Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](Br)=[CH:7][CH:8]=1)(=[O:3])[CH3:2].C[Sn](C)C.C[Sn](C)C.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:4]1[S:5][C:6]([C:6]2[S:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=2)=[CH:7][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Br)s1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccc(C(C)=O)s2)s1
Temperature: -5 °C

Procedure:
To a slurry of 1 g tetrakis(triphenyl phosphine) Palladium (0) in 30 ml of dry toluene was added a solution of 6.26 g (30.5 mmol) of 2-acetyl-5-bromo thiophene in 30 ml of dry toluene under argon. The reaction was heated to reflux and to this solution was added dropwise a solution of 5 g (15.26 mmol) of hexamethylditin (99%) in 50 ml toluene (dry) over a period of 1.5 h. The reaction mixture was refluxed for another 6 h and then cooled down to -5° C. Light yellow crystals of the product were isolated by suction filtration and were washed with hexane. The product was then continuously extracted through Whatman filter paper #42 with dioxane using a soxhlet apparatus until all of the product was dissolved and collected in the boiling flask. Slow cooling of the dioxane solution resulted in needle shaped light yellow crystals of the monomer which were separated by suction filtration and dried in vacuum. A Yield of 2.56 g (67%) having the following characteristics was obtained: mp 235° C. (lit. mp 233.5°-234° C.); UV/vis λmax (CHCl3): 367 (log ε=4.19), 262 (3.57); FT-IR (KBr,cm-1): 3070, 1797 1656, 1611, 1511, 1433, 1361, 1302, 1270, 1089, 1036, 1020, 937, 897, 881, 792, 745, 673, 611, 593, 555, 463, 442; 1H NMR (CDCl3 300 MHz, TMS) δ 2.58 (s,6H), 7.30 (d,2H), 7.62 (d,2H). Anal. calcd. for C12 H10S2 : C, 57.58; H, 4.03; N, 0.0. Found: C, 57.48; H, 3.87; N, 0.0.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:36][CH2:37][OH:38].N([O-])=O.[Na+].[BrH:43]>CC#N.O.[Cu]Br>[Br:43][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:36][CH2:37][OH:38]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(CCO)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(CCO)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 6-(N-(4-amino-3-(2-hydroxyethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (250 mg, 0.465 mmol) in MeCN (1 mL) maintained at 0° C. was added sodium nitrite (80 mg, 1.16 mmol) dissolved in water (0.50 mL). followed by 48% aqueous HBr (0.25 mL). The resulting mixture was treated with copper(I) bromide (133 mg, 0.930 mmol) in 48% aqueous HBr (0.30 mL). After stirring at 60° C. for 1 hour the reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic solution was washed with water, dried over sodium sulfate, and concentrated to dryness at reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane/EtOAc) to afford the title compound in 65% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36-8.51 (m, 1H) 8.05 (s, 1H) 7.92 (dd, J=8.89, 5.37 Hz, 2H) 7.49-7.62 (m, 1H) 7.31-7.49 (m, 3H) 7.09-7.26 (m, 2H) 4.69 (t, J=5.28 Hz, 1H) 3.46-3.60 (m, 2H) 3.30-3.40 (m, 3H) 2.72-2.87 (m, 5H) 2.04-2.22 (m, 1H) 0.70-1.06 (m, 3H) 0.41 (br. s., 1H).). LCMS (m/z, ES+)=601, 603 (M+H+).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([C@H:27]2[C@@H:36]([C:37]([OH:39])=O)[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29](=[O:40])[N:28]2[CH3:41])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC=CC=1>[CH2:5]([O:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][C:16]2[C:37](=[O:39])[C:36]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29](=[O:40])[N:28]([CH3:41])[C:27]=3[C:15]=2[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN1C(=O)c2ccccc2[C@H](C(=O)O)[C@@H]1c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cn1c2c(c3ccccc3c1=O)C(=O)c1cc(OCc3ccccc3)c(OCc3ccccc3)cc1-2
Reaction time: 0.5 h
Yield: 14.1 %

Procedure:
Thionyl chloride (8.1 mL) was added with stirring to the cis acid 12g (0.7 g, 2.1 mmol). The result was a yellowish-brown mixture that became orange within 15 min and after 30 min was red. After 4 h, the reaction mixture was diluted with benzene (25 mL) and evaporated to dryness. The brownish-red solid was recrystallized from methanol and passed through a short column (SiO2), eluting with chloroform, to give a brown solid (0.14 g, 24%): MP 198-200° C.; 1H NMR (DMSO-d6) δ8.43 (d, J=8.0 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H), 7.39 (m, 13H), 5.34 (s, 1H), 5.29 (s, 1H), 3.93 (s, 1H); CIMS m/z (relative intensity) 474 (MH+, 100). Anal. Calcd for C31H23NO4: C, H, N.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][N+:15]([O-:17])=[O:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.Cl.O>C(O)C>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][N+:15]([O-:17])=[O:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Reaction time: 0.08 h
Yield: 62 %

Procedure:
(4-Acetamidophenylsulphonyl)nitromethane (obtained as described in J Het. Chem., 1977, 14, 1415) (10.0 g, 38.8 mmol) was added in one portion to a boiling mixture of concentrated hydrochloric acid (20 ml), water (100 ml) and ethanol (40 ml). The mixture was stirred at reflux until a clear solution formed (about 20 minutes) and then for a further 5 mins. The hot reaction mixture was poured into an excess of ice-cold saturated sodium bicarbonate solution and then extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4) and the solvent was removed by evaporation. There was thus obtained (4 aminophenylsulphonyl)nitromethane as a pale yellow solid (5.2 g, 62% yield), m.p. 132°-133° C., microanalysis, found: C, 39.2; H, 3.8: N, 12.9%; C7H8N2O4S requires: C, 38.9; H, 3.7; N, 12.95%.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>C(O)C>[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][C:18]([NH:21][C:3]2[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: Nc1ccc(-c2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccc(-c3ccccc3)cc2)[nH]c1=O
Temperature: 80 °C
Yield: 40 %

Procedure:
Ethyl 2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (60 mg, 0.233 mmol) was added to 1,1′-biphenyl-4-amine (79 mg, 0.467 mmol) dissolved in ethanol. The solution was heated in an oil bath to 80° C., while stirring, in reflux, for 72 hours. The sample was filtered and dried. 1H-NMR confirmed the structure (31 mg, 40% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)=[O:6].C1(C)C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:5]([OH:6])[C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:8]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cccc(Cl)c2)C1
Temperature: -15 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of (R)-tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate (92 g, 0.286 mol) in anhydrous THF (300 mL) at −15° C. under nitrogen was added drop wise a solution of 1M R-CBS-oxazaborolidine in toluene (45 mL, 45 mmol, 0.15 eq). After stirring for 1 hr at −15° C., a solution of 10 M BH3 in THF (33 mL, 0.33 mol, 1.1 eq) was added drop wise. After addition, the reaction mixture was stirred for 2 h at −15° C. TLC indicated the starting material was consumed. Methanol (200 mL) was added drop wise carefully at −15° C. The solvent was removed under reduced pressure, the residue was purified by column chromatography on silica gel eluting with AcOEt/hexane (1:30→1:15) to provide a light yellow oil (82 g, HPLC≧70%, ratio≧3:1). The mixture was dissolved in ethyl acetate until the alcohol was just dissolved (about 5 mL/1 g), the solvent was removed on the rotary evaporator until a few of crystals appeared. The solution was cooled to room temperature slowly and stood for 1-2 h. To the above solution was added hexane (about 300 mL) and then filtered, the crystals were washed with cool hexane and recrystallized another two times to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate as the pure isomer (32.5 g, ee.≧99%, yield 35% for two steps).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:24]([NH:26][C@@H:27]([C:32](O)=[O:33])[C@@H:28]([CH2:30][CH3:31])[CH3:29])=[O:25])[CH:13](CC1C=CC=CC=1)[C:14](=[O:16])[OH:15])=O)C1C=CC=CC=1.Cl.[CH3:36][O:37][CH2:38][C@H:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH3:36][O:37][CH2:38][C@H:39]([NH:46][C:32](=[O:33])[C@@H:27]([C@@H:28]([CH2:30][CH3:31])[CH3:29])[NH:26][C:24](=[O:25])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH2:11])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COC[C@H](N)c1ccccc1
Reactant: CC[C@@H](C)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C(=O)O
Agent: Cl
Product: CC[C@@H](C)[C@@H](NC(=O)[C@@H](N)CC(=O)O)C(=O)N[C@@H](COC)c1ccccc1
Yield: 22.1 %

Procedure:
The same process as in Example 15 was repeated, except that N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-isoleucine was used in place of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-valine and that (R)-α-methoxymethylbenzylamine hydrochloride was used in place of (R)-α-ethoxymethylbenzylamine hydrochloride, and α-L-aspartyl-D-isoleucine (R)-α-methoxymethylbenzylamide was obtained as a solid product. The total yield was 22.1%.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH3:5][C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH3:5][C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]#[N:4])[CH2:24][CH2:23]2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)o1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c(NC3CCN(CC#N)CC3)nc3ccccc32)o1
Temperature: 45 °C
Yield: 80.4 %

Procedure:
A mixture of 2 parts of 2-chloroacetonitrile, 8 parts of 1-[(5-methyl-2-furanyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 3.1 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred and heated overnight at 45° C. The reaction mixture was poured into water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 7.3 parts (80.4%) of 4-[[1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidineacetonitrile; mp. 177.3° C. (int. 36).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29]S(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[Cl:34])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: Oc1ccccc1Cl
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccccc2Cl)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 91.1 %

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (403 mg) was reacted with 2-chlorophenol (390.2 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-(2-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl) propanamide (390.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[O:7])=[C:4]([O:26][CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH:3]=1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[O:7])=[C:4]([O:26][CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH:3]=1
Reactant: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)NCCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)NCCN1CCNCC1

Procedure:
The product of step (c) (0.55 g) was dissolved in dichloromethane (15 ml) and trifluoroacetic acid (3 ml) added. After 1 hour the solvent was evaporated and the product obtained as a solid (0.9 g), m.p. 120-122° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](O)=[O:34])[N:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:62]([O:69][C:70]([CH:72]1[CH2:76][CH2:75][NH:74][CH2:73]1)=[O:71])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:74]3[CH2:75][CH2:76][CH:72]([C:70]([O:69][CH2:62][C:63]4[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=4)=[O:71])[CH2:73]3)=[O:34])[N:28]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)n(-c3ccccc3)n2)CC1
Reactant: O=C(OCc1ccccc1)C1CCNC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC(C(=O)OCc4ccccc4)C3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 1.14 g 4-{(S)-4-tert-butoxycarbonyl-2-[(5-carboxymethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 10 ml DMF were added 719 mg HOBt, 900 mg EDC, 1.6 ml DIPEA and 1.50 g pyrrolidine-3-carboxylic acid benzyl ester hydrotrifluoroacetate. After stirring for 12 h the reaction mixture was diluted with ethyl acetate, washed with aqueous LiCl (4%) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 2.32 g.
Reaction SMILES: C([CH:9]([O:16][C:17]([NH:19][CH2:20][C:21]1([CH2:27][C:28]([O:30][CH2:31][CH2:32][C:33]#[N:34])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.[CH:35]1[CH:40]=[C:39](Cl)[CH:38]=[C:37]([C:42]([O:44]O)=[O:43])[CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:42]([O:44][CH:9]([O:16][C:17]([NH:19][CH2:20][C:21]1([CH2:27][C:28]([O:30][CH2:31][CH2:32][C:33]#[N:34])=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:35][CH:36]=1
Reactant: N#CCCOC(=O)CC1(CNC(=O)OC(C(=O)c2ccccc2)c2ccccc2)CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CCCOC(=O)CC1(CNC(=O)OC(OC(=O)c2ccccc2)c2ccccc2)CCCCC1
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 2-cyanoethyl 1-{[(α-benzoylbenzyloxy)carbonyl]aminomethyl}-1-cyclohexane acetate (9) (115 mg, 0.248 mmol) in 4 mL of CH2Cl2 was added to a mixture of mCPBA (77%, 111 mg, 0.497 mmol) and Na2CO3 (52.7 mg, 0.497 mmol) at room temperature. The resulting suspension was stirred at room temperature with TLC monitoring. After completion of the reaction (about 8 hours) the reaction mixture was diluted with CH2Cl2, washed with saturated NaHCO3 solution and brine and dried over Na2SO4. After concentration in vacuo the residue was purified on silica gel (40% ethyl acetate in hexane) to afford 89 mg (75%) of the title compound. 1H NMR (CDCl3): δ 8.08 (2H, dd, J=6.8, 1.6 Hz); 7.91 (1H, s); 7.63-7.54 (3H, m); 7.44-7.40 (5H, m); 5.42 (1H, t, J=6.4 Hz); 4.22 (2H, t, J=6.2 Hz); 3.25 (2H, dd, J=6.4, 4.6 Hz); 2.65 (2H, t, J=6.2 Hz); 2.35 (2H, s); 1.53-1.37 (10H, m). 13C NMR (CDCl3): δ 172.11; 164.73; 154.75; 136.29; 133.70; 130.18; 129.85; 129.63; 128.85; 128.68; 126.85; 117.11; 91.41; 58.94; 47.93; 10.06; 38.09; 34.15; 26.00; 21.55; 18.16.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[O:9]=[C:5]1[NH:6][CH2:7][CH2:8][N:4]1[CH2:3][CH2:2][NH:1][C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: O=C=Nc1ccccc1
Reactant: NCCN1CCNC1=O
Solvent: c1ccccc1
Product: O=C(NCCN1CCNC1=O)Nc1ccccc1
Reaction time: 4 h

Procedure:
To a mixture of 6.5 g of commercially available 1-(2-aminoethyl)-2-imidazolidone and 50 ml benzene was added 5.5 ml of phenyl isocyanate. The strongly exothermic reaction was moderated by cooling to 25°. The mixture was stirred at 25° for 4 hr. It was cooled in ice and the mixture was filtered. The solid product was crystallized from 250 ml of acetone to give 6.8 g of white 1-[2-(2-oxo-1-imidazolidinyl)ethyl]-3-phenylurea, mp 162°-164°.
Reaction SMILES: [F-].[Cs+].FC(F)(F)S(O[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[CH2:10])(=O)=O.[F:20][C:21]1[CH:22]=[C:23]([CH2:40][N:41]2[CH2:44][CH:43]([C:45]([O:47][CH3:48])=[O:46])[CH2:42]2)[CH:24]=[CH:25][C:26]=1[C:27]1[S:28][C:29]2[C:34]([N:35]=1)=[CH:33][CH:32]=[C:31]([Sn](C)(C)C)[N:30]=2>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:20][C:21]1[CH:22]=[C:23]([CH2:40][N:41]2[CH2:42][CH:43]([C:45]([O:47][CH3:48])=[O:46])[CH2:44]2)[CH:24]=[CH:25][C:26]=1[C:27]1[S:28][C:29]2[C:34]([N:35]=1)=[CH:33][CH:32]=[C:31]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[CH2:10])[N:30]=2
Reactant: COC(=O)C1CN(Cc2ccc(-c3nc4ccc([Sn](C)(C)C)nc4s3)c(F)c2)C1
Reactant: C=C(OS(=O)(=O)C(F)(F)F)c1ccccc1F
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Product: C=C(c1ccc2nc(-c3ccc(CN4CC(C(=O)OC)C4)cc3F)sc2n1)c1ccccc1F
Temperature: 45 °C

Procedure:
A sealable tube was charged with Cu(I) iodide (7.32 mg, 0.0384 mmol), cesium fluoride (0.117 g, 0.769 mmol), 1-(2-fluorophenyl)vinyl trifluoromethane-sulfonate (0.208 g, 0.769 mmol), tetrakis(triphenylphosphine) palladium (0) (0.0222 g, 0.0192 mmol), methyl 1-((3-fluoro-4-(5-(trimethylstannyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate (0.200 g, 0.384 mmol), flushed with argon, diluted with 0.8 mL DMF, sealed, and heated to 45° C. overnight. The reaction mixture was partitioned between EA, water, saturated sodium bicarbonate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography, 12 g, 0-100% EA/hexanes provided methyl 1-((3-fluoro-4-(5-(1-(2-fluorophenyl)vinyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate as an oil which slowly solidified to a tan solid. MS (ESI) m/z: calculated: 477.1; Observed: 478.1 (M++1).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13]C(=O)CC)(=[O:12])[CH2:10][CH3:11].Cl(O)(=O)(=O)=O>>[C:1]([O:8][CH:1]([O:13][C:9](=[O:12])[CH2:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH2:2][CH3:3]
Reactant: O=Cc1ccccc1
Reactant: CCC(=O)OC(=O)CC
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCC(=O)OC(OC(=O)CC)c1ccccc1

Procedure:
Benzaldehyde (1.5 mol) and propionic anhydride (1.5 mol) were reacted in the presence of 0.5 ml perchloric acid by the procedure of Example 4. The resulting benzylidene bispropionate distilled at 104°C. (0.1 mm/Hg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:15]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH4+].[OH-]>C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc(C(=O)O)c(N)c1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(C(N)=O)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-amino-4-methoxy-benzoic acid (3.00 g, 17.9 mmol) in THF (90 mL), EDCl (7.89 g, 41.1 mmol) and HOBt (7.95 g, 51.9 mmol) were added and stirred at room temperature for 30 minutes. Then, N-methylmorpholine (6.15 g, 60.0 mmol) and aqueous 50% (v/v) NH4OH (12 mL, 171.4 mmol) were added. The mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate (4×100 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous sodium sulfate. Solvent was evaporated to give 2-amino-4-methoxy-benzamide as an off-white solid. Yield: 1.80 g, (60%).
Reaction SMILES: F[C:2]12[O:14][CH2:13][CH2:12][O:11][CH:3]1[CH:4]=[C:5]([CH:9]=[CH:10]2)[CH2:6][CH2:7][NH2:8].Cl[C:16]1[C:17]2[C:30]([CH3:31])=[CH:29][S:28][C:18]=2[N:19]=[C:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[N:21]=1>>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:20]2[N:21]=[C:16]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:2]4[O:14][CH2:13][CH2:12][O:11][C:3]=4[CH:4]=3)[C:17]3[C:30]([CH3:31])=[CH:29][S:28][C:18]=3[N:19]=2)[CH:23]=1
Reactant: NCCC1=CC2OCCOC2(F)C=C1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Product: Cc1csc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluoro3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C@H:15]2[CH2:17][C@@H:16]2[CH:18]=[CH:19][O:20][CH3:21])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.O=[Pt]=O>[CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C@H:15]2[CH2:17][C@@H:16]2[CH2:18][CH2:19][O:20][CH3:21])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC=C[C@H]1C[C@@H]1c1cncc(OCc2ccccc2)c1
Agent: O=[Pt]=O
Solvent: ClCCl
Product: COCC[C@H]1C[C@@H]1c1cncc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.3 %

Procedure:
In a 100 mL round-bottom flask, PtO2 (77 mg, 0.34 mmol, 0.05 equiv.) was added under N2 at room temperature to a solution of 3-(benzyloxy)-5-[(1S,2S)-2-(2-methoxyvinyl)cyclopropyl]pyridine (1.90 g, 6.75 mmol) in CH2Cl2 (18 mL). A H2 balloon was attached, and the atmosphere was exchanged three times. The reaction mixture was stirred at room temperature for 6 h, after which time TLC analysis indicated that the starting material had disappeared completely. The catalyst was filtered off and washed with CH2Cl2 (2×5 mL). The combined filtrates were concentrated in vacuo to yield crude 3-(benzyloxy)-5-[(1S,2R)-2-(2-methoxyethyl)cyclopropyl]pyridine (1.90 g) as a yellowish oil. LC-MS (ESI) m/z 284 (M+H+).