Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:5][C:6]2[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=2)[CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:19]([CH3:22])=[N:20][N:21]=4)[C:13]=3[CH:12]=[C:11]2[C:23](O)=[O:24])[CH2:4][CH2:3][CH2:2]1.[CH:29]([N:32](CC)C(C)C)(C)[CH3:30].C(N)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:65]([OH:71])([C:67]([F:70])([F:69])[F:68])=[O:66]>CN1CCCC1=O.CC#N>[F:68][C:67]([F:70])([F:69])[C:65]([OH:71])=[O:66].[F:68][C:67]([F:70])([F:69])[C:65]([OH:71])=[O:66].[N:1]1([CH2:5][C:6]2[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=2)[CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:19]([CH3:22])=[N:20][N:21]=4)[C:13]=3[CH:12]=[C:11]2[C:23]([NH:32][CH2:29][CH3:30])=[O:24])[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cccc(CN4CCC4)c3)n12
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: CCNC(=O)c1cc2c(ccc3nnc(C)n32)n1Cc1cccc(CN2CCC2)c1

Procedure:
To a solution of 6-[3-(azetidin-1-ylmethyl)benzyl]-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.017 g, 0.045 mmol, from Step 7) in N-methylpyrrolidinone (1 mL) was added N,N-diisopropylethylamine (0.032 mL, 0.18 mmol) and ethylamine (0.010 g, 0.018 mmol, Aldrich), followed by the addition of HATU (0.022 g, 0.059 mmol). When the reaction was complete as determined by LCMS, the reaction was diluted with MeCN, and TFA was added to aid in solubility. The product was purified via preparative HPLC-MS (Waters SunFire C18, 5 μm 30×100 mm, (H2O, 0.1% TFA) MeOH, flow rate: 60 mL/min). Yield: (10 mg, 35%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:42]=[C:43]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:44][NH:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:50][CH:49]=1)=[O:47]>CN(C=O)C.O>[Cl:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:11]([Cl:10])[C:12]=1[C:13]([N:63]1[CH2:62][CH2:61][N:60]([C:43](=[O:42])[CH2:44][NH:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)=[O:47])[CH2:65][CH2:64]1)=[O:15]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2c(Cl)cccc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 16.8 %

Procedure:
DIPEA (159.8 mg, 0.21 mL, 1.2 mmol) was added to a stirred solution of 2,6-dichloro-benzoic acid (59 mg, 0.3 mmol) in DMF (3 mL). HOBT (45.9 mg, 0.34 mmol) and EDCI (130.4 mg, 0.68 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (120 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 25 mg (16.3% yield) of biphenyl-4-carboxylic acid {2-[4-(2,6-dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 86.98%. 1H NMR (CDCl3): δ 7.96-7.86 (d, 2H), 7.72-7.56 (dd, 4H), 7.5-7.34 (m, 6H), 7.32-7.2 (m, 2H), 4.4-4.24 (dd, 2H), 4.0-3.8 (bs, 2H), 3.8-3.6 (m, 3H), 3.6-3.5 (t, 1H), 3.4-3.24 (q, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:18][C:17](=O)[C:12]2[C:13]([CH3:16])=[CH:14][O:15][C:11]=2[CH2:10]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:18]/[C:17](=[N:24]\[NH:23][C:20]([NH2:22])=[NH:21])/[C:12]2[C:13]([CH3:16])=[CH:14][O:15][C:11]=2[CH2:10]1
Reactant: Cc1coc2c1C(=O)CC(c1c(Cl)cccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1c(Cl)cccc1Cl)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 119.6 %

Procedure:
To a mixture of 6-(2,6-dichlorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.42 g) and aminoguanidine hydrochloride (157 mg) were added ethanol (30 ml) and 6N hydrochloric acid (0.12 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2,6-dichlorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 44) (0.33 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[O-2].[Mg+2].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[CH3:25][C:26]1([CH3:66])[N:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46])[C:29](=[O:51])[N:28]([C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[C:54]([C:61]([F:64])([F:63])[F:62])[CH:53]=2)[C:27]1=[O:65]>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH3:25][C:26]1([CH3:66])[N:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][S:40]([CH2:41][CH2:42][CH2:43][C:44]([F:49])([F:50])[C:45]([F:48])([F:47])[F:46])=[N:5][C:3](=[O:4])[C:2]([F:7])([F:6])[F:1])[C:29](=[O:51])[N:28]([C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[C:54]([C:61]([F:63])([F:64])[F:62])[CH:53]=2)[C:27]1=[O:65]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: NC(=O)C(F)(F)F
Agent: [Rh+3]
Agent: CC(=O)[O-]
Agent: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCC/S(CCCC(F)(F)C(F)(F)F)=N/C(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(CCCC(F)(F)C(F)(F)F)=NC(=O)C(F)(F)F
Temperature: 23 °C

Procedure:
2,2,2-trifluoroacetamide (106 mg, 0.94 mmole), magnesium oxide (76 mg, 4 eq.), rhodium acetate in the dimer form (5.2 mg, 0.025 eq.) and iodobenzene diacetate (228 mg, 1.5 eq.) are added at 23° C. to a solution of Example 1 (300 mg, 0.48 mmole) in anhydrous CH2Cl2 (5 ml). Stirring is maintained for 6 hours at 23° C. then the reaction mixture is filtered under vacuum. The filtrate is poured into water (25 ml) and extracted with AcOEt (2×25 ml). The organic phases are combined and washed successively with water (25 ml) and salt water (25 ml). After drying over Na2SO4, the organic solution is filtered and concentrated under vacuum. The evaporation residue is purified on a silica column (eluent: Heptane/AcOEt:5/5 to 3/7). After collection and concentration of the pure fractions, the expected compound is obtained in the form of a colourless oil with a yield of 34% (77 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[Br:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35]([CH:39]=1)[C:36](O)=[O:37].[Cl-].[NH4+]>C(OCC)(=O)C.CN(C=O)C.O>[Br:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35]([CH:39]=1)[C:36]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:37]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Aniline (99 μl), WSC.HCl (209 mg), and HOBt.H2O (167 mg) were added to a DMF (5 ml) solution containing 5-bromonicotinic acid (200 mg), followed by stirring at room temperature for 3 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. Diisopropylether and hexane were added to the obtained residue, solid matter was collected by filtration, and a white solid of 5-bromo-N-phenylnicotinamide (268 mg) was thus obtained.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[N:11][CH2:12][C:13]3[N:14]([C:15]([CH2:18]Cl)=[N:16][N:17]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[I-].[K+].[CH2:29]([NH2:32])[CH:30]=[CH2:31]>O1CCCC1>[CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[N:11][CH2:12][C:13]3[N:14]([C:15]([CH2:18][NH:32][CH2:29][CH:30]=[CH2:31])=[N:16][N:17]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: C=CCN
Reactant: CCSc1cccc2c1C(c1cccc(Cl)c1)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNCc1nnc2n1-c1cccc(SCC)c1C(c1cccc(Cl)c1)=NC2

Procedure:
In the manner given in Example 31, 7-(ethylthio)-1-(chloromethyl)-6-(m-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4] benzodiazepine, potassium iodide and allylamine in tetrahydrofuran are reacted to give 7-(ethylthio)-1-[(allylamino)methyl]-6-(m-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.Cl.[CH2:16]([NH:23][CH2:24][CH2:25]Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O.C(Cl)Cl.CO>[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:25][CH2:24][NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: ClCCNCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CNCCOc2ccc(-n3ccnc3)cc2)cc1
Temperature: 25 °C

Procedure:
To a chilled suspension of 39.5 g (0.823 mol) 50% sodium hydride in 500 mL dimethylformamide add 37.32 g (0.233 mol) 4-(1H imidazol-1-yl)phenol. When the addition is complete, stir the reaction mixture at room temperature until gas evolution ceases. After this time, chill the reaction mixture below 0° C. and slowly add 60.22 g (0.292 mol) N-benzyl(2-chloro)ethylamine hydrochloride. When the addition is complete, heat the reaction mixture to 65° C. Follow the progress of the reaction by thin-layer chromatography on silica gel (methylene chloride:methanol) (9:1). At the completion of the reaction, add 20 mL water to the cooled mixture. Filter the slats and remove the solvents in vacuo to obtain an oil. Column chromatograph the oil on silica gel using methylene chloride+methanol (1+99→1+19) as eluent. Collect the appropriate fractions and remove the solvents to obtain the title compound as the free base. Dissolve the free base in excess methanolic HCl solution and remove the solvent in vacuo to provide the title compound.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[C:5]([C:7]1[CH:8]=[N:9]C=C[CH:12]=1)#[N:6]>>[C:8]([C:7]1[CH:5]=[N:6][C:1]([OH:4])=[CH:2][CH:12]=1)#[N:9]
Reactant: CC(=O)[O-]
Reactant: N#Cc1cccnc1
Product: N#Cc1ccc(O)nc1
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
To an Erlenmeyer flask equipped with navels was filled a nutrient solution containing 1 g of yeast extract, 1 g of glucose, 0.3 g of K2HPO4, 0.1 g of KH2PO4, 1 mg of FeSO4, 50 mg of MgSO4, 1 mg of MnSO4 and 100 ml of water, and the resultant mixture was sterilized at 120° C. for 20 minutes. After cooling to 30° C., the mixture was added with separately sterilized 1 mg of CuSO4 and 0.2 g of 3-cyanopyridine as an inducer. One of the microorganisms listed in Table 1 which was incubated on nutrient agar medium for 24 hours was inoculated into the above mixture with a platinum loop, and the mixture was incubated at 30° C. for 24 hours using a rotary shaker of 160 rpm. After 24 hours, the broth was recovered and centrifuged. The cells separated were suspended in and washed with 0.02 mol of an acetate buffer (pH 5.5) and centrifuged to give a resting cell. To a 100 ml reactor was added 20 ml of 1.0% 3-cyanopyridine (pH 5.5), and the mixture was heated at 30° C., and mixed with the resting cell obtained above. The resultant mixture was stirred sufficiently for 24 hours to give 3-cyano-6-hydroxypyridine. The product was identified by means of HPLC, IR and 1H-NMR. Table 1 shows the results.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:12]([NH2:15])([CH3:14])[CH3:13]>>[CH:12]([NH:15][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])([CH3:14])[CH3:13]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc(F)cc1F
Yield: 95.5 %

Procedure:
The title compound (0.3804 g; 95%) was prepared by the same method as that described in Example 1, using 2,4-difluorobenzoyl chloride (0.3532 g, 2.00 mmol) and isopropylamine (0.26 ml, 3.05 mmol).
Reaction SMILES: [NH2:1][C:2]1SC(CO)=N[N:6]=1.CSC(=NC#N)SC.[NH2:17][CH2:18][CH2:19][S:20][CH2:21][C:22]1[C:27]([Br:28])=[CH:26][CH:25]=[CH:24][N:23]=1.CN.Br.Br.NCCSC[C:38]1C(Br)=CC=[CH:40][N:39]=1>C(O)C>[C:2]([NH:6][C:40]([NH:17][CH2:18][CH2:19][S:20][CH2:21][C:22]1[C:27]([Br:28])=[CH:26][CH:25]=[CH:24][N:23]=1)=[N:39][CH3:38])#[N:1]
Reactant: NCCSCc1ncccc1Br
Reactant: Nc1nnc(CO)s1
Agent: Br
Agent: CN
Agent: CSC(=NC#N)SC
Solvent: CCO
Product: CN=C(NC#N)NCCSCc1ncccc1Br
Reaction time: 8 h

Procedure:
A solution sodium nitrite (2.28 g) in water (10 ml) was added dropwise to a stirred mixture of 3-amino-2-hydroxymethylpyridine (4.8 g) in aqueous hydrobromic acid (48%, 10 ml) and water (5 ml) at 0.5° C. This solution of the diazonium salt was added to a hot solution of cuprous bromide (2.5 g) in 60% hydromic acid and following cessation of nitrogen evolution the mixture was heated on the steam bath for 0.5 hours, diluted with water and saturated with hydrogen sulphide. Filtration, concentration to low bulk and extraction with chloroform yielded 3-bromo-2-hydroxymethylpyridine (4.8 g). This was dissolved in aqueous hydrobromic acid (48%, 50 ml), cysteamine hydrochloride (3.22 g) added and the solution obtained was heated under reflux for 6 hours. Concentration, followed by recrystalliation from aqueous ethanol afforded 2-((2-aminoethyl)thiomethyl)-3-bromopyridine dihydrobromide (6.1 g), m.p. 252°-254°. (Found: C, 23.7; H, 3.4; N, 6.7; S, 7.9; C8H11Br N2S.2HBr. requires: C, 23.5; H, 3.2; N, 6.9; S, 7.8). (ii) Sequential reaction of dimethylcyanodithioimidocarbonate with 2-((2-aminoethyl)thiomethyl)-3-bromopyridine) and excess methylamine at room temperature in ethanol, the methylamine being added after initial standing overnight and the solution then allowed to stand for a further four hours, followed by chromatographic purification on a column of silica gel with elution by ethyl acetate and final recrystallisation from ethyl acetate-petroleum ether gave N-cyano-N'-[2-((3-bromo-2-pyridyl)methylthio)ethyl]-N"-methylguanidine m.p. 114°-116°. (Found: C, 40.6; H, 4.4; N, 21.4; S, 9.8. C11H14Br N5S. requires: C, 40.3; H, 4.3; N, 21.3; S, 9.8).
Reaction SMILES: [CH2:1]([O:5][CH:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)[CH3:7])[CH:2]([CH3:4])[CH3:3].CO.O.[OH-].[Li+]>O1CCCC1>[CH2:1]([O:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1)[CH3:7])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(C(C)OCC(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)COC(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of methyl 4-(1-isobutoxyethyl)benzoate (180 mg, 0.76 mmol) in tetrahydrofuran:methanol:water=3:1:1 (4 mL) was added lithium hydroxide (100 mg, 2.4 mmol). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuum and quenched with aqueous 1N hydrochloric acid (5 mL). The residue was taken up with water (50 mL) and extracted with dichloromethane (50 mL). The combined extract was dried over sodium sulphate, evaporated and purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give the product 4-(1-isobutoxyethyl)benzoic acid (132 mg, 78%) as pale solid.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[N:6][CH:5]=[CH:4][N:3]=1.[I-].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([Zn+])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Cu]I.CC(N(C)C)=O>[F:1][C:2]1[C:7]([CH:20]2[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:18][CH2:19]2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1nccnc1I
Reactant: CC(C)(C)OC(=O)N1CCC([Zn+])CC1
Agent: [Cu]I
Agent: [Fe+2]
Agent: [I-]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2F)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
In an oven-dried flask were charged 2-fluoro-3-iodopyrazine (0.829 g, 3.70 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(ii) complex with dichloramethane (0.091 g, 0.111 mmol), copper(i) iodide (0.042 g, 0.222 mmol), and DMA (3 mL). The resulting mixture was degassed with alternating vacuum/nitrogen purges. The (1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide (1.951 g, 5.18 mmol) solution from previous step was filtered into the mixture. It was degassed one more time and then heated to 80° C. with stirring for 16 h. After cooling to RT, the reaction mixture was treated with methyl bert-butylether (13 ml) and 1 N NH4Cl (13 ml). The organic layer was partitioned between EtOAc and 1 N NH4Cl and the aqueous layer was back extracted with EtOAc (2×). The combined organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The crude material was chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 20% EtOAc in hexane, to provide tert-butyl 4-(3-fluoropyrazin-2-yl)piperidine-1-carboxylate as orange oil. MS (ESI, pos. ion) m/z: 226.0 (M-56).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@@H:12]1[CH2:14][O:13]1.[C:15]([O:19][C:20](=[O:28])[NH:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1)([CH3:18])([CH3:17])[CH3:16]>C(O)C>[C:15]([O:19][C:20](=[O:28])[NH:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:14][C@H:12]([OH:13])[C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC1CCCN1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCCC2CNC(=O)OC(C)(C)C)ccc2c1COC2=O

Procedure:
Six vials containing a solution of 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (325 mg, 1.67 mmol) in 12 mL ethanol added to tert-butyl(pyrrolidin-2-ylmethyl)carbamate (333 mg, 1.67 mmol) were prepared. The reaction mixtures were microwaved at 140° C. for 55 minutes. The solutions were combined and the solvents were removed in vacuo. The resulting residue was purified by HPLC to afford two diastereomers of tert-butyl({1-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]pyrrolidin-2-yl}methyl)carbamate:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:16])=[C:10]2[O:14][CH:13](O)[CH2:12][C:11]=12)=[O:5])[CH3:2].C(OC(C1C=CC(Cl)=C2OC(OC)CC=12)=O)C.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:16])=[C:10]2[O:14][CH:13]=[CH:12][C:11]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)c2c1CC(O)O2
Agent: CCOC(=O)c1ccc(Cl)c2c1CC(OC)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Cl)c2occc12
Reaction time: 5 h

Procedure:
A mixture of 7-chloro-2-hydroxy-2,3-dihydro-benzofuran-4-carboxylic acid ethyl ester and 7-chloro-2-methoxy-2,3-dihydro-benzofuran-4-carboxylic acid ethyl ester (3.36 g, see above) in toluene (20 mL) is added dropwise to a solution of PTSA (0.69 mmol) in toluene (14 mL) which is heated to reflux. Heating is continued for 5 h, an additional portion of PTSA (0.69 mmol) is added and the mixture is again heated to reflux for 150 min. The solvents are removed in vacuo and the residue is purified by flash chromatography (gradient: heptane to heptane/EtOAc 95/5) to give the desired product. 1H-NMR (CDCl3): δ=7.95 (d, J=8.3 Hz, 1H); 7.81 (s, 1H); 7.45 (s, 1H); 7.38 (d, J=8.0 Hz, 1H); 4.47 (q, J=7.0 Hz, 2H); 1.48 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1I)([CH3:4])([CH3:3])[CH3:2].[O:16]=[C:17]1[C@@H:21]([NH:22][S:23]([C:26]2[S:30][C:29]3[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:28]=3[CH:27]=2)(=[O:25])=[O:24])[CH2:20][CH2:19][N:18]1[CH2:36][C:37]#[CH:38].C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>CN(C=O)C.CCOC(C)=O.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)I>[C:1]([O:5][C:6]([N:7]1[C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:13]2[CH:38]=[C:37]1[CH2:36][N:18]1[CH2:19][CH2:20][C@H:21]([NH:22][S:23]([C:26]2[S:30][C:29]3[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:28]=3[CH:27]=2)(=[O:25])=[O:24])[C:17]1=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCN1CC[C@H](NS(=O)(=O)c2cc3ccc(Cl)cc3s2)C1=O
Reactant: CC(C)(C)OC(=O)Nc1cnccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1c(CN2CC[C@H](NS(=O)(=O)c3cc4ccc(Cl)cc4s3)C2=O)cc2ccncc21
Temperature: 100 °C
Yield: 49.1 %

Procedure:
A mixture of (4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (0.85 g, 2.65 mmol), 6-chlorobenzo[b]thiophene-2-sulfonic acid (2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-amide (0.98 g, 2.65 mmol), Pd(PPh3)2Cl2 (95 mg), copper iodide (18 mg) and triethylamine (1.45 mL) in 8 ml of DMF is heated at 100° C. for 1.5 hours. The reaction mixture is cooled to 50° C. and DBU is added. The resulting mixture is heated at 50° C. for 1.5 hours. After cooling, the crude mixture is diluted with EtOAc and washed with saturated NH4Cl solution, water and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 1% MeOH/CH2Cl2 to 4% MeOH/CH2Cl2 to afford the title compound (0.73 g, 1.3 mmol) as a tan solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:34][NH:35][C:36]([OH:37])=[C:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5=[N:34][NH:35][C:36]([OH:37])=[C:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]c(O)c3CC4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]c(O)c3CC4)cc2)CCC1
Reaction time: 0.01 h
Yield: 19.8 %

Procedure:
tert-butyl(1-(4-(3-hydroxy-8-phenyl-4,5-dihydro-2H-pyrazolo[3,4-f]quinolin-7-yl)phenyl)cyclobutyl)carbamate (19 mg, 0.037 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (3 mg, 17% yield). 1H-NMR (500 MHz, CD3OD) δ 8.05 (1H, s), 7.49 (2H, d), 7.44 (2H, d), 7.27-7.34 (3H, m), 7.20-7.27 (2H, m), 3.25 (2H, t), 2.87 (2H, t), 2.72-2.82 (2H, m), 2.54-2.65 (2H, m), 2.18-2.30 (1H, m), 1.90-2.03 (1H, m). LCMS (Method A) RT=3.40 min, M+H+=409.19.