Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[N:12]=[C:11]([C:13]3[O:21][C:20]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[CH:14]=3)[O:10][N:9]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[C:25]([N+]([O-])=O)=[N:26][CH:27]=[CH:28][CH:29]=1.CC(O)=O>CS(C)=O>[CH3:22][O:23][C:24]1[C:25]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][C:8]3[N:12]=[C:11]([C:13]4[O:21][C:20]5[CH:19]=[CH:18][N:17]=[CH:16][C:15]=5[CH:14]=4)[O:10][N:9]=3)[CH2:3][CH2:2]2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1cc2oc(-c3nc(CC4CCNCC4)no3)cc2cn1
Reactant: COc1cccnc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COc1cccnc1N1CCC(Cc2noc(-c3cc4cnccc4o3)n2)CC1
Temperature: 25 °C

Procedure:
2-(3-Piperidin-4-ylmethyl-[1,2,4]oxadiazol-5-yl)furo[3,2-c]pyridine (Preparation 12, 50 mg, 0.176 mmol) and 3-methoxy-2-nitropyridine (41 mg, 0.264 mmol) were shaken in DMSO (1 mL) at 100° C. for 20 h. The reaction mixture was allowed to cool to room temperature, before being acidified with AcOH. Purification by RP-HPLC yielded the title compound: RT=4.99 min; m/z (ES+)=392.4 [M+H]+.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:13]=[C:12]([O:14]C(=O)C)[C:11]([O:18][CH3:19])=[CH:10][C:4]=1[CH2:5][NH:6][C:7](=[O:9])[CH3:8].[OH-].[Na+]>O1CCOCC1>[Cl:1][C:3]1[CH:13]=[C:12]([OH:14])[C:11]([O:18][CH3:19])=[CH:10][C:4]=1[CH2:5][NH:6][C:7](=[O:9])[CH3:8]
Reactant: COc1cc(CNC(C)=O)c(Br)cc1OC(C)=O
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(CNC(C)=O)c(Cl)cc1O

Procedure:
10% Aq. hydrochloric acid (2.5 ml) was added to a solution of 2-chloro-4-acetoxy-5-methoxy-N-acetyl-benzylamine 2 (0.45 g, 1.66 mmol) in dioxane (15 ml) and the mixture was refluxed for 2 hours. After cooling, the solvent was reduced under vacuum and the residue was basified with 10% aq. NaOH. The resulting solid was collected by filtration, washed with cold water and dried to furnish the title compound as white solid in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:16]C(Cl)=O)(Cl)Cl>C(Cl)Cl>[F:11][C:10]1[C:2]2[NH:1][C:13](=[O:16])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(F)cccc1C(=O)O
Solvent: ClCCl
Product: O=c1[nH]c2c(F)cccc2c(=O)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
To 2-amino-3-fluoro-benzoic acid (2.3 g) in DCM (20 mL) was added trichloromethylchloroformate (3.0 g) and the mixture was stirred at rt for 16 hours. The reaction was then concentrated to provide 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (2.5 g).
Reaction SMILES: [OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:19]1[C:24](=[O:25])[CH2:23][CH2:22][O:21][CH2:20]1>C(#N)C>[CH2:10]([O:9][C:7]([C:4]1[CH:3]=[C:2]([O:1][CH:19]2[C:24](=[O:25])[CH2:23][CH2:22][O:21][CH2:20]2)[NH:6][N:5]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1cc(O)[nH]n1
Reactant: O=C1CCOCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OC2COCCC2=O)[nH]n1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (7.0 g, 45 mmol) and 24.9 g g of potassium carbonate in 500 ml of acetonitrile was added 8.0 g of 3-bromo-tetrahydro-pyran-4-one, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. 9.0 g (78%) of the desired product was obtained as a white solid. M.Pt. 121-123° C.; (M+H) 255.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][NH:22][O:23][CH3:24].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH3:24][O:23][N:22]([CH3:21])[C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
2(S)-(tert-Butoxycarbonylamino)-3-phenylpropionic acid (39.80 g, 0.150 mol), N,O-dimethylhydroxylamine hydrochloride (21.95 g, 0.225 mol), EDC hydrochloride (31.52 g, 0.165 mol) and HOBT (20.25 g, 0.150 mol) were stirred in dry, degassed DMF (200 mL) at 20° C. under nitrogen. N-Methylmorpholine is added to obtain pH 7. The reaction was stirred overnight, the DMF distilled under high vacuum, and the residue partitioned between ethyl acetate and 2% potassium hydrogen sulfate. The organic phase was washed with saturated sodium bicarbonate, water, and saturated brine, and dried with magnesium sulfate. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([F:23])=[C:12]([C:14]3[C:15]([C:21]#[N:22])=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:13]=2)OC1.Br[C:26]1[N:30]2[N:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:37])[CH3:36])=[N:34][C:29]2=[N:28][CH:27]=1>>[F:20][C:17]1[CH:16]=[C:15]([C:21]#[N:22])[C:14]([C:12]2[CH:13]=[C:8]([C:26]3[N:30]4[N:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:36])[CH3:37])=[N:34][C:29]4=[N:28][CH:27]=3)[CH:9]=[CH:10][C:11]=2[F:23])=[CH:19][CH:18]=1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)c3)cnc2n1
Yield: 54 %

Procedure:
5′-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-4,2′-difluorobiphenyl-2-carbonitrile (see Example 4) was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol in 54% yield using a similar procedure to that described in Example 3, step f, to give a yellow solid: mp 215° C.; 1H NMR (360 MHz, CDCl3) δ 1.71 (6H, s), 3.27 (1H, br s), 7.35-7.59 (4H, m), 8.09-8.15 (2H, m), 8.26 (1H, s), 8.78 (1H, s); MS (ES+) m/z 392 [M+H]+. Anal. Found: C, 64.38; H, 3.88; N, 17.66%. Required for C21H15F2N5O: C, 64.45; H, 3.86; N, 17.89%.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:8]=[CH:7][N:6]=1.[C:27]([O:31][CH2:32][CH2:33][C:34](O)=[O:35])([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:27]([O:31][CH2:32][CH2:33][C:34]([N:16]1[CH2:17][CH2:18][CH:13]([O:12][C:9]2[C:10]([CH3:11])=[C:5]([O:4][C:3]3[CH:19]=[CH:20][C:21]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:22][C:2]=3[F:1])[N:6]=[CH:7][N:8]=2)[CH2:14][CH2:15]1)=[O:35])([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Reactant: CC(C)(C)OCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)CCOC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
Mixture of 4-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine (76 mg, 0.2 mmole), 3-tert-butoxy-propionic acid (0.26 mmole, 1.3 eq), HATU (0.26 mmole, 1.3 eq), and triethylamine (0.4 mmole, 2 eq) in 2 mL DMF was stirred at room temp for 2 hours. Mixture was purified by HPLC to give compound C161 as a white solid (88 mg, 86%). 1H NMR (CDCl3, 400 MHz) δ 1.20 (s, 9H), 1.91-1.96 (m, 2H), 2.02-2.10 (m, 2H), 2.22 (s, 3H), 2.72 (t, 2H), 3.11 (s, 3H), 3.62-3.64 (m, 2H), 3.72 (t, 2H), 3.86-3.91 (m, 2H), 5.41-5.46 (m, 1H), 7.44 (t, 1H), 7.78-7.82 (m, 2H), 8.23 (s, 1H). Exact mass calculated for C24H32FN3O6S 509.2, found 510.6 (MH+).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:35][C:19]3=[N:20][CH:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=4[CH3:34])[C:27]([O:29][CH3:30])=[O:28])[CH:23]=[C:18]3[CH:17]=2)=[CH:12][CH:11]=1>[Al].ClCCCl.CCOC(C)=O>[Br:8][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:27]([O:29][CH3:30])=[O:28])[CH:23]=2)[O:35][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reaction time: 8 h

Procedure:
The reaction flask was wrapped in aluminum foil. NBS (175 mg, 0.983 mmol) was added to a stirring solution of methyl 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (289 mg, 0.800 mmol) in DCE (8 mL) at room temperature. It was allowed to stir overnight. The mixture was diluted with EtOAc and quenched with 10% sodium metabisulfate and washed with sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) the expected product consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (1H, d, J=2.01 Hz), 8.16-8.26 (2H, m), 8.06 (1H, d, J=2.26 Hz), 7.95 (1H, dd, J=8.03, 1.76 Hz), 7.87 (1H, d), 7.45-7.57 (3H, m), 3.86 (3H, s), 2.34 (3H, s). LC-MS retention time: 2.85 min; m/z (MH+): 440, 442. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[C:4]([O:11][CH3:12])[CH:3]=1.Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[N:8]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(N)=S
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2OC)nc1C
Yield: 77.6 %

Procedure:
In ethanol (50 ml), 4-chloro-2-methoxythiobenzamide (4.00 g, 20.0 mmol) prepared in the Step 7-1-2 was suspended, and ethyl 2-chloroacetoacetate (3.62 g, 22.0 mmol) was added to the suspension. The mixture was heated under reflux overnight. After the mixture was allowed to cool, the solvent was distilled off under a reduced pressure, and ethyl acetate and a saturated sodium bicarbonate solution were added to the mixture. The resulting mixture was subjected to extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated. The residue was suspended in ethyl acetate-n-hexane (ethyl acetate:n-hexane=1:1) and separated by filtration. The separated product was washed with the same solvent and dried under a reduced pressure to give the title compound (4.84 g, 78%) as a light-yellow powder.
Reaction SMILES: N[C:2]1[N:6]2[CH:7]=[C:8](SC3C=CC=CC=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(Cl)(Cl)Cl.COC(Cl)=O>C(N(CC)CC)C>[N:4]1[CH:3]=[CH:2][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: Nc1cnc2ccc(Sc3ccccc3)cn12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: c1ccn2ccnc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.0 g. of 3-amino-6-(phenylthio)imidazo [1,2-a] pyridine in 25 ml. of chloroform containing 0.401 g. of triethyl amine is treated dropwise with 0.378 g. of methylchloroformate. The reaction mixture is stirred for 3 hours at room temperature. The chloroform is removed in vacuo and the residue is triturated with water. The solids are collected by filtration, washed well with water and dried. Recrystallization from dimethylformamideethane yields pure 3-(methoxycarbonylamino) 6-phenylthio)imidazo [1,2-a] pyridine m.p. 211°-215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[F:8].C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:19]=[O:20]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:8])=[CH:4][N:5]=[CH:6][C:7]=1[CH:19]=[O:20]
Reactant: Fc1cnccc1Cl
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cncc(F)c1Cl
Temperature: -78 °C
Reaction time: 5 h

Procedure:
4-Chloro-3-fluoropyridine (1 g) was dissolved in tetrahydrofuran (15 ml), and the solution was then cooled to −78° C. Lithium diisopropylamide (1.1 M solution in tetrahydrofuran and n-hexane, 7.6 ml) was added dropwise thereto, and the mixture was stirred at the same temperature as above for 5 hours. Then, N,N-dimethylformamide (1 ml) was added thereto, and the mixture was further stirred for 30 minutes while being heated to room temperature. Saturated saline was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate) to obtain the title compound (521 mg).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:33])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCc1ccc(Cl)cc1
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCc1ccc(Cl)cc1
Yield: 62.5 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-chloro-benzyloxy)-phenylamine (0.029 g, 0.08 mmol) was treated with 4-chlorophenyl isocyanate (0.014 g, 0.09 mmol, 1.2 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 63 (0.027 g, 0.05 mmol, 65%) as a white solid. LCMS m/z (%)=545 (M+H79Br35Cl35Cl, 65), 547 (M+H79Br35Cl35Cl, 100), 549 (M+H81Br35Cl37Cl79Br37Cl37Cl, 45), 551 (M+H81Br37Cl37Cl, 6). 1H NMR (400 MHz, acetone-d6) δ: 8.23 (s, 1H), 8.17 (s, 1H), 7.66 (dd, J=2.7, 9.0 Hz, 1H), 7.56 (d, J=8.9 Hz, 2H), 7.50 (s, 1H), 7.46 (d, J=2.7 Hz, 1H), 7.37 (d, J=8.7 Hz, 2H), 7.33 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.9 Hz, 2H), 7.22 (d, J=9.0 Hz, 1H), 5.14 (AB quartet, J=12.3, 24.8 Hz, 2H), 3.69 (s, 3H).
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1(C)C=CC=CC=1.[CH3:39][O:40][C@H:41]1[C@@H:45]2[CH2:46][C@H:47]3[C@H:52]([C:53](=O)[C@@H:44]2[C@@H:43]([CH3:55])[O:42]1)[CH2:51][CH2:50][CH2:49][CH2:48]3>>[CH3:39][O:40][C@H:41]1[C@@H:45]2[CH2:46][C@H:47]3[C@H:52]([C:53](=[CH2:2])[C@@H:44]2[C@@H:43]([CH3:55])[O:42]1)[CH2:51][CH2:50][CH2:49][CH2:48]3
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CO[C@@H]1O[C@H](C)[C@H]2C(=O)[C@@H]3CCCC[C@H]3C[C@@H]12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C1[C@H]2[C@@H](C[C@@H]3CCCC[C@@H]13)[C@H](OC)O[C@@H]2C
Yield: 87.7 %

Procedure:
Similarly to Example 7, 6665.6 mg(5 equivalents) of methyltriphenylphosphonium iodide and 16.5 ml(5 equivalents) of sodium bis(trimethylsilyl)amide-toluene solution(1M) were reacted with 786.0 mg of (1R,3R,3aS,4aR,8aS,9aR)-1-methoxy-3-methyl-4-oxo-dodecahydronaphtho[2,3-c]furan to obtain 683.5 mg of (1R,3R,3aR,4aR,8aS,9aR)-1-methoxy-3-methyl-4-methylene-dodecahydronaphtho[2,3-c]furan(yield 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH:11]1[O:16][C:15](=[O:17])[CH:14]=[CH:13][CH2:12]1.I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>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.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C@@H:11]1[O:16][C:15](=[O:17])[CH2:14][C@@H:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12]1
Reactant: Ic1ccccc1
Reactant: O=C1C=CCC(CCc2ccc(Cl)cc2Cl)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1C[C@@H](c2ccccc2)C[C@H](CCc2ccc(Cl)cc2Cl)O1
Temperature: 80 °C

Procedure:
A mixture of compound (1a) (270 mg, 1.0 mmol), iodobenzene (224 mg, 1.1 mmol), triethylamine (160 μl, 1.1 mmol) and tetrakis(triphenylphosphine)palladium 10 mg) was placed under argon nd heated at 80° C. for 16 hours. The dark mixture was cooled and distributed between ethyl acetate (100 ml) and 1N HCl (100 ml). The organic layer was separated and washed with water (2×50 ml), dried and evaporated. The residue was purified by flash chromatography on silica gel using CHCl3 acetone, 20:1 (V:V) as eluant.
Reaction SMILES: COC1C2C(=CC=C([C:13]([OH:15])=[O:14])C=2)C=CN=1.Br[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[N:22][C:21]([NH2:27])=[CH:20]2>>[NH2:27][C:21]1[N:22]=[CH:23][C:24]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:13]([OH:15])=[O:14])=[CH:26][CH:25]=2
Reactant: COc1nccc2ccc(C(=O)O)cc12
Reactant: Nc1cc2cc(Br)ccc2cn1
Product: Nc1cc2cc(C(=O)O)ccc2cn1

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate 12, Steps 2-3, using 6-bromoisoquinolin-3-amine. +ESI (M+H) 189.0; 1H NMR (400 MHz, DMSO-d6, δ): 13.15 (br. s., 1H), 8.94 (s, 1H), 8.20 (s, 1H), 7.91 (m, 1H), 7.62-7.59 (m, 1H), 6.78 (s, 1H), 6.14 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)=[CH:8][C:6]=2[CH:7]=1.[CH3:17][O:18][C:19](=[O:31])[C@H:20]([N:28]=[C:29]=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1COCC1>[CH3:17][O:18][C:19](=[O:31])[C@H:20]([NH:28][C:29]([O:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)=[CH:8][C:6]=2[CH:7]=1)=[O:30])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)N=C=O
Reactant: OCc1cc2cc(-c3ccsc3)ccc2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1cc2cc(-c3ccsc3)ccc2o1
Temperature: 50 °C
Yield: 47.6 %

Procedure:
A mixture of 2-hydroxymethyl-5-thiophen-3-yl-benzofuran 22 (0.31 g, 1.35 mmole), (R)-2-isocyanato-3-phenyl-propionic acid methyl ester 5 (0.33 g, 1.6 mmole), triethylamine (0.43 ml), and THF (25 ml) was heated to 50° C. under a nitrogen atmosphere for 14 hrs. The solvent was removed under reduced pressure and the residue was purified by chromatography giving about 0.28 g of (R)-2-(5-thiophen-3-yl-benzofuran-2-ylmethoxycarbonylamino)-3-phenylpropionic acid methyl ester 23, mp. 105-106° C.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:12])[CH:10]=[CH2:11])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(OC)cc1
Yield: 98.8 %

Procedure:
Anisole (108 mg), acryloyl chloride (154 mg), and aluminium chloride (199 mg) were reacted in dichloromethane (1.5 mL) at from −20° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (160 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].N[C:9](N)=[O:10].N>>[CH2:2]1[NH:1][C:9](=[O:10])[N:4]([CH2:5][CH2:6][OH:7])[CH2:3]1
Reactant: NC(N)=O
Reactant: NCCNCCO
Agent: N
Product: O=C1NCCN1CCO
Temperature: 230 °C
Yield: 97.6 %

Procedure:
A mixture of 93.3 g of 2-(2-aminoethylamino) ethanol (0.9 moles) and 52.1 g of urea (0.87 moles) was heated slowly to 230° C. with stirring. The evolution of ammonia began when the temperature reached 130° C. The reaction mixture was heated at 230° C. for 2 hours. The mixture solidified to a light-yellow solid after it had cooled to room temperature to afford 110.5 g of hydroxyethylethyleneurea. Recrystallized from acetone, M.P.: 55-57.50° C.; 1 H NMR (DMSO-d6): d 6.3 (s, 1 H), 4.6 (s, 1 H), 3.5-3.0 (m, 8 H).
Reaction SMILES: [K+].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH-:12])(=[O:11])=[O:10])=[N:7][CH:8]=1.[Cl:13][C:14]1[C:19]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[C:18](Cl)[N:17]=[C:16]([CH3:30])[N:15]=1.O>CS(C)=O>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][C:18]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:14]([Cl:13])[N:15]=[C:16]([CH3:30])[N:17]=2)(=[O:11])=[O:10])=[N:7][CH:8]=1
Reactant: Cc1ccc(S([NH-])(=O)=O)nc1
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.6 %

Procedure:
At room temperature 2.95 g of 5-methyl-2-pyridine sulfonamide potassium salt (Example 3c) was added to a suspension of 2 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-methyl-pyrimidine (Example 7b) in 30 ml DMSO. The mixture was stirred at room temperature for 48 h and was then poured onto 300 ml of water. The aqueous solution was extracted twice with 200 ml of diethyl ether. The organic layers were extracted with water and the aqueous layers were combined and acidified with 3 ml of acetic acid to pH 4. Precipitation of the product was enhanced by adding 100 ml of saturated aqueous sodium chloride and cooling the mixture to 0° C. Eventually, the precipitate was filtered off, washed with cold water and dried under high vacuum to give 2.26 g of 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide as a beige powder. LC-MS: tR=4.79 min, [M+1]+=421.42, [M−1]−=419.46.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C:11](=[O:25])[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3[CH2:22][CH2:23][CH2:24][C@H:18]3[CH2:17]2)=[O:15])[CH:6]=[CH:7][C:8]=1OC.[Cl:26]C1C=CC(C(CCC(O)=O)=O)=CC=1>>[Cl:26][C:8]1[CH:7]=[CH:6][C:5]([C:11](=[O:25])[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3[CH2:22][CH2:23][CH2:24][C@H:18]3[CH2:17]2)=[O:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CCC(=O)N2CCN3CCC[C@H]3C2)cc1OC
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Product: O=C(CCC(=O)N1CCN2CCC[C@H]2C1)c1ccc(Cl)cc1

Procedure:
279 mg of the title compound were prepared as described for 1-(3,4-dimethoxy-phenyl)-4-((S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl)butane-1,4-dione, using 3-(4-chlorobenzoyl) propionic acid instead of 3-(3,4-dimethoxybenzoyl)propionic acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6]O)[CH3:2].S(Cl)([Cl:12])=O>C(Cl)Cl>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][Cl:12])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCN(CC)CCCO
Solvent: ClCCl
Product: CCN(CC)CCCCl
Yield: 36.9 %

Procedure:
A solution of 3-diethylamino-1-propanol (Aldrich) (10 g, 76 mmol) in DCM was stirred at 0° C. A solution of thionyl chloride (DCM 30 mL) was then added drop-wise such that the reaction temperature remained at 0° C. Once addition is complete, the reaction was refluxed for one hour. The reaction was allowed to cool and the excess DCM and thionyl chloride were removed under vacuum. The residue was basified (pH8–9) using 2N NaOH and the aqueous mixture extracted with DCM (3×100 mL). The organic extracts were combined, dried (MgSO4) and evaporated to give a brown oil. The oil was distilled (160°–165° C.) to give the product as a clear oil (4.2 g 36.9%).