Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][CH:18]=[C:19]([C:22]([CH3:24])=O)[C:20]=2[OH:21])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].[NH:25]([C:27]([NH:29][C:30]1[S:34][C:33]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=1)=[S:28])[NH2:26]>Cl.O>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][CH:18]=[C:19]([C:22](=[N:26][NH:25][C:27]([NH:29][C:30]3[S:34][C:33]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=3)=[S:28])[CH3:24])[C:20]=2[OH:21])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(NC(=S)NN)s1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC(=S)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Dimethylformamide (1.3 ml) and conc. hydrochloric acid (1 drop) were added to 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (70 mg, 0.26 mmol) synthesized in Reference Synthetic Example 33 and methyl 5-hydrazinocarbonothioylamino-2-thiophenecarboxylate (59 mg, 0.26 mmol) synthesized in Reference Synthetic Example 57, and the mixture was stirred overnight at room temperature. Water was added, and the precipitated solid was filtered. The obtained solid was extracted with chloroform, dried over anhydrous sodium sulfate. The organic layer was concentrated, and purified with a silica gel column chromatography (chloroform/methanol=95/5) to obtain the desired product as a pale yellow solid (112 mg, yield 90%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:36])[C@@H:22]([NH2:35])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([O:31][CH2:32][CH2:33][CH3:34])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][F:41])[C@@H:16]1[CH3:44])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:36])[C@@H:22]([NH:35][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([O:31][CH2:32][CH2:33][CH3:34])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:42])([CH3:43])[CH2:40][F:41])[C@@H:16]1[CH3:44])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CCCOc1cc(F)cc(C[C@H](N)[C@H](O)[C@H]2CO[C@@H](OCC(C)(C)CF)[C@H](C)N2C(=O)OC(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)[C@H]2CO[C@@H](OCC(C)(C)CF)[C@H](C)N2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add acetic anhydride (43 μL, 0.44 mmol) to a solution of (2R,3S,5R)-5-[(1S,2S)-1-Hydroxy-2-amino-3-(3-propoxy-5-fluorophenyl)-propyl]-2-(3-fluoro-2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (231 mg, 0.44 mmol) and triethylamine (92 μL, 0.65 mmol) in dichloromethane (4.6 mL) and stir at room temperature for 30 minutes. Concentrate reaction mixture under a stream of nitrogen and subject residue to silica gel chromatography, eluting with 0-100% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38]Br)[CH:32]=2)[O:11][C@@H:10]1[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:49]1[C:57]2[C:52](=[CH:53][C:54](B3OC(C)(C)C(C)(C)O3)=[CH:55][CH:56]=2)[CH2:51][CH2:50]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:54]3[CH:53]=[C:52]4[C:57](=[CH:56][CH:55]=3)[CH2:49][CH2:50][CH2:51]4)[CH:32]=2)[O:11][C@@H:10]1[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)CCC2
Temperature: 100 °C
Yield: 69.4 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(3-(bromomethyl)-4-chlorophenyl)-tetrahydro-2H-pyran (106) (580 mg, 0.8 mmole) in toluene/EtOH (9 mL/8 mL) were added 2-(2,3-dihydro-1H-inden-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (121) (400 mg, 1.6 mmol), tetrakis(triphenylphosphin)palladium (180 mg, 0.16 mmol), and Cs2CO3 (2.1 g, 2.32 mmol) at room temperature. The mixture was stirred at 100° C. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the title compound (425 mg, 70%).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([CH3:20])[CH:16]=2)=[CH:5][CH:4]=1)#[N:2].OO.[OH-].[Na+].S(=O)(=O)(O)[OH:28]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([CH3:20])[CH:16]=2)=[CH:21][CH:22]=1)(=[O:28])[NH2:2]
Reactant: Cc1cc(CCCCCCCOc2ccc(C#N)cc2)on1
Reactant: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(CCCCCCCOc2ccc(C(N)=O)cc2)on1
Reaction time: 8 h

Procedure:
A mixture of 4.47 g (0.015 mole) of 5-[7-(4-cyanophenoxy)heptyl]-3-methylisoxazole (Example 5), 8 ml of 30% hydrogen peroxide, 8 ml of 95% ethanol and 0.6 ml of 6 N sodium hydroxide was stirred for ten minutes. There was then added 10 ml of 95% ethanol and the reaction mixture was warmed at 40°-50° C. for 4.5 hours, then held at room temperature overnight and treated with 5% sulfuric acid to neutral pH. The mixture was cooled and the solid product collected by filtration to give 4.4 g of 5-[7-(4-carbamylphenoxy)heptyl]-3-methylisoxazole, m.p. 153°-154° C., and recrystallized from methanol.
Reaction SMILES: [N+:1]([C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=O)[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[CH:5]=1)([O-])=[O:2].Cl.[NH2:21][OH:22].Cl>N1C=CC=CC=1>[N:21](=[C:8]1[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[CH2:5][C:4](=[N:1][OH:2])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]1=2)[OH:22]
Reactant: O=c1c2ccccc2cc([N+](=O)[O-])c2ccccc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1Cc2ccccc2C(=NO)c2ccccc21
Temperature: 0 °C

Procedure:
A mixture of 50.00 g of the product mixture from the stannous chloride reduction of 10-nitro-5H-dibenzo[a,d]cyclohepten-5-one and 62.61 g (0.901 mol) of hydroxylamine hydrochloride in 500 ml of pyridine was refluxed for 6 hr, poured into 3000 ml of ice water and 100 ml of conc. HCl, and extracted with CH2Cl2. The extracts were washed with brine, dried, treated with activated charcoal, filtered, and concentrated in vacuo to give a solid suspended in pyridine. The solid was removed by filtration and the pyridine treated as above to give a white solid. The solids were combined giving 44.09 g of 5,10-dioximino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as a white solid which had incorporated pyridine. The pyridine could not be removed by heating, high vacuum, or recrystallization: mp 220°-221°; NMR (DMSO-d6 /TMS) δ 11.62 (s, 1H, =NOH), 11.57 (s, 1H, =NOH), 7.50-7.00 (m, 8H, arom), and 3.97 (br s, 2H, benzylic); IR (CHCl3) 2.79, 3.34, 6.33, 6.99, 8.20, 8.34, 9.39, 9.74, 10.09, 10.79, 12.65 and 14.34μ.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.[C:23]1(OB(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=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>[CH3:22][O:21][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:11]=[C:10]2[CH2:12][CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]
Reactant: OB(O)Oc1ccccc1
Reactant: COc1ccc2nc(Cl)cc(CCNC(=O)C(F)(F)F)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2nc(-c3ccccc3)cc(CCNC(=O)C(F)(F)F)c2c1
Yield: 91713 %

Procedure:
A solution of N-[2-(2-chloro-6-methoxyquinolin-4-yl)ethyl]-2,2,2-trifluoroacetamide (0.5 g, 1.5 mmol), tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) and phenylboric acid (0.2 g, 1.65 mmol) in benzene (4.2 ml) was mixed with an aqueous solution (1.9 ml) of sodium carbonate (2 mol). This reaction mixture was heated under reflux in an atmosphere of argon for 64 hours. The reaction mixture was poured into water, and the organic layer was extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (ethyl acetate:hexane=4:6) to obtain the title compound (515 g, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: OCCCCCCCCCCCBr
Reactant: COc1cc(CC#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CC#N)ccc1OCCCCCCCCCCCO
Temperature: 80 °C
Reaction time: 48 h
Yield: 74.3 %

Procedure:
11.0 g (67 mmol) of [4-hydroxy-3-methoxy-phenyl]acetonitrile and 20.4 g (81 mmol) of 11-bromoundecan-1-ol were dissolved in 100 mL of N,N-dimethylformamide. 18.7 g (135 mmol) of potassium carbonate and 2.2.0 g (13 mmol) of potassium iodide were added and the suspension was heated to 80° C. After 48 h, the reaction mixture was cooled to room temperature and poured to icy water. The aqueous layer is extracted twice with ethyl acetate. Combined organic layers are washed with brine and evaporated to dryness. The crude is purified twice on column chromatography (SiO2, Heptane/ethyl acetate: 7/3) and dried overnight at 40° C. 16.6 g of {4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}acetonitrile are obtained as a yellow solid (74% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[O:37][CH:38]=[CH:39][CH:40]=2)[S:34][CH:35]=1.O>CN(C)C=O>[O:37]1[CH:38]=[CH:39][CH:40]=[C:36]1[C:33]1[S:34][CH:35]=[C:31]([CH2:30][O:3][C:4]2[CH:28]=[CH:27][C:7]([CH2:8][N:9]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]3)=[CH:6][CH:5]=2)[N:32]=1
Reactant: ClCc1csc(-c2ccco2)n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccco4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(2-furyl)thiazole (299 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-[2-(2-furyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (643 mg, yield: 84%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23]Br.O>CC(=O)CC>[Br:21][CH2:22][CH2:23][O:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1
Reactant: BrCCBr
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: BrCCOc1ccc2c(c1)[nH]c1ccccc12
Reaction time: 28 h

Procedure:
A mixture of 2-hydroxycarbazole (30 g; mfd. by Aldrich), potassium carbonate (113.1 g; mfd. by KANTO CHEMICAL) and 1,2-dibromoethane (211 mL; mfd. by TOKYO KASEI KOGYO) in 2-butanone (165 mL; mfd. by Wako Pure Chemical Industries) was stirred vigorously at a reflux temperature for 28 hours. The reaction solution was poured into water (1050 mL) all at once and stirred. The precipitated crystal obtained by filtration was washed with water (1 L) and 2-propanol (250 mL), and then dried under reduced pressure at room temperature to give the title compound (43.43 g) as a white solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[NH2:5][C:6]1[CH:13]=[C:12](F)[C:9]([C:10]#[N:11])=[CH:8][N:7]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[NH2:5][C:6]1[CH:13]=[C:12]([NH:4][CH:1]([CH3:3])[CH3:2])[C:9]([C:10]#[N:11])=[CH:8][N:7]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)Nc1cc(N)ncc1C#N
Temperature: 50 °C

Procedure:
A mixture of isopropylamine (1.83 ml, 21.3 mmol), 6-amino-4-fluoronicotinonitrile (intermediate 21, 972 mg, 7.09 mmol) and diisopropylethylamine (3.71 ml, 21.3 mmol) in DMA (17 ml) was heated at 50° C. in a septum sealed reaction vessel for 48 h. The reaction mixture was then cooled, evaporated and purified by normal phase chromatography using an 40 g RediSep® column, eluting with a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated. The residue was partitioned between DCM and 10% aqueous citric acid solution, the aqueous layer washed 2× with DCM, basified with NaHCO3, extracted with DCM (4×), the combined organic extracts from the basic extraction dried over Na2SO4 and evaporated to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 6.31 (s, br, 2H), 5.71 (d, br, 1H), 5.58 (s, 1H), 3.61-3.49 (m, 1H), 1.14 (d, 6H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([CH3:11])[N:5]=[C:4]([SH:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C.Br[CH2:26][CH2:27][CH2:28]Br>O>[OH:10][CH2:9][CH2:8][C:7]1[C:2](=[O:1])[N:3]2[C:4]([S:12][CH2:26][CH2:27][CH2:28]2)=[N:5][C:6]=1[CH3:11]
Reactant: Cc1nc(S)nc(O)c1CCO
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nc2n(c(=O)c1CCO)CCCS2
Temperature: 25 °C
Yield: 58 %

Procedure:
A mixture of 30 parts of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidineethanol, 25 parts of potassium carbonate, 270 parts of N,N-dimethylacetamide and 75 parts of water was stirred at room temperature and 36 parts of 1,3-dibromopropane were added at once: temperature rose to 50° C. The whole was stirred overnight at room temperature. The reaction mixture was evaporated and water was added to the residue. The solid product was washed with water and dried in vacuo at 100° C., yielding 21 parts (58%) of 3,4-dihydro-7-(2-hydroxyethyl)-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one; mp. 155° C. (intermediate 1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[NH:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[CH3:3].NC1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20]C=1O>C1COCC1>[CH3:25][O:24][C:22]1[CH:23]=[CH:3][C:2]2[O:4][C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:15])[F:14])[CH:7]=3)=[N:16][C:20]=2[CH:21]=1
Reactant: COc1ccc(O)c(N)c1
Reactant: CCOC(=N)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2oc(-c3cccc(C(F)(F)F)c3)nc2c1
Reaction time: 8 h

Procedure:
A solution of compound 13 and compound 12 (850 mg, 6.13 mmol) in THF (10 mL) was heated to reflux and allowed to stir overnight. The reaction mixture was allowed to cool and the THF evaporated (in vacuo). The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over MgSO4 and treated with activated carbon Norit A. The mixture was filtered through Celite 521, and evaporated (in vacuo) and the residue was purified using column chromatography (20% Ethyl acetatelhexanes) to afford compound 10 as a light yellow solid.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:9]=[CH:8][N:7]2[C:10](I)=[CH:11][N:12]=[C:6]2[CH:5]=1.[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][OH:14])=[CH:17][CH:18]=3)=[CH:11][N:12]=[C:6]2[CH:5]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Clc1ccn2c(I)cnc2c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCc1ccc(-c2cnc3cc(Cl)ccn23)cc1

Procedure:
Charge a 50 mL round bottom flask equipped with: a magnetic stirrer, temperature controlled heating mantle, N2 atmosphere, condenser, with 7-chloro-3-iodo-imidazo[1,2-a]pyridine (1.0 g, 3.6 mmol), 4-(hydroxymethyl)phenyl boronic acid (570 mg, 3.75 mmol), 2 M K2CO3 (7 mL), dimethoxy ethane DME (25 mL). Deoxygenate with a nitrogen purge and add Pd(TPP)4 (200 mg, 0.17 mmol 5 mol %) and heat the reaction to 65° C. for 48 hours. Cool the reaction and siphon off the lower aqueous phase (5 mL). Evaporate the reaction under vacuum at 42° C. to remove DME. Take up the residue in CH2Cl2 and wash with water (15 mL). Concentrate the CH2Cl2 and chromatograph giving an oil that solidified on standing to an ivory solid 670 mg (72%) MS (ES), m/z 259.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16](O)=[O:17])[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][OH:26])[CH:11]=1)#[N:2].[NH2:27][C@@H:28]([CH3:31])[CH2:29][OH:30].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[OH:30][CH2:29][C@@H:28]([NH:27][C:16]([C:14]1[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][OH:26])[CH:11]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[C:1]#[N:2])[CH:15]=1)=[O:17])[CH3:31]
Reactant: C[C@H](N)CO
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3ccccc3CO)c2)c(C#N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)CO)cc(-c3ccccc3CO)c2)c(C#N)c1
Temperature: 25 °C

Procedure:
A reaction vial was charged with 2-Cyano-2″-hydroxymethyl-4-methyl-[1,1′;3′,1″]terphenyl-5′-carboxylic acid (50.00 mg, 0.1456 mmol), (2S)-2-aminopropan-1-ol (13.12 mg, 0.1747 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (110.7 mg, 0.2912 mmol), N,N-diisopropylethylamine (0.06341 mL, 0.3640 mmol) and N,N-dimethylformamide (5.0 mL, 64 mmol) and the reaction stirred at room temperature over night. The reaction mixture was then purified by prep HPLC to get the compound as white solid.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>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>[O:24]1[CH:28]=[CH:27][C:26]([C:2]2[N:7]3[CH:8]=[N:9][N:10]=[C:6]3[C:5]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:4][CH:3]=2)=[CH:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3cnnc23)CC1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccoc3)n3cnnc23)CC1
Temperature: 100 °C
Yield: 97.3 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(5-bromo-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate (800 mg, 2.08 mmol), furan-3-ylboronic acid (349 mg, 3.12 mmol), Pd(PPh3)4 (240 mg, 0.312 mmol), Cs2CO3 (1.00 g, 3.12 mmol), 1,4-dioxane (11 mL) and water (4 mL). The resulting mixture was heated under N2 at 100° C. overnight. Work-up: the reaction mixture was filtered. The filter cake was washed with EtOAc (10 mL) and the filtrate was extracted with more EtOAc (10 mL×3). The combined organic solutions were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 2% methanol in dichloromethane, to afford 0.75 g (97%) of the product as a yellow solid. MS m/z: 371 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]2[S:6][C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=3)=[CH:8][C:4]=2[CH:3]=1.C(Cl)(Cl)[Cl:28]>>[Cl:28][C:8]1[C:4]2[CH:3]=[C:2]([CH3:1])[CH:26]=[CH:25][C:5]=2[S:6][C:7]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:11]([C:21]([F:22])([F:23])[F:24])[CH:10]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1ccc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2c1
Product: Cc1ccc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)c(Cl)c2c1
Yield: 56 %

Procedure:
To a solution of 5-methyl-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene (184 mg, 0.5 mmol) in CHCl3 (2.5 mL) is added SO2Cl2 (44 μL, 1.1 eq.). The mixture is heated to reflux overnight (about 14 hours). All the solvent is removed under reduced pressure. The residue is extracted with CH2Cl2 (50 mL), washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered, and concentrated to give an oil. The mixture is purified by column chromatography (EtOAc/Hexane, gradient) to give 112 mg of 3-chloro-5-methyl-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene in 56% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([NH2:12])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19].C(N(CC)CC)C>O1CCCC1>[CH3:27][O:26][C:22]1[CH:21]=[C:17]([CH:16]=[C:15]([O:14][CH3:13])[C:23]=1[O:24][CH3:25])[C:18]([NH:12][C:5]1[C:6](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:19]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COC(=O)c1cc(Cl)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a solution of 1.3 g of methyl 5-chloroanthranilate and 1.8 g of 3,4,5-trimethoxybenzoylchloride in 30 ml of tetrahydrofuran is added 1.5 g of triethylamine under cooling, and the mixture is stirred at room temperature for 2 hours and then heated under reflux for 1 hour. The reaction mixture is concentrated under reduced pressure and to the residue is added water. The precipitated crystals are collected by filtration and recrystallized from a mixture of chloroform and ether to obtain 1.4 g of methyl N-(3,4,5-trimethoxybenzoyl)-5-chloroanthranilate as colorless prisms.