Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([F:28])[CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[S:33][CH:34]=1.CC(C)([O-])C.[K+]>COCCOC.O.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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[S:33][CH:34]=[C:30]([CH3:29])[CH:31]=4)=[CH:3][C:4]=3[F:28])(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: Cc1csc(B(O)O)c1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cc(C)cs2)cc1F
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-fluorobenzenesulfonamide (E103) (100 mg, 0.21 mmol) and (4-methyl-2-thienyl)boronic acid (60 mg, 0.42 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated in vacuo and purified using an SCX cartridge eluting with methanol followed by ammonia (2M in methanol) The appropriate fractions were combined and evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E110). MS (ES+) m/e 490 [M+H]+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][C:8]([C:18]1[CH:17]=[CH:16][C:15]2[O:11][CH2:12][CH2:13][C:14]=2[CH:19]=1)=[O:9]
Reactant: O=C(Cl)CCCl
Reactant: c1ccc2c(c1)CCO2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCCl)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.8 %

Procedure:
To a solution of AlCl3 (2.22 g, 1.0 eq) in 50 mL CH2Cl2 was added 3-chloropropanoyl chloride (2.54 g, 1.2 eq) dropwise. The mixture was stirred at rt for 10 min, then 2,3-dihydrobenzofuran (2.0 g, 1.0 eq) was added. After stirring at rt overnight, the mixture was quenched with cold water and then extracted with CH2Cl2. The extract was dried over Na2SO4, filtered, the filtrate was concentrated and purified by column chromatography on silica gel to give the desired product (1.5 g, 62%). 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.68 (t, J=8.8 Hz, 2H), 3.92 (t, J=6.8 Hz, 2H), 3.40 (t, J=8.8 Hz, 2H), 3.26 (t, J=6.8 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]([C:9]2[O:17][C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:18][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:11]=3[CH:10]=2)[C:7]([C:27]#[N:28])=[C:6]([CH3:29])[NH:5][C:4]=1[CH3:30])#[N:2].[C:31](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[C:27]([C:7]1[CH:8]([C:9]2[O:17][C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:18][C:19](=[O:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:11]=3[CH:10]=2)[C:3]([C:1]#[N:2])=[C:4]([CH3:30])[N:5]([CH3:31])[C:6]=1[CH3:29])#[N:28]
Reactant: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)C(C#N)=C(C)N1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)C(C#N)=C(C)N1C
Reaction time: 0.5 h

Procedure:
A solution of 100 mg (0.253 mmol) N-[2-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)furo-[3,2-c]pyridin-4-yl]benzamide (Example 4) in DMF (1.4 ml) was cooled to 0° C., and 99 mg (0.30 mmol) caesium carbonate were added at this temperature. After stirring for 30 min, 19 μl (0.30 mmol) methyl iodide were added dropwise at room temperature, and the mixture was stirred at rt overnight. After this, additional methyl iodide (20 μL) was added, and stirring at rt was continued for further 48 h. The reaction mixture was then filtered, and the filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA, isocratic 40:60 v/v) to give 5.6 mg (5% of th.) of the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH2:10]([C:13]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[NH:15][N:14]=1)[CH2:11][CH3:12]>>[N+:6]([C:17]1[C:13]([CH2:10][CH2:11][CH3:12])=[N:14][NH:15][C:16]=1[C:18]([OH:20])=[O:19])([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: CCCc1cc(C(=O)O)[nH]n1
Agent: O=S(=O)(O)O
Product: CCCc1n[nH]c(C(=O)O)c1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
Fuming sulfuric acid (17.8 ml) was added dropwise to stirred, ice-cooled fuming nitric acid (16.0 ml). The resulting solution was heated to 50° C. and 3-n-propyl-1H-pyrazole-5-carboxylic acid (16.4 g, 0.106 mol; Chem. Pharm. Bull., 1984, 32, 1568) added portionwise over 30 minutes whilst maintaining the reaction temperature below 60° C. The resulting solution was heated for 18 hours at 60° C., allowed to cool, then poured onto ice. The white precipitate was filtered, washed with water and dried by suction to yield the title compound as a white solid (15.4 g), m.p. 170-172° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:11])[C:9]#[N:10].[CH2:12](N)[CH2:13][NH2:14]>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:9]1[NH:14][CH2:13][CH2:12][N:10]=1)[CH3:11]
Reactant: CC(C#N)c1ccccc1I
Reactant: NCCN
Product: CC(C1=NCCN1)c1ccccc1I

Procedure:
rac-2-[1-(2-Iodo-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2-iodo-phenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): white solid; MS (EI): 301.0 ((M+H)+.).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1.[OH-].[Na+]>ClCCl>[CH2:5]([O:4][C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccccc1-c1ccccc1

Procedure:
A solution of 21.7 g (0.2 mol) of ethyl chloroformate in 20 ml of dichloromethane is slowly added dropwise to a mixture of 25 g of 2-aminobiphenyl (0.148 mol) and 79 g of pyridine (1 mol) in 150 ml of dichloromethane while stirring. After stirring for 12 hours, 100 ml of 10% strength NaOH are added. The aqueous phase is separated off and shaken with dichloromethane. After the dichloromethane extract has been dried over sodium sulfate, the solvent is removed under reduced pressure and the red oil which remains is worked up by column chromatography (silica gel 60, 0.043 . . . 0.060 mm, eluant: hexane/ethyl acetate=9:1). Yield: 31.7 g=89%.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20]I>C1COCC1>[CH3:20][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][C:11]1=[O:19]
Reactant: O=C1CC(c2ccccc2)c2ccccc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)CC(c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (1.2 eq., 0.537 g of 60% dispersion in mineral oil) in THF (50 mL) under N2 at 0° C. was added the product from Step A (1.0 eq., 2.50 g) in THF (50 mL) via cannula over a period of 5 minutes. The resulting pale yellow mixture was stirred at 0° C. for 10 minutes, then MeI (2.0 eq., 1.39 mL) was added. The opaque yellow mixture was allowed to slowly (ice bath not removed) warm to ambient temperature with stirring for 15 hours. 1M Aq. HCl (50 mL) and EtOAc (250 mL) were added and the phases partitioned. The organic phase was washed with dilute NaHCO3 (1×100 mL), brine (1×100 mL), then dried over MgSO4, filtered, concentrated, and the residue purified by flash chromatography eluting with CH2Cl2/EtOAc (19:1 gradient to 15:1) to provide 1-methyl-4-phenyl-3,4-dihydrocarbostyril.
Reaction SMILES: S(O[CH2:12][C@H:13]([C@@H:15]([CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)[OH:16])[OH:14])(C1C=CC(C)=CC=1)(=O)=O.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH2:29]([N:36]1[CH2:12][C@@H:13]([OH:14])[C@H:15]([OH:16])[CH2:17]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](O)COS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Yield: 45.8 %

Procedure:
To a 1,4-dioxane (20 mL) solution of 1,4-di-O-tosyl-D-threitol (9.15 g, 21.25 mmol), benzylamine (9.29 mL, 85.0 mmol) was added, and the mixture was heated to reflux under a nitrogen stream for 4 days while stirring. The reaction liquor was returned to room temperature, and then a saturated aqueous solution of sodium hydrogen carbonate (50 mL) was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography using silica gel [NH(basic)-silica gel 100 g, ethyl acetate to chloroform/methanol (10/1)], to obtain the title compound (1.88 g, 46%) as an oily matter.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20]CCCCCCCCCCO)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]#[C:42][C:43]#[C:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][OH:54]>>[Si:1]([O:18][CH2:19][CH2:20][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]#[C:42][C:43]#[C:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][OH:54])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCCCCCCCCCCCCO)(c1ccccc1)c1ccccc1
Reactant: OCCCCCCCCCC#CC#CCCCCCCCCCO
Product: CC(C)(C)[Si](OCCCCCCCCCC#CC#CCCCCCCCCCO)(c1ccccc1)c1ccccc1
Yield: 26 %

Procedure:
This substance was synthesized following the same procedure as for (1) and obtained in comparable yields using 9.40 g of (3) (28.1 mmol) as diol component. 4.25 g of 1-(tert-Butyldiphenylsilyl)oxy-10,12-Docosadiyne-22-ol (7.24 mmol) was obtained in a yield of 26%. 1H NMR (250.13 MHz): δ (ppm)=1.05 (s, 9H, tert-butyl), 1.26 (br, 20H, —CH2—CH2—CH2—CH2—CH2—), 1.53 (m, 8H, —O—CH2—CH2— and —C≡C—CH2—CH2—), 2.24 (t, 4H, 3J=6.8 Hz, —C≡C—CH2—), 3.64 (t, 2H, 3J=6.5 Hz, —Si—O—CH2), 3.65 (t, 2H, 3J=6.5 Hz, HO—CH2—), 7.40 (m, 6H, phenyl), 7.69 (m, 4H, phenyl). 13C NMR (75.48 MHz): δ (ppm)=25.69, 25.72, 26.9, 28.30, 28.34, 28.8, 29.00, 29.04, 29.30, 29.34, 29.4, 32.5, 32.8, 63.1, 64.0, 127.5, 129.5, 134.1, 135.6.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[C:11]([Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])#[CH:12].C(N(CC)CC)C>O1CCOCC1.[Cu]I.Cl[Pd]Cl>[CH:17]([Si:13]([C:11]#[C:12][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1)([CH:14]([CH3:16])[CH3:15])[CH:20]([CH3:21])[CH3:22])([CH3:19])[CH3:18]
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: Ic1ccn2ccnc2c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)[Si](C#Cc1ccn2ccnc2c1)(C(C)C)C(C)C
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
Combine 7-iodo-imidazo[1,2-a]pyridine (2.64 g, 10.82 mmol), ethynyl-triisopropyl-silane (3.61 mL, 16.23 mmol), copper (I) iodide (0.103 g, 0.541 mmol) and triethylamine (7.54 mL, 54.09 mmol) in 1,4-dioxane (50 mL). Bubble nitrogen through the mixture for five minutes. Add [1,1′-Bis(diphenyl-phosphino)ferrocene] dichloropalladium(II) (0.442 g, 0.541 mmol, 1:1 complex with dichloromethane). Attach a reflux condenser, and heat the mixture to 85° C., stir overnight (15 hours), and cool to room temperature. Filter the mixture through Celite® 521. Concentrate the solution in vacuo to a dark brown oil and use as is. MS(ES), m/z 299 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([CH2:14][O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
tert-Butyl (2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (500 mg; 2.3 mmol) in pyridine (20 mL) was cooled to 0° C. To this cooled solution was added a solution of p-toluenesulfonyl chloride (483 mg, 2.53 mmol) in pyridine (5 mL) over a period of 1 hour. The reaction mixture was allowed to slowly warm to ambient temperature and stirring was continued at ambient for 48 hours. The volatiles were removed in vacuo, and the residue was redissolved in toluene and concentrated again in vacuo. The crude material was triturated with ethyl acetate. This was further purified by chromatography on a 12 g silica gel column eluted with 5% ethyl acetate/hexanes for 3 minutes and then eluted with a gradient to 100% ethyl acetate over 20 minutes. The title compound was isolated as an oil (397 mg; 64% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82-7.69 (m, 2H), 7.48 (d, J=7.9 Hz, 2H), 4.92 (d, J=2.8 Hz, 1H), 4.23-3.82 (m, 4H), 3.12 (dd, J=25.5, 13.9 Hz, 2H), 2.42 (d, J=3.6 Hz, 3H), 1.87 (d, J=20.3 Hz, 2H), 1.35 (dd, J=23.0, 13.0 Hz, 9H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]=1[C:24]([OH:26])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O=S(Cl)[Cl:29]>>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]=1[C:24]([Cl:29])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cccc(-c2ccccc2)c1C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCOc1cccc(-c2ccccc2)c1C(=O)Cl

Procedure:
20 ml of SOCl2 was added to 4 g (1.13×10-2 mol) of decyloxybiphenylcarboxylic acid, and the mixture was heated at reflux for 3.5 hours. Excessive SOCl2 was evaporated to obtain decyloxybiphenylcarboxylic acid chloride.
Reaction SMILES: C([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]2)C1C=CC=CC=1>CO.[Pd].C(OCC)(=O)C>[OH:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]2
Reactant: COc1ccc2c(c1OCc1ccccc1)CCN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1O)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed a solution of tert-butyl 5-(benzyloxy)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (5.5 g, 14.89 mmol, 1.00 equiv) in MeOH (20 mL) and Pd/C (0.55 g). To the above H2 (enough, gas) was introduced in. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 3.6 g (87%) of tert-butyl 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylate as a light yellow solid. MS (ESI) m/z 224 ([M+H-t-butyl]+); Rf: 0.15 (starting material) and 0.32 (product) in ethyl acetate:petroleum ether=1:5.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][C@H:45]([C:48]([OH:50])=O)[CH2:46][OH:47])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:51]([O:55][C:56](=[O:63])[NH:57][CH2:58][CH:59]([OH:62])[CH2:60][NH2:61])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C>[CH2:34]([O:41][C:42](=[O:43])[NH:44][C@@H:45]([CH2:46][OH:47])[C:48]([NH:61][CH2:60][CH:59]([OH:62])[CH2:58][NH:57][C:56]([O:55][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:63])=[O:50])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(O)CN
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: CC(C)(C)OC(=O)NCC(O)CNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
362.8 mg (0.954 mmol) of HATU and 123.3 mg (0.954 mmol) of N,N-diisopropylethylamine are added to a solution of 207.5 mg (0.867 mmol) of N-[(benzyloxy)carbonyl]-L-serine in 10 ml of anhydrous DMF. After stirring at RT for 15 min, 165 mg (0.867 mmol) of tert-butyl(3-amino-2-hydroxypropyl)carbamate are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O.O.[Sn](Cl)Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(Br)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cccnc1Nc1cccc(Br)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Compound 1 (4.9 g, 16.6 mmol) was dissolved in ethanol (20 ml). Tin (II) Chloride dihydrate (7.5 g, 33.3 mmol) was added and the solution stirred at 70° C. for 4 hours to provide the title compound. The product was confirmed by LC-MS. Addition of excess triethylamine caused a solid to form. The solid was filtered and the solution evaporated to leave an off white solid. The solid as recrystallized from ethanol to leave the title compound (3.8 g, 86%). [M+H] calc'd for C11H10BrN3, 265; found 265.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][NH2:16])[N:8]=1>C(#N)C>[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][NH:16][C:7]([NH:8][CH3:9])=[N:6][C:5]#[N:4])[N:8]=1
Reactant: NCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: CC#N
Product: CNC(=NC#N)NCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 24 h

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-aminoethylthio)pyrimidine (0.25 g.), acetonitrile (5 ml.) and dimethyl (cyanoimido)dithiocarbonate (0.12 g.) was left at room temperature for 24 hours and then evaporated to dryness. The residue was dissolved in a 33% w/v solution of methylamine in ethanol, and the solution left at room temperature for 24 hours and then evaporated to dryness. The residue was recrystallised from ethanol to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[2-(2-cyano-3-methylguanidino)ethylthio]pyrimidine, m.p. 218°-221°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.[NH2-:13].[Na+]>CN(C)C1C=CC=CC=1>[NH2:13][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: COc1ccc2ccncc2c1
Reactant: [NH2-]
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: COc1ccc2ccnc(N)c2c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
A solution of 8.0 g of 7-methoxyisoquinoline in 45 ml of N,N-dimethylaniline was warmed at 60° C., and then 5.9 g of sodium amide was added. The reaction mixture was heated at 130° C. over a period of 2 hours, and stirred for further 1 hour under the same conditions. After being cooled, the reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel and recrystallized from benzene to give 5.7 g of the title compound as colorless flakes.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[C:8]([O:14]COC)=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:5]1[CH:6]=[C:7]([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)[C:8]([OH:14])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCOc1c(C(C)=O)cc(C(C)(C)C)cc1-c1ccc(C(F)(F)F)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(=O)c1cc(C(C)(C)C)cc(-c2ccc(C(F)(F)F)nc2)c1O
Temperature: 40 °C
Yield: 87.1 %

Procedure:
To a solution of 1-(5-(tert-butyl)-2-(methoxymethoxy)-3-(6-(trifluoromethyl)pyridin-3-yl)phenyl)ethan-1-one (440 mg, 1.15 mmol) in methanol (5 mL) was added para-toluenesulfonic acid (330 mg, 1.72 mmol) and the reaction mixture heated to 40° C. After 30 minutes the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered and purified by flash chromatography on silica eluting with 0-100% ethyl acetate in hexanes to yield 1-(5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)phenyl)ethan-1-one (338 mg, 87%) as a cream colored solid.
Reaction SMILES: [F:1][C:2]1([F:23])[C:20]2[C:5](=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][C:13]=4F)=[N:9][C:8]=3[CH:19]=2)[C:4]([F:22])([F:21])[O:3]1.[C:24](=O)([O-])[O-:25].[K+].[K+].CO>O>[F:23][C:2]1([F:1])[C:20]2[C:5](=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][C:13]=4[O:25][CH3:24])=[N:9][C:8]=3[CH:19]=2)[C:4]([F:21])([F:22])[O:3]1
Reactant: O=C([O-])[O-]
Reactant: Fc1cnccc1-c1nc2cc3c(cc2o1)C(F)(F)OC3(F)F
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cnccc1-c1nc2cc3c(cc2o1)C(F)(F)OC3(F)F
Temperature: 60 °C
Yield: 44.8 %

Procedure:
A mixture of 0.28 g of 5,5,7,7-tetrafluoro-2-(3-fluoropyridin-4-yl)-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole, 0.24 g of potassium carbonate and 3 ml of methanol was stirred while heating at 60° C. for 3.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.13 g of 5,5,7,7-tetrafluoro-2-(3-methoxypyridin-4-yl)-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole (hereinafter, referred to as “active compound 88”).