Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[C:21]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[CH2:36][CH2:35]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2cccc3ccccc23)CC1
Yield: 74 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(1-naphthyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:19]([OH:21])=O)[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18].CCN(C(C)C)C(C)C.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:19]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:21])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18]
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
N-propylphosphonic acid anhydride, cyclic trimer (50 wt % solution in EtAc) (8.57 ml, 14.68 mmol) was added at room temperature in one portion to a stirred solution of 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (2 g, 5.65 mmol), DIPEA (4.9 mL, 28.2 mmol) and morpholine (0.543 mL, 6.2 mmol) in DCM (14 mL). The mixture was stirred at room temperature for 1 h then water (1 mL) was then added. The reaction mixture was stirred for 15 mins and extracted with DCM. The combined organic layers were washed with water; the organic layer was washed with brine, dried over magnesium sulfate and concentrated to afford 8-bromo-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one (1.90 g, 79%) as a beige solid. Mass Spectrum: m/z [M+H]+=423.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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.O>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:21])([F:20])[F:9])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)c1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 71.6 %

Procedure:
A mixture of 2,4-dichloro-pyrimidine (4.0 g, 27 mmol), 4-trifluoromethyl phenyl boronic acid (5.1 g, 27 mmol), tetrakis(triphenylphosphine)palladium(0) (1.5 g, 1.3 mmol), potassium phosphate (11 g, 54 mmol), 1,2-dimethoxyethane (50 mL) and water (10 mL) was heated to 80° C. under a blanket of nitrogen in a sealed tube. After 5 h, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified directly by FCC to afford a white solid (5.0 g, 72%). MS (ESI): mass calcd. for C11H6ClF3N2, 258.0; m/z found, 259.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.74 (d, J=5.2, 1H), 8.23 (d, J=8.1, 2H), 7.80 (d, J=8.2, 2H), 7.71 (d, J=5.2, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([CH3:8])=[N:6][CH:7]=1>C(O)(=O)C.O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ncc(Br)cc1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-bromo-2-methyl-3-nitro-pyridine (stage 75.1.5, 765 mg, 3.53 mmol) in acetic acid (7 ml) and water (1.75 ml) was added in three portions iron powder (591 mg, 10.6 mmol). The reaction mixture was stirred for 2.5 h at rt then quenched with 20 ml of 10 M aqueous NaOH, 20 g ice and 20 ml EtOAc before being filtered over Celite. The solid was washed with EtOAc and the filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give the title compound as a gray solid. (HPLC: tR 1.52 min (Method A); M+H=187, 189 MS-ES).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.F[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][N:7]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:30])[F:29])[CH:20]=2)[CH:2]([CH3:1])[CH2:3]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1CN(C(=O)OCc2ccccc2)CCN1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(C(=O)OCc2ccccc2)CCN1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A 1.01 g portion of benzyl 3-methylpiperazine-1-carboxylate synthesized in Reference Example 10, 814 mg of 4-fluoro-2-trifluoromethylbenzonitrile and 2.38 g of potassium carbonate were added to 20 ml of DMF and stirred at 100° C. for 20 hours. This was mixed with water, extracted with ethyl acetate and dried, and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography to obtain 440 mg of the title compound from ethyl acetate-hexane (3:1, v/v) eluate.
Reaction SMILES: C1(S([CH2:10][C:11](=O)[C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([CH3:19])[CH:13]=2)(=O)=O)C=CC=CC=1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+].[CH2:46]([NH2:49])[CH2:47][NH2:48].[OH-].[K+]>ClCCl.O.C(O)C>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[CH:10]=[N:49][CH:46]=[CH:47][N:48]=2)=[CH:13][C:14]=1[CH3:19]
Reactant: Cc1cc(C(=O)CS(=O)(=O)c2ccccc2)ccc1Br
Reactant: NCCN
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cc1cc(-c2cnccn2)ccc1Br
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
A stirred solution of (4-bromo-3-methylbenzoyl)methyl phenyl sulphone (D42, 1.5 g, 0.0044 mole) in dichloromethane (30 ml) at 0° C. under argon was treated with trifluoroacetic acid (0.70 ml, 0.005 mole) followed by trifluoroacetic anhydride (0.77 ml, 0.010 mole). After 30 minutes the solution was concentrated in vacuo, and the residue treated with a solution of sodium hydrogen carbonate (1.47 g, 0.017 mole) in water (30 ml), followed by ethanol (50 ml) and dichloromethane (50 ml). After 30 minutes, the two phase system was treated with ethylenediamine (0.33 ml, 0.005 mole) and stirred well at room temp. for 18 h, then the dichloromethane layer was separated, dried and concentrated in vacuo. The residue was dissolved in ethanol (30 ml) treated with potassium hydroxide (0.28 g, 0.005 mole) and heated under reflux for 6 h, then concentrated under vacuum and the residue treated with water (30 ml) and extracted with dichloromethane (2×50 ml). The combined extract was dried (Na2 SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 25-40% ether/60-80 petrol to afford the title compound as a yellow solid (300 mg, 27%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[C:11]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=O)=[CH:4][CH:3]=1.C1COCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)[C@H]1C[C@@H]1c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CCN(CC)C[C@H]1C[C@@H]1c1ccc(Br)cc1

Procedure:
Following the general procedure, reaction of 6c (3.55 g assayed, 12.0 mmol) with 1 M BH3 in THF (42.0 mL, 42.0 mmol) afforded 7c in an assay yield of 2.98 g (10.6 mmol, 88% assay yield, 99% peak area). A sample was concentrated in vacuo to an oil to provide the standard.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7](Br)([CH3:9])[CH3:8].[C:11]([O:20]C)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14].[OH-].[Na+]>C(O)C.CN(C)C=O>[CH:7]([O:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[C:11]([OH:20])=[O:19])([CH3:9])[CH3:8]
Reactant: CC(C)Br
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.00 g (36.2 mmol) of potassium carbonate and 3.27 g (26.6 mmol) of isopropyl bromide were added to a mixture of 2.00 g (13.2 mmol) of methyl salicylate and 10 ml of dimethylformamide, and they were stirred at room temperature overnight and then at 70° C. for 4 hours. 12.0 ml (36 mmol) of 3 M aqueous sodium hydroxide solution and 6.0 ml of ethanol were added to the reaction mixture, and they were stirred at 80° C. for 6 hours and then concentrated under reduced pressure. Water was added thereto. After washing with ethyl acetate, the aqueous layer was neutralized with hydrochloric acid. After the extraction with ethyl acetate, the extract was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].C[O-].[Na+].CO.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:30](=O)[CH2:31][CH2:32][CH3:33])[C:26](OC)=[O:27])=[CH:20][CH:19]=1)#[N:11]>CO.O1CCOCC1>[O:27]=[C:26]1[NH:4][CH:2]=[N:3][C:30]([CH2:31][CH2:32][CH3:33])=[C:25]1[CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12]([C:10]#[N:11])=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:23][CH:22]=1
Reactant: N=CN
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CCCc1nc[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.7 %

Procedure:
To an ice-cooled mixture of formamidine hydrochloride (3.73 g) and methanol (25 mL) was added dropwise 28% sodium methoxide-methanol solution (13.7 mL), and a mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (5.90 g), 1,4-dioxane (18 mL) and methanol (25 mL) was added dropwise. The mixture was stirred at room temperature for 12 hr. The solvent of the reaction mixture was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and the diluted solution was washed with 0.1 M aqueous hydrochloric acid solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude crystals. The crude crystals were washed with diisopropyl ether to give the title compound as a colorless solid (3.40 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([CH3:15])=[N:9]1.[CH:16]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[CH:16]1([CH:13]([C:11]2[C:10]([CH3:15])=[N:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:12]=2)[OH:14])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1nn(-c2ccccc2Cl)cc1C=O
Solvent: C1CCOC1
Product: Cc1nn(-c2ccccc2Cl)cc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a solution (5 mL) of 1-(2-chlorophenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (0.27 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (2.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.29 g, 79%) as a pale-yellow oil.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[S:7]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:28])([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C@@H:12]([CH2:29][C:30]([OH:32])=O)[CH2:11]1)(=[O:9])=[O:8].Cl.[CH3:34][NH:35][O:36][CH3:37].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O.O>[CH3:37][O:36][N:35]([CH3:34])[C:30](=[O:32])[CH2:29][C@H:12]1[CH2:11][N:10]([S:7]([C:3]2[S:2][CH:6]=[CH:5][CH:4]=2)(=[O:8])=[O:9])[CH2:15][CH2:14][N:13]1[C:16]1[CH:17]=[CH:18][C:19]([C:22]([OH:28])([CH3:27])[C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=1
Reactant: CNOC
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CC(=O)O)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CON(C)C(=O)C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
A solution of ((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetic acid hydrochloride (1.55 g, 3.01 mmol), N,O-dimethylhydroxylamine hydrochloride (0.323 g, 3.31 mmol, Sigma-Aldrich, St. Louis, Mo.), and Hünig's base (1.05 mL, 6.02 mmol) in DMF (20 mL) was stirred at 0° C. To this mixture was added HATU (1.26 g, 3.31 mmol). The reaction was stirred for 3 h at room temperature and then diluted with EtOAc (30 mL) and water (20 mL). The organic layer was separated and then washed with water (2×20 mL) and brine (20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (80 g silica gel, 0 to 100% EtOAc in hexanes) to give N-methoxy-N-methyl-2-((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetamide (1.48 g) as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([O-:23])(=[O:22])=[O:21])[CH:8]=2)[N:3]=1.[Na+:24].[Na+]>C1COS(=O)(=O)CC1>[CH3:1][C:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=[O:16])=[O:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([O-:23])(=[O:21])=[O:22])[CH:8]=2)[N+:3]=1[CH2:11][CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16].[Na+:24].[Na+:24]
Reactant: CC1=Nc2ccc(S(=O)(=O)[O-])cc2C1(C)CCCCS(=O)(=O)[O-]
Agent: O=S1(=O)CCCCO1
Agent: [Na+]
Product: CC1=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)CCCCS(=O)(=O)[O-]
Temperature: 150 °C
Yield: 217.1 %

Procedure:
Disodium 2,3-dimethyl-3-(4-sulphonatobutyl)-3H-indole-5-sulphonate (1.0 g) and 1,4-butanesultone (10 ml) were mixed and heated under nitrogen at 150° C. for 52 hrs to give a dark purple slurry. After cooling, the mixture was triturated with ethyl acetate: the solid portion was collected by filtration, washed with ethyl acetate and diethyl ether, then dried under high vacuum over phosphorus pentoxide to give the title product (1.45 g), which was used directly without purification.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.N1CCCC1.[CH2:17]([OH:20])[C:18]#[CH:19]>[Cu]I.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-].[NH4+]>[NH2:11][C:6]1[C:5]2=[CH:4][CH:3]=[C:2]([C:19]#[C:18][CH2:17][OH:20])[N:10]2[N:9]=[CH:8][N:7]=1
Reactant: C#CCO
Reactant: Nc1ncnn2c(Br)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCNC1
Product: Nc1ncnn2c(C#CCO)ccc12
Temperature: 85 °C

Procedure:
7-Bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (1.0 g, 4.69 mmol), copper(I) iodide (89 mg, 0.47 mmol, 0.1 eq.) and tetrakis(triphenylphosphine)palladium(0) (542 mg, 0.47 mmol, 0.1 eq.) were charged into a microwave reactor vial and evacuated for 1 h. The vessel was then vented with argon, pyrrolidine (15 mL) and 2-propyn-1-ol (2.63 g, 47 mmol, 10 eq.) were added, and the vessel was crimp-capped and heated to 85° C. for 120 min in a single-mode microwave device. After cooling, the reaction mixture was poured into 120 mL of concentrated aqueous ammonium chloride solution which was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and evaporated, and the residue was purified by flash chromatography (Biotage silica column, ethyl acetate). The resulting product (222 mg) appeared pure by LC-MS (method 6) and was used for further transformations.
Reaction SMILES: N[C@H](C(O)=O)CC1C=CC(O)=CC=1.O=C([C@H:17]([CH2:19][C:20]1[CH:27]=[C:25]([OH:26])[C:23]([OH:24])=[CH:22][CH:21]=1)[NH2:18])O.C1C2C(=CC(C(C=2)=O)=O)NC1C(O)=O.C1C(O)=C2NC(C(O)=O)=C(C3SC4=CC(CC(N)C(O)=O)=CC(=O)C4=NC=3)SC2=CC=1CC(N)C(O)=O.CC1C(=O)C(=O)C2C3C4C(=C(C)C(C(C=4C4=CNC=1C=24)=O)=O)NC=3>>[OH:26][C:25]1[CH:27]=[C:20]2[C:21](=[CH:22][C:23]=1[OH:24])[NH:18][CH:17]=[CH:19]2
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: Cc1c(=O)c(=O)c2c3c[nH]c4c(C)c(=O)c(=O)c(c5c[nH]c1c52)c43
Agent: NC(Cc1cc(O)c2c(c1)SC(c1cnc3c(=O)cc(CC(N)C(=O)O)cc-3s1)=C(C(=O)O)N2)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: Oc1cc2cc[nH]c2cc1O

Procedure:
As reported, for example, in Prota, Progress in the Chemist of Melanins and Related Metabolites, Med. Res. Reviews, 8:525-56 (1988), melanins are naturally occurring pigments present in hair and skin. In humans biosynthesis takes place in tyrosinase containing melanocytes. The tyrosinase enzyme catalyzes the hydroxylation of tyrosine to dopa and its subsequent oxidation to dopachrome. Once formed, dopachrome undergoes a series of complex reactions in the formation of eumelanins and phaeomelanins. Melanins provide black and deep brown pigments, and are formed by oxidative polymerization of 5,6-dihydroxyindole derived biogenetically during the melanogenesis. On the other hand, phaeomelanins provide yellow to reddish brown pigmentation to hair, and are formed by oxidative polymerization of cystein-S-yl-dopas via 1,4-benzothiazine intermediates.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:9][S:10][C:11](SC)=[N:12][C:13]#[N:14]>N1C=CC=CC=1>[CH3:9][S:10][C:11](=[N:12][C:13]#[N:14])[NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1ccncc1N
Reactant: CSC(=NC#N)SC
Solvent: c1ccncc1
Product: CSC(=NC#N)Nc1cnccc1N
Temperature: 25 °C
Reaction time: 96 h
Yield: 58 %

Procedure:
3,4-Diaminopyridine (4 g, 36.6 mmol) was suspended in anhydrous pyridine (100 ml), and S,S'-dimethyl N-cyanodithioiminocarbonate (8.0 g, 55.0 mmol) was added thereto. The mixture was stirred at room temperature for 4 days. The resulting powder was collected from the reaction mixture by filtration, and washed with ether (100 ml) to obtain crude crystals. The crystals were purified by recrystallization from methanol-ether to obtain 1.91 of the intended product as a white powder (yield: 58%). On the other hand, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, eluent: chloroform:methanol=4:1 (v/v)) to obtain 2.8 g of the intended product (total yield: 95%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:17])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)OC(C)(C)C)CC1=O
Reaction time: 0.17 h
Yield: 56 %

Procedure:
To a solution of 3-oxopiperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.50 mmol) in DMF (20 mL) cooled on an ice-bath was added sodium hydride (120 mg, 3.00 mmol, 60% dispersion in mineral oil) and the resulting mixture stirred for 10 min. Methyl iodide (233 μL, 532 mg, 3.75 mmol) was added and the resulting mixture stirred at room temperature for 18 h. The reaction mixture was quenched with H2O and extracted with EtOAc. The combined organics were dried (Na2SO4) and concentrated in vacuo affording 4-Methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester as a yellow oil (300 mg, 56%). 1H NMR (CDCl3, 300 MHz): δ 4.08 (s, 2H); 3.65 (t, J=5.4 Hz, 2H); 3.35 (t, J=5.4 Hz, 2H); 3.00 (s, 3H); 1.47 (s, 9H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:19])[CH2:6][CH:7]1[CH:14]2[CH2:15][CH:10]3[CH2:11][C:12]([O:17][CH3:18])([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2>CO>[CH3:18][O:17][C:12]12[CH2:16][CH:8]3[CH2:9][CH:10]([CH2:15][CH:14]([CH:7]3[CH2:6][C:5]([OH:19])=[O:4])[CH2:13]1)[CH2:11]2
Reactant: COC(=O)CC1C2CC3CC1CC(OC)(C3)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC12CC3CC(C1)C(CC(=O)O)C(C3)C2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Aqueous 2.5 N sodium hydroxide solution 0.13 ml was added to methanol 2 ml solution of 5-methoxy-2-adamantyl acetic acid methyl ester 50.0 mg obtained in referential example 9 and stirred at room temperature for 7 hours. Reaction mixture was concentrated in vacuo. Saturated sodium bicarbonate solution was added to the residue and washed with ether. Aqueous layer was adjused to pH 1 by adding 12 N hydrochloric acid, and extracted with ethyl acetate, then dried by adding anhydrous sodium sulfate. After removal of the drying agent, the filtrate was concentrated in vacuo to obtain the product as a mixture of stereoisomer. (a mixture of stereoisomer 1:1 measured by gas chromatography)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[N:9]=[C:23]([C@@H:19]3[CH2:20][CH2:21][CH2:22][N:18]3[C:16]([O:15][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:17])[NH:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(F)c(Br)cc2[nH]1
Reaction time: 16 h
Yield: 76.2 %

Procedure:
To a solution of 4-bromo-5-fluorobenzene-1,2-diamine (1.7 g, 8.4 mmol) in DMSO (42 mL) was added (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.8 g, 8.4 mmol) followed by HATU (3.5 g, 9.3 mmol) and N,N-diisopropyl-N-ethylamine (3.7 mL, 21.1 mmol), and the solution was stirred for 16 hours. The reaction mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4), filtered and concentrated. Acetic acid (40 mL) was added, and the mixture was stirred at 60° C. for 4 hours. Then, the reaction mixture was cooled and concentrated. The residue was azeotroped 2 times with toluene to give crude product which was purified by flash chromatography (0-50% EtOAc/hexane) to give the title compound (2.5 g, 6.4 mmol, 77%).