Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22](=[O:23])[NH:21][C:20]3[C:15]2=[N:16][C:17]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[N:18][C:19]=3[C:24]([O:26]CC)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:36]C1C(C(OCC)=O)=NC(C2C=CC=C(O)C=2)=NC=1NC1CCN(C(OC(C)(C)C)=O)CC1>ClCCl>[OH:35][C:31]1[CH:30]=[C:29]([C:17]2[N:16]=[C:15]3[C:20]([NH:21][C:22](=[O:23])[N:14]3[CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[C:19]([C:24]([NH2:36])=[O:26])[N:18]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1nc(-c2cccc(O)c2)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1N
Reactant: CCOC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2C1CCNCC1
Yield: 19 %

Procedure:
Ethyl 9-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-6-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)-2-(3-hydroxyphenyl)pyrimidine-4-carboxylate (0.120 g, 0.260 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.425 g, 2.62 mmol) in dichloromethane (10 mL) were reacted according to General Procedure F and purified via biotage chromatography (0-70% EtOAc in hexanes) to afford the title compound (0.050 g, 19%). MS (ESI) m/z 484.3 [M+1]+.
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][N:8]([CH2:10][CH2:11][CH:12]1[CH2:18][N:17](CC2C=CC=CC=2)[C:16](=[O:26])[C:15]2[CH:27]=[CH:28][CH:29]=[N:30][C:14]=2[O:13]1)[CH3:9].[OH-].[Na+].CN(C)C=O>O>[CH3:9][N:8]([CH3:7])[CH2:10][CH2:11][CH:12]1[CH2:18][NH:17][C:16](=[O:26])[C:15]2[CH:27]=[CH:28][CH:29]=[N:30][C:14]=2[O:13]1
Reactant: CN(C)CCC1CN(Cc2ccccc2)C(=O)c2cccnc2O1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCC1CNC(=O)c2cccnc2O1
Reaction time: 0.33 h

Procedure:
A solution of 3.0 g (0.006 mole) of 2-[2-(dimethylamino ethyl]-2,3-dihydro-4-phenylmethylpyrido[3,2-f][1,4]oxazepin-5(4H)-one oxalate [1:1.5]-hemihydrate in about 50 ml of water was made basic with dilute aqueous sodium hydroxide solution and then extracted with three 50 ml portions of benzene. The combined benzene extract was dried over anhydrous sodium sulfate and concentrated on the rotary evaporator (steam bath/50 mm). The residue was dried further by azeotroping 2 times with about 50 ml of dry benzene, evaporating to dryness each time. The final residue was dissolved in 40 ml of liquid ammonia and small spheres of sodium were added with stirring to the solution until a blue color persisted for 20 minutes. (Addition time was about 1 hr). Three grams of ammonium chloride was added slowly and the ammonia was allowed to evaporate. The residue was suspended in chloroform and the mixture was filtered. The filtrate was concentrated and the residue chromatographed on preparative high pressure liquid chromatograph using a silica gel column and eluting with 75% ethyl acetate/25% dimethylformamide. The yield of product was 0.1 g (7%). The chemical ionization mass spectrophotometer gave a peak at 236 corresponding to a molecular weight of 235. The 1H NMR spectrum of the subject compound was obtained in CDCl3 containing 1% tetramethylsilane (TMS) and is consistent with the proposed structure and dimethylformamide (DMF) and mineral oil as minor impurities. The chemical shifts, multiplicities, and assignments are given below:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([OH:22])=O)=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:43][C:44]1([CH3:56])[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH3:56][C:44]1([NH:43][C:20]([C:19]2[C:13]3[C:14](=[N:15][CH:16]=[C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:12]=3)[NH:17][CH:18]=2)=[O:22])[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45]1
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)n[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(C)CCN(C(=O)OC(C)(C)C)C5)c4n3)n[nH]c2c1
Reaction time: 16 h
Yield: 47 %

Procedure:
To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), EDCI (123 mg, 0.64 mmol), DMAP (110 mg, 0.90 mmol) and DIEA (131 mg, 1.02 mmol) in 6 mL of DMF was added tert-butyl 3-amino-3-methylpyrrolidine-1-carboxylate (100 mg, 0.54 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, extracted with ethyl acetate (150 mL). The organic phase was evaporated at 40° C. under reduced pressure and the residue was triturated with petroleum ether then decanted and dried to give crude tert-butyl 3-methyl-3-(2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)pyrrolidine-1-carboxylate (76 mg, 47.0%) as a yellow solid. MS: (M+H)+=476.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[S:8][C:7]=2[CH:31]=1.C[N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([NH2:33])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[S:8][C:7]=2[CH:31]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)O)cc2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(N)=O)cc2)cc1
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
To a 30 mL vial, (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (98 mg, 0.23 mmol) was dissolved in DMF (2 mL). The vial was charged with HATU (129 mg, 0.34 mmol) and DIEA (0.119 mL, 0.68 mmol) and the mixture was stirred for 10 min. A color change from pale orange to a dark orange was observed. To the solution was added NH4Cl (24.24 mg, 0.45 mmol) and the reaction mixture was stirred for 30 min at room temperature. The reaction was quenched with sat. aq. NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated to afford the crude product. The crude material was purified by column chromatography (SiO2, 1-10% MeOH/DCM) to afford (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (77 mg, 0.18 mmol, 79% yield) as an off white solid. 1H NMR (400 MHz, CD3OD) δ ppm=8.00 (s, 4H), 7.59-7.70 (m, 2H), 7.45-7.55 (m, 2H), 7.42 (d, J=2.02 Hz, 1H), 7.24 (d, J=8.59 Hz, 1H), 6.84-7.02 (m, 4H), 6.52 (d, J=15.66 Hz, 1H), 3.88 (s, 2H), 3.79 (s, 3H). LC/MS (m/z, MH+): 432.3.
Reaction SMILES: [H-].[Na+].Cl.Cl[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:17](=[O:25])[C:16]2=[CH:26][S:27][CH:28]=[C:15]12>CN(C)C=O>[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([CH2:5][CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:17](=[O:25])[C:16]2=[CH:26][S:27][CH:28]=[C:15]12
Reactant: ClCCN1CCCCC1
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2cscc2C(=O)N(CCN2CCCCC2)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.31 g. of 55% sodium hydride-mineral oil dispersion and 0.65 g. of N-(2-chloroethyl)piperidine hydrochloride in 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.40 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The dried chloroform extracts are concentrated to an oil which is purified by preparative thin layer chromatography (tlc) on silica gel with 10:1 benzene:methanol as eluent. The oil obtained is crystallized from hexane to give white crystals, m.p. 84°-88° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:20][CH:11](SCC2C=CC=CC=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([N:35]1[C:40](=[O:41])[C:39]([CH3:42])=[CH:38][N:37]([Si](C)(C)C)[C:36]1=[O:47])(C)(C)C>C(=O)([O-])[O-].[Cd+2].C1(C)C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[S:20][C@@H:11]([N:37]2[CH:38]=[C:39]([CH3:42])[C:40](=[O:41])[NH:35][C:36]2=[O:47])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([Si](C)(C)C)c(=O)n([Si](C)(C)C)c1=O
Reactant: c1ccc(COC[C@H]2SC(SCc3ccccc3)C[C@@H]2OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cd+2]
Solvent: Cc1ccccc1
Product: Cc1cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)S2)c(=O)[nH]c1=O
Reaction time: 0.5 h

Procedure:
A suspension of benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-D-erythro-pentofuranoside (22.5 g, 51.6 mmol), bis TMS-thymine (46 g, 170 mmol), mercuric bromide (20.5 g, 56.7 mmol), cadmium carbonate (29.3 g, 170 mmol) and dry toluene (1 L) was boiled under reflux, with stiring, for 24 hours. The hot mixture was then filtered and the solids were washed with toluene. The filtrate was successively washed with potassium iodide solution (30%) and water and then evaporated. The residue was taken up in 4:1 methanol-water, stirred for 30 minutes, the suspension filtered and the filtrate evaporated. The residue was applied to a silica gel column (hexane-ethyl acetate (1:1)) and combination of the appropriate fractions gave the title product as a clear colourless syrup. 1H NMR indicated the ratio of α- to β- anomers to be 2.8:1. Further column chromatography gave more of the separated anomers. The first compound to be eluted from the column was 3',5'-di-O-benzyl-4'-thio-thymidine as a colourless syrup. This could be crystallised from methanol to give colourless crystals m.p. 140°-142° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[S:9][C:10]([C:12]([O:14]C(C)(C)C)=[O:13])=[CH:11][C:7]=2[CH:6]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[S:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2sc(C(=O)OC(C)(C)C)cc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2sc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of benzo[b]thiophene-2,5-dicarboxylic acid 2-tert-butyl ester 5-methyl ester (3.018 g, 10.32 mmol) and TFA (20 mL) in CH2Cl2 (50 mL) was allowed to stir at rt for four days. The reaction mixture was concentrated and dried under high vacuum to give benzo[b]thiophene-2,5-dicarboxylic acid 5-methyl ester as a pale solid. MS (EI): cal'd 237.0 (MH+), exp 237.1 (MH+).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[CH:11]=1)#[N:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:29][C:30]1[CH:31]=[C:32]([C:37]2[N:41]=[C:40]([CH:42]3[CH2:45][N:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43]3)[O:39][N:38]=2)[CH:33]=[CH:34][C:35]=1[CH3:36]>ClCCl.N1C=CC=CC=1>[C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([NH:29][C:30]3[CH:31]=[C:32]([C:37]4[N:41]=[C:40]([CH:42]5[CH2:45][N:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43]5)[O:39][N:38]=4)[CH:33]=[CH:34][C:35]=3[CH3:36])=[O:17])=[CH:13][N:14]=2)[CH:11]=1)#[N:2]
Reactant: N#CCCCc1ccc2ncc(C(=O)O)n2c1
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(CCCC#N)cn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 6-(3-cyanopropyl)imidazo[1,2-a]pyridine-3-carboxylic acid (25) (50 mg, 0.218 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (20 μL, 0.240 mmol). Then, a drop of anhydrous DMF was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated and the crude solid was dried under vacuum. To a mixture of the acid chloride and methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (31 mg, 0.109 mmol) cooled to ° C. under Argon was added anhydrous pyridine (2 mL). The reaction was stirred to room temperature under Argon for 20 minutes. The solvent was concentrated. The crude product methyl 3-(3-(3-(6-(3-cyanopropyl)imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F59) was purified by silica chromatography. 1H NMR (400 MHz, d6-DMSO) δ 10.13 (s, 1H), 9.38-9.36 (m, 1H), 8.66 (s, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.86-7.82 (m, 2H), 7.63-7.60 (m, 1H), 7.51 (d, J=8.0 Hz, 1H), 4.39-4.34 (m, 2H), 4.31-4.24 (m, 1H), 4.21-4.18 (m, 2H), 3.59 (s, 3H), 2.81-2.77 (m, 2H), 2.60-2.52 (m, 2H), 2.38 (s, 3H), 1.97-1.90 (m 2H). MS m/z 500.52 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]1([CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl.CCCCCC>[C:11]1([CH:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:18][NH:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CNCC(c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a stirring solution of 4-methoxybenzylamine (1.4 g, 0.010 mole) and 2,2-diphenylacetaldehyde (2.0 g, 0.010 mole) in dichloromethane (50 mL) was added sodium triacetoxyborohydride (2.38 g, 0.011 mole) and acetic acid (2.0 mL). The reaction mixture was stirred overnight. The reaction mixture was concentrated and the residue was dissolved in EtOAc. The EtOAc solution was washed with saturated aqueous NaHCO3. The organic extracts were dried over Na2SO4, filtered, and concentrated. The crude mixture was subjected to column chromatography over silica gel (silica gel 60, EM Science) using 30% EtOAc: Hexane as eluent to afford 1.75 g (54% yield) of the title compound as a yellow oil. MS (ESI) 318.0 (M+H+).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:41]2[NH:42][N:43]=[CH:44][CH:45]=2)=[CH:11][C:12]([CH2:39][CH3:40])=[C:13]([CH:38]=1)[O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:20]([CH2:35][CH2:36][CH3:37])=[C:21]([CH:32]=[CH:33][CH:34]=1)[O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26])C1C=CC=CC=1.B(F)(F)F.CCOCC>C(S)C.C(OCC)C.O>[CH2:39]([C:12]1[CH:11]=[C:10]([C:41]2[NH:42][N:43]=[CH:44][CH:45]=2)[C:9]([OH:8])=[CH:38][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:20]([CH2:35][CH2:36][CH3:37])=[C:21]([CH:32]=[CH:33][CH:34]=1)[O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26])[CH3:40]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3ccn[nH]3)cc2CC)cccc1Oc1ccccc1C(=O)O
Agent: FB(F)F
Solvent: CCS
Solvent: CCOCC
Solvent: O
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccn[nH]3)cc2CC)cccc1Oc1ccccc1C(=O)O
Reaction time: 1 h
Yield: 23.7 %

Procedure:
A solution of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(2H-pyrazol-3-yl)phenoxy]propoxy}-2-propylphenoxy)benzoic acid (300 mg, 0.490 mmol) in ethanethiol (2.5 mL) was treated with boron trifluoride etherate (2 mL) at room temperature for 3 h, at which time an additional portion of boron trifluoride etherate (1 mL) was added and stirring resumed for an additional 1 h. The mixture was diluted with diethyl ether and water. The organic layer was separated, washed with water, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate/85% hexane to 60% ethyl acetate/40% hexane) of the residue provided 60 mg (24%) of the title compound as a white solid. 1H NM (CDCl3) δ 8.23 (d, J=8Hz, 1H), 7.61 (s, 1H), 7.42 (t, J=7 Hz, 1H), 7.30 (s, 1H), 7.19 (d, J=8 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 6.69 (d, J=8 Hz, 1H), 6.61 (s, 1H), 6.60 (d, J=8 Hz, 1H), 6.54 (s, 1H), 4.20 (m, 4H), 2.58 (m, 4H), 2.33 (quintet, J=6 Hz, 2H), 1.48 (hextet, J=8 Hz, 2H), 1.17 (t, J=8 Hz, 3H), 0.86 (t, J=7 Hz, 3H); TOF MS ES+ exact mass calculated for C30H33N2O6 (p+1): m/z=517.2339. Found: 517.2334. IR (CHCl3, cm−1) 2965, 1738, 1454. Anal. Calcd for C30H32N2O6: C, 69.75; H, 6.24; N, 5.42. Found: C, 69.73; H, 6.33; N, 5.25.
Reaction SMILES: C[N:2]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.CCOCC>[CH2:26]([O:25][C:23]([N:2]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:24])[CH3:27]
Reactant: CN1Cc2ccccc2C(Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)N1Cc2ccccc2C(Oc2ccc([N+](=O)[O-])cc2)C1

Procedure:
A mixture of 2-methyl-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline of Example 23 (6.0 g, 0.021 mole), ethyl chloroformate (2.9 g, 0.026 mole) and potassium carbonate (10 g) in benzene (100 ml) is refluxed for four hours. The reaction mixture is diluted with ether, washed with water, dilute HCl, again with water, then dried (saturated NaCl, anhydrous MgSO4). An analytical sample is twice recrystallized from hexanes/acetone (10:1) to yield 2-ethoxycarbonyl-4-(p-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline, m.p. 118°-119° C.
Reaction SMILES: [CH2:1]([O:3][C:4](OCC)(OCC)[CH3:5])[CH3:2].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13]>C(OC(=O)C)(=O)C>[C:12](/[C:14](=[C:1](\[O:3][CH2:4][CH3:5])/[CH3:2])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13]
Reactant: CCOC(C)(OCC)OCC
Reactant: CCOC(=O)CC#N
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)/C(C#N)=C(\C)OCC
Temperature: 95 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
A mixture of 1,1,1-triethoxyethane (25 g, 154.11 mmol, 1.00 equiv), ethyl 2-cyanoacetate (15 g, 132.61 mmol, 0.86 equiv) in acetic anhydride (100 mL) was stirred at 95° C. for 8 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. The solid was collected by filtration to give 4.4 g (16%) of (E)-ethyl 2-cyano-3-ethoxybut-2-enoate as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 4.31-4.19 (m, 4H), 2.61 (s, 3H), 1.46 (t, J=6.3 Hz, 3H), 1.32 (t, J=6.3 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.31 min, m/z=184.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:4](=[O:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.FC(F)(F)C(O)=O.[I:30]N1C(=O)CCC1=O.[Al]>O.C(Cl)Cl>[I:30][C:7]1[N:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[C:4](=[O:12])[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)[C:2]=1[CH3:1]
Reactant: COC(=O)c1ncc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: O=C1CCC(=O)N1I
Agent: [Al]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 5 h
Yield: 46 %

Procedure:
Methyl 5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (described in the synthesis of SM2, 1.5 g, 4.8 mmol), dry DCM (7.0 mL), trifluoroacetic acid (3.0 mL) and N-iodosuccinimide (1.0 g, 4.5 mmol) were mixed and stirred at RT in the dark (flask covered with aluminum foil). After 5 h, water (5 mL) was added and the mixture was concentrated by rotary evaporation. Water (3 mL) was added once more and the mixture was concentrated as described above. The resulting mixture was diluted with acetonitrile to a total volume of 50 mL. Purification by preparative HPLC with acetonitrile-water as eluent (neutral eluent) gave 0.905 g (46% yield) of the title compound as a yellow crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:22])[C:17]#[C:18][CH2:19][CH2:20][CH3:21].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:22][CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH3:21])[N:3]=[CH:4][N:5]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Reactant: CCCC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 89.5 %

Procedure:
In 9 ml of N,N-dimethylformamide were dissolved 217 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 141 mg of 2-hexyn-1-ol, to which 58 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 7 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 247 mg of 4-(2,3-difluorophenyl)-6-(2-hexynyloxy)pyrimidine (the present compound (118)).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[P:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]2[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=2[O:10]1>>[CH:19]1[C:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[P:9]([N:7]([P:9]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[C:12]4[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=4[O:10]3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[O:10][C:11]=2[CH:22]=[CH:21][CH:20]=1
Reactant: ClP1Oc2ccccc2-c2ccccc21
Reactant: NC1CCCCC1
Product: c1ccc2c(c1)OP(N(C1CCCCC1)P1Oc3ccccc3-c3ccccc31)c1ccccc1-2

Procedure:
By using the molar equivalent of cyclohexylamine and two molar equivalents of 6-chloro-dibenz[c,e][1,2]oxaphosphorine, under otherwise the same conditions as those described in Example 1, there is obtained N,N-bis-(dibenz[c,e][1,2]oxaphosphorin-6-yl)-N-cyclohexylamine having a melting point of 191° C. (Compound III).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FS([C:21]([F:26])([F:25])C(O)=O)(=O)=O.C([O-])(O)=[O:28].[Na+]>CC#N.CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:10](=[O:28])[N:11]([CH:21]([F:26])[F:25])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: Clc1ncc(Br)cc1OCc1ccccc1
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=c1c(OCc2ccccc2)cc(Br)cn1C(F)F
Temperature: 50 °C
Yield: 34.4 %

Procedure:
3-(Benzyloxy)-5-bromo-2-chloropyridine (100 mg, 0.335 mmol), 2-(fluorosulfonyl)difluoroacetic acid (179 mg, 1.005 mmol), and NaHCO3 (30 mg, 0.357 mmol) were combined in CH3CN (2 mL) then heated to 50° C. After heating overnight the mixture was cooled to RT and diluted with EtOAc. The resulting mixture was filtered through a pad of Celite® and concentrated. Flash column (Biotage-SNAP-10 g, 0-10% EtOAc/hexanes) gave the title compound (38 mg, 34%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.69 (t, J=60.06 Hz, 1 H); 7.42-7.35 (m, 5 H); 7.22 (d, J=2.2 Hz, 1 H); 6.68 (d, J=2.3 Hz, 1 H); 5.10 (s, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH:36]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)=[O:37]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([CH:36]=[O:37])[CH:43]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc(Cn2c(C(=O)OC)c(OS(=O)(=O)C(F)(F)F)c3cc(Cl)ccc3c2=O)cc1
Product: COC(=O)c1ccc(Cn2c(C(=O)OC)c(-c3cccc(C=O)c3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 6-chloro-2-(4-methoxycarbonylbenzyl)-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester and 3-formylphenylboronic acid.