Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[CH3:10][N:11]1[C:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:14]=2[CH:13]=[N:12]1.[CH:29]([S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][C:36]=1[CH3:44])(=[O:34])=[O:33])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:29]([S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([N:26]2[CH2:27][CH2:28][C:23]3([C:14]4[CH:13]=[N:12][N:11]([CH3:10])[C:15]=4[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[O:22]3)[CH2:24][CH2:25]2)=[O:40])=[CH:37][C:36]=1[CH3:44])(=[O:34])=[O:33])([CH3:31])[CH3:30]
Reactant: Cc1cc(C(=O)O)ccc1S(=O)(=O)C(C)C
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1S(=O)(=O)C(C)C
Temperature: 40 °C
Yield: 67.6 %

Procedure:
Triethylamine (152 μL, 1.1 mmol) was added to a mixture of 1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] dihydrochloride (108 mg, 0.33 mmol), 4-(isopropylsulfonyl)-3-methylbenzoic acid (80 mg, 0.33 mmol), HATU (126 mg, 0.33 mmol), and dichloromethane (2 mL) at 25° C. The mixture was heated at 40° C. for 3 h. The mixture was concentrated and the residue was purified by column chromatography (0-100% ethyl acetate/hexanes) to give (4-(isopropylsulfonyl)-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (107 mg, 65%) as a fluffy white solid. ESI-MS m/z calc. 479.6, found 480.3 (M+1)+. Retention time: 2.24 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:30]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(C(F)(F)F)c4)c3O2)cc1
Yield: 65.4 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-(trifluoromethyl)phenylboronic acid (0.372 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.383 g (65%) of (±)-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a white solid. mp 90-93° C.; Anal. calcd. for C23H19F3O4S: C, 61.6; H, 4.27. Found: C, 61.52; H, 4.21.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3ccccc3)C2=O)CC1
Yield: 66 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and benzyl bromide, to give the desired product as a white solid (66%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([Cl:13])=[N:8][N:7]=[C:6]2Cl)#[N:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:19][NH2:20].C(N(CC)CC)C>O1CCCC1>[Cl:13][C:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[C:6]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:16]([Cl:15])[CH:17]=2)=[N:7][N:8]=1
Reactant: N#Cc1ccc2c(Cl)nnc(Cl)c2c1
Reactant: COc1ccc(CN)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl

Procedure:
6-Cyano-1,4-dichlorophthalazine (66.2 g) prepared in Preparative Example 3 and 3-chloro-4-methoxybenzylamine (92 g) were suspended in 1200 ml of tetrahydrofuran, followed by the addition of 250 ml of triethylamine. The obtained mixture was heated under reflux for 6 hours.
Reaction SMILES: [CH2:1]([O:3][S:4]([CH2:7]P(OCC)(OCC)=O)(=[O:6])=[O:5])[CH3:2].C([Li])CCC.[Cl:21][C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2[CH:31]1[CH:35]2[O:36][C:37]([CH3:40])([CH3:39])[O:38][CH:34]2[CH:33]([CH:41]=O)[O:32]1>C1COCC1.CCCCCC>[Cl:21][C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2[C@H:31]1[C@@H:35]2[O:36][C:37]([CH3:40])([CH3:39])[O:38][C@@H:34]2[C@@H:33]([CH:41]=[CH:7][S:4]([O:3][CH2:1][CH3:2])(=[O:5])=[O:6])[O:32]1
Reactant: CC1(C)OC2C(C=O)OC(n3cnc4c(Cl)ncnc43)C2O1
Reactant: CCOP(=O)(CS(=O)(=O)OCC)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOS(=O)(=O)C=C[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of (diethoxy-phosphoryl)-methanesulfonic acid ethyl ester (7.991 g, 0.03070 mol) in THF (100 mL), at −78° C. under an atmosphere of nitrogen, was added dropwise 2.5M n-butyllithium in hexane (13 mL), and the solution was stirred for 30 minutes. Freshly prepared 6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]-dioxole-4-carbaldehyde (13.10 g, 0.03026 mol) in THF (100 mL) was added over 15 min at −78° C. The reaction was allowed to slowly warm to −10° C. over 4 hours with stirring. The reaction was quenched with water (400 mL) and 5M ammonium chloride in water (100 mL) and extracted with methylene chloride (600 mL). The organic phase was concentrated in vacuo and the residue was purified by flash chromatography (30 to 100% EtOAc:hexanes) to yield the product as a foam (10.5 g, 81%).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH:38]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25]>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Product: COC=C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 29.0 g of methoxymethyl-triphenylphosphonium-chloride in 200 ml of t-butyl methyl ether was treated with 9.7 g of potassium t-butylate at -10° C. within 3 minutes while gassing with argon in a sulphonation flask provided with a mechanical stirrer. The orange suspension was stirred at about 0° C. for 1 hour, then treated dropwise at -10° C. within 10 minutes with a solution of 12.0 g of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde in 90 ml of t-butyl methyl ether and stirred at 0° C. for a further 45 minutes. The mixture was subsequently partitioned three times in diethyl ether/water. The organic extracts were washed twice with water, dried over magnesium sulphate, filtered and evaporated. In order to separate triphenylphosphine oxide, the residue was dissolved in ethyl acetate and the solution was diluted with petroleum ether, filtered and evaporated. Chromatographic separation of the yellowish, crystalline residue (16.3 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 10.1 g (74%) of p-[trans-4-(2-methoxyvinyl)cyclohexyl]benzonitrile as white crystals.
Reaction SMILES: CN(C=O)C.[C:6]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)([CH3:9])([CH3:8])[CH3:7].Cl[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:6]([C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:16][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1Oc1cccc(C(C)(C)C)c1
Temperature: 60 °C
Yield: 89.2 %

Procedure:
A 50 ml two-necked round-bottomed flask equipped with a magnetic bar, a thermometer and a reflux condenser is charged with DMF (50 ml), 3-tert-butyl-phenol (1.5 g), 2-chloro-3-methyl-5-nitro-pyridine (1.73 g) and potassium carbonate (2.76 g). The reaction mixture is heated at 60° C. for 2 hours. After cooling the mixture to room temperature it is then poured into water (200 ml). The mixture is then extracted with ethylacetate (2×40 ml). The combined organic layers are dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification of this crude material by flash chromatography over silica gel with hexane/ethyl acetate 4:1 (v:v) gives 2.55 g of the compound as a yellow oil.
Reaction SMILES: S(O[CH2:12][C@H:13]1[O:17][C:16](=[O:18])[NH:15][CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[C-:19]#[N:20].[Na+]>CO.O>[C:19]([CH2:12][CH:13]1[O:17][C:16](=[O:18])[NH:15][CH2:14]1)#[N:20]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CNC(=O)O2)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CCC1CNC(=O)O1
Yield: 70 %

Procedure:
To a stirring solution of (S)-5-tosyloxymethyl-1,3-oxazolidine-2-one (0.54 g, 1.99 mmol) in MeOH-water (15-3 mL) was added NaCN (0.39 g, 8.00 mmol) at room temperature and then heated to reflux for 4 h. After completion of the reaction, solvent in the reaction mixture was completely evaporated and the residue was purified by column chromatography employing EtOAc-hexane (70:30) as eluent to afford pure 5-cyanomethyl-1,3-oxazolidine-2-one in 70% yield. [α]26D=+4.5 (c 1.0, MeOH); IR (Neat) 3349, 2918, 2839, 2243, 1710, 1255, 1051 cm1; 1HNMR (200 MHz, CD3OD) δ 2.57 (d, 2H, J=6.6 Hz), 3.20-3.55 (m, 2H), 4.00-4.18 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[S:14])[NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:16][C:17](=O)[CH3:18]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]2[S:14][CH:16]=[C:17]([CH3:18])[N:13]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C(N)=S)C1
Reactant: CC(=O)CCl
Solvent: CO
Product: Cc1csc(C2CN(C(=O)OC(C)(C)C)C2)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To 145 mg (0.67 mmol) 3-thiocarbamoyl-azetidine-1-carboxylic acid tert-butyl ester in 3 mL MeOH in a sealed tube was added 64 μL (0.8 mmol) chloroacetone, and the reaction was stirred at 90° C. for 3 hours. After evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 8:2 to 6:4).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[C:1]([C:4]1[O:5][C:6]2[C:12]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cccc2oc(C(C)=O)cc12
Product: COc1ccc(S(=O)(=O)Cl)c2oc(C(C)=O)cc12
Yield: 93 %

Procedure:
There was reacted 0.95 g (5 mmole) of 2-acetyl-4-methoxybenzofuran with chlorosulfonic acid as in Example 1, yielding 1.3 g of 2-acetyl-4-methoxy-7-chlorosulfonylbenzofuran (yield: 93%, MS (m/z): 288 (M+), 273, 253 and 189). The obtained chlorosulfonyl compound was reacted with glycine ethyl ester hydrochloride to give an ester compound (yield: 97%, MS (m/z): 354 (M+), 281, 252 and 188), which was then hydrolyzed to give 2-acetyl-4-methoxy-7-(N-carboxymethylsulfamoyl)benzofuran (yellow plates, yield: 84%). The physical constants are shown in Table 4.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24]>CCOCC>[F:27][C:26]([F:29])([F:28])[S:23]([O:11][C:8]1[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH:9]=1)(=[O:24])=[O:22]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(OC1=CCC2(CC1)OCCO2)C(F)(F)F
Temperature: -15 °C
Yield: 65 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-one (1.0 equiv) was dissolved in Ether (0.1M) and stirred at −15° C. then 1M NaHMDS (1.05 equiv.) was added and stirred for 70 min then Tf2O (1.05 equiv.) added and reaction allowed to slowly warm to rt. The mixture was stirred for 28 hr, washed with sat. aq. NaHCO3 and then water. Aqueous layers combined and extracted with ether. Organic layers combined, dried over MgSO4, filtered, and concentrated. The residue was purified by column (ethyl ether:hexanes=1:4) to give 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (65%). LC/MS (m/z): MH+=289.0, Rt=0.97. HPLC Rt=3.77.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:19][O:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24]>>[CH3:19][O:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:22]=1[C:23]([N:7]1[CH2:8][CH:4]2[CH:5]([CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3]2)[CH2:6]1)=[O:24]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: COc1ccc(C(=O)N2CC3CN(c4cnc5ccccc5n4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2,4-dimethoxybenzoic acid. MS (ESI): mass calculated for C23H24N4O3, 404.47; m/z found 405.3 [M+H]+.
Reaction SMILES: [C:1]([O:5]CC#C)(=[O:4])[CH:2]=[CH2:3].[CH:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1.C[SiH](C)Cl>>[CH:11]12[CH2:12][CH:13]([CH:9]=[CH:10]1)[CH2:3][CH:2]2[C:1]([OH:5])=[O:4]
Reactant: C#CCOC(=O)C=C
Reactant: C1=CCC=C1
Agent: C[SiH](C)Cl
Product: O=C(O)C1CC2C=CC1C2
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The propargyl ester of 2-norborn-5-ene carboxylic acid was prepared by Diels-Alder reaction of propargyl acrylate and cyclopentadiene at ambient temperature. Dimethylchlorosilane (56.4g) was added portionwise to 100 grams of this norbornene carboxylate ester and 0.16 g Karstedt catalyst under nitrogen at 70° C. After exotherming to 80° C., the mixture was stirred for 3 hours at 70° C., stripped under light vacuum and then distilled. The product, ##STR13## (84% purity by GC), distilled at 100°-105° C. at 0.07 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:24]2[CH2:25][CH2:26][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23]2)=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2oncc2C(=O)O)c1
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(-c2oncc2C(=O)N2CCC(c3ccccc3)C2)c1
Temperature: 25 °C

Procedure:
5-(3-methylphenyl)-isoxazole-4-carboxylic acid (46.9 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O2: 332.1525, found 332.1531.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:27]I>O1CCCC1>[CH:1]1([N:4]([CH3:27])[C:5]2[C:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(NC3CC3)nc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(cyclopropylamino)-2-phenylquinoxaline-6-carboxylate (182.4 mg, 0.56 mmol, 1.00 equiv, 98%) in tetrahydrofuran (17 mL). Sodium hydride (274.5 mg, 11.44 mmol, 20.00 equiv) was added. The resulting solution was stirred for 1 h at room temperature. This was followed by the dropwise addition of CH3I (809.4 mg, 5.70 mmol, 10.00 equiv) with stirring at 0° C. The resulting solution was allowed to react, with stirring, overnight at room temperature. The resulting mixture was concentrated under vacuum and diluted with 10 ml of water. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solid was collected by filtration and washed with water and methanol. This resulted in 66.5 mg (36%) of 3-(cyclopropyl(methyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:20]([C:29](O)=[O:30])=[C:19]([CH3:32])[NH:18][C:17]=2[CH3:33])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]1([CH2:40][CH2:41][CH2:42][NH2:43])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.Cl.Cl>CN(C)C1C=CN=CC=1.ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:17]([CH3:33])=[N:18][C:19]([CH3:32])=[C:20]([C:29](=[O:30])[NH:43][CH2:42][CH2:41][CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)=C(C)N1
Reactant: NCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cc1nc(C)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(-c2cccc(Cl)c2)c1C(=O)NCCCc1ccccc1

Procedure:
1.13 g (2.37 mmol) of 4-[5-carboxy-4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyl] piperazine-1-carboxylic acid-t-butyl ester, 0.51 ml (3.59 mmol) of 3-phenylpropylamine, 548 mg (2.86 mmol) of WSC hydrochloride and 21 mg (0.17 mmol) of 4-dimethylaminopyridine were stirred in 10 ml of dichloromethane at room temperature overnight. After adding 25 ml of water and 25 ml of 1 N hydrochloric acid, the reaction mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (chloroform/methanol=300/1) to obtain the title compound.
Reaction SMILES: [PH:1]([OH:3])[OH:2].[C:4]1([CH:10]([NH2:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OCC)C>C(O)C>[PH2:1](=[O:2])[OH:3].[C:11]1([CH:10]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH2:17])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OPO
Agent: NC(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: O=[PH2]O

Procedure:
To a solution of 8 g (121.2 mmol) of phosphonous acid in 30 ml of anhydrous ethanol, cooled to 0° C., are added dropwise 22.21 g (121.2 mmol) of diphenylmethylamine, while taking care to ensure that the temperature does not exceed 25° C. After addition, a white precipitate forms, to which 200 ml of diethyl ether are added. The precipitate is filtered off, rinsed with diethyl ether and then dried. 22.66 g of product are recovered (yield=98.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH2:11].CN(C)/[CH:18]=[N:19]/[N:20]=[CH:21]/N(C)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][N:11]1[CH:21]=[N:20][N:19]=[CH:18]1
Reactant: CCCCC(CN)c1ccc(Cl)cc1Cl
Reactant: CN(C)/C=N/N=C/N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCC(Cn1cnnc1)c1ccc(Cl)cc1Cl
Yield: 125.7 %

Procedure:
A mixture of 10 g (0.04 mole) of 2-(2,4-dichlorophenyl)hexyl amine, 5.7 g (0.04 mole) of N,N-dimethyl formamide azine and 0.5 g of p-toluene sulfonic acid in 100 ml of dry toluene is heated under reflux for 16 hours. The solvent is evaporated to give 15 g of a white solid which can be further purified by recrystallization from benzene to give 7.5 g of pure product.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][S:5]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:27](O)=[O:28])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH2:30][N:31]2[CH2:32][CH2:33][CH2:34][CH2:35]2)[C:27]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[S:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:14][CH2:15]2)=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(O)C(CN1CCCC1)c1ccc(Cl)cc1
Reactant: C[C@@H]1SCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1SCc2ncnc(N3CCN(C(=O)C(CN4CCCC4)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a solution of (S)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (1 g, 3.23 mmol) and 2-(4-chlorophenyl)-3-(pyrrolidin-1-yl)propanoic acid (2 g, 7.88 mmol) in DCM (40 mL) were added HBTU (1.5 g, 3.96 mmol) and triethylamine (2.75 mL, 19.8 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was dissolved in ethyl acetate (200 mL) and washed with brine (5×100 mL) and water (3×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate-DCM/MeOH (20:1) to give 2-(4-chlorophenyl)-1-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-(pyrrolidin-1-yl)propan-1-one (0.713 g, 46.7%). 1H NMR (CDCl3, 400 MHz) δ 8.47 (s, 1H), 7.38-7.28 (m, 4H), 4.75 (m, 1H), 4.54 (m, 1H), 4.17 (m, 2H), 3.88-3.25 (m, 14H), 2.12 (m, 4H), 1.43 (m, 3H). MS (APCI+) [M+H]+ 473.