 ml of dimethylsulfoxide is added, the reaction mixture is stirred for 15 minutes, then poured into water and made alkaline by adding aqueous ammonia up to a pH value of 8 to 9. The precipitate is filtered off, wash 3 times with 20 ml of water each and dried to give the title compound in a yield of 1.1 g (0.002913, mole, 74%).
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[C:8]([NH:10][C@@H:11]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1)[C@H:12]([OH:26])[CH2:13][NH:14][C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[CH:19]=2)[CH2:17][CH2:16]1)=[O:9])[CH:2]=[CH2:3].CC(O)=[O:41].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.CCOCC>[CH2:1]([S:4]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[C:8]([NH:10][C@@H:11]([CH2:27][C:28]1[CH:29]=[C:30]([F:35])[CH:31]=[C:32]([F:34])[CH:33]=1)[C@H:12]([OH:26])[CH2:13][NH:14][C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[CH:19]=2)[CH2:17][CH2:16]1)=[O:9])=[O:41])[CH:2]=[CH2:3]
Reactant: CC(=O)O
Reactant: C=CCSc1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNC2(c3cccc(CC)c3)CC2)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCS(=O)c1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNC2(c3cccc(CC)c3)CC2)c1
Reaction time: 0.5 h

Procedure:
3-(allylthio)-N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)benzamide (325 mg, 0.606 mmol) was dissolved in CH2Cl2 (10 mL) and AcOH (1 mL)and treated with mCPBA (104 mg, 0.606 mmol). The reaction mixture was stirred for 2.5 h, at which time more mCPBA (20 mg, 0.11 mmol) was added and stirring continued for 30 min. more. The organic layer was diluted with Et2O and washed with 15% sodium thiosulfite solution. The organic was washed with brine, then dried (MgSO4) and concentrated to give an oil, which was chromatographed with 25% to 50% EtOAc in hexanes to give the title compound. (LRMS (M+H) m/z 553.8)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[C:5]([CH:16]=[CH2:17])=[C:4]([NH:18][CH3:19])[N:3]=1.[CH2:20]([Mg]Br)[CH:21]=[CH2:22].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[CH2:22][CH:21]=[CH2:20])[C:5]([CH:16]=[CH2:17])=[C:4]([NH:18][CH3:19])[N:3]=1
Reactant: C=CC[Mg]Br
Reactant: C=Cc1c(NC)nc(Cl)nc1C(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC(O)(c1ccccc1)c1nc(Cl)nc(NC)c1C=C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-chloro-6-(methylamino)-5-vinylpyrimidin-4-yl)(phenyl)methanone (142 mg) in THF (2.6 mL) at rt was added allylmagnesium bromide (1.0 M solution in THF, 1.1 mL) dropwise, and the reaction mixture was stirred at rt for 30 min. The reaction was worked up with EtOAc/sat. NH4Cl, and the crude product was purified by prep. TLC eluting with 30% EtOAc/Hexanes to give the title compound as a colorless oil (133 mg). LC-MS (M−H2O+H)+=298.18.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[O:13][CH2:12][C@H:11]2[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:6]=[CH:7][C:8]=1[OH:9].[CH2:29](N(CC)CC)[CH3:30].C(O)(=O)C>O>[CH3:21][O:20][C:16]1[CH:15]=[C:14]2[C:19]([C@H:10]([C:5]3[CH:6]=[CH:7][C:8]4[O:9][C:29]([CH3:30])=[N:2][C:3]=4[CH:4]=3)[C@H:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[CH2:12][O:13]2)=[CH:18][CH:17]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(C)cc1)[C@H]2c1ccc(O)c(N)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)OC[C@@H](c1ccc(C)cc1)[C@H]2c1ccc2oc(C)nc2c1
Temperature: 25 °C

Procedure:
To a stirred mixture of (±)-cis4-(3-amino-4-hydroxyphenyl)-7-methoxy-3-(4-methylphenyl)-chromane hydrochloride (0.475 g, 1.19 mmol), triethylamine (0.173 ml, 1.25 mmol) and acetic acid (15 ml) was heated to gentle reflux for 18 h., giving a deep red coloured mixture. This was cooled to room temperature, poured into water (100 ml) and the product extracted into ethyl acetate (2×100 ml). The combined extracts were washed with water (6×50 ml), brine, dried over magnesium sulfate and evaporated to give a dark gum. This was purified by column chromatography on silica gel 60, with a 1:1 petrol/ethyl acetate eluent. This gave the product, on vacuum drying, as a stable pale pink coloured foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O.[NH:12]1[C:20](=[O:21])[C:18](=O)[C:16](=[O:17])[NH:15][C:13]1=[O:14]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[N:9]=[C:16]([OH:17])[C:18]([C:20]([NH:12][C:13]([NH2:15])=[O:14])=[O:21])=[N:10]2
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)NC(=O)c1nc2cc(Cl)c(Cl)cc2nc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4,5-dichloro-o-phenylenediamine (36.2 mmole) and alloxan monohydrate (36.2 mmole) in 10% aqueous acetic acid was stirred at room temperature for a period of 2 hours. Concentration of the reaction mixture gave N-(6,7-dichloro-2-hydroxy-3-quinoxalinoyl)urea which was added to 50% aqueous sulfuric acid and the mixture was heated at a temperature of 135° C. for a period of 3 hours. After cooling the precipitated material was collected by filtration, washed with water and then was slowly added to a 5% aqueous solution of sodium bicarbonate. The insoluble material was collected by filtration and was washed successively with water and ethanol to give 6,7-dichloro-2-hydroxyquinoxaline.