Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH:19]([O:22][CH3:23])[C:20]#[CH:21])[CH:16]=[C:15]([O:24][CH3:25])[C:14]=1[O:26][CH3:27]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:21]#[C:20][CH:19]([O:22][CH3:23])[C:17]2[CH:16]=[C:15]([O:24][CH3:25])[C:14]([O:26][CH3:27])=[C:13]([O:12][CH3:11])[CH:18]=2)=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1I
Reactant: C#CC(OC)c1cc(OC)c(OC)c(OC)c1
Product: COc1cc(C(C#Cc2c(C)nc(N)nc2N)OC)cc(OC)c1OC
Yield: 93.5 %

Procedure:
2,4-Diamino-5-iodo-6-methylpyrimidine (250 mg) was allowed to react with 1,2,3-Trimethoxy-5-(1-methoxyprop-2-ynyl)benzene (473 mg) as per the general procedure to afford 2,4-Diamino-5-(3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-ynyl)-6-methylpyrimidine as a yellow powder (335 mg, 93%): Rf=0.29 (9:1, CHCl3:MeOH); mp=127-129° C.; 1H NMR (DMSO-d6) δ 6.84 (s, 2H), 6.37 (s, 2H), 5.34 (s, 1H), 3.78 (s, 6H), 3.66 (s, 3H), 3.35 (s, 3H), 2.23 (s, 3H); 13C NMR (DMSO-d6) δ 167.6, 164.3, 161.1, 152.8, 137.2, 134.8, 104.6, 95.7, 87.5, 81.8, 73.1, 60.0, 55.8, 55.3, 22.4; HRFAB[M+Li]359.1701 (calculated C18H22N4O4Li: 359.1719). (R)-4-Isopropyl-3-(2-(3,4,5-trimethoxyphenyl)acetyl)oxazolidin-2-one. To a flame-dried 100 mL round-bottom flask was added 3,4,5-trimethoxyphenylacetic acid (2.10 g, 9.29 mmol). THF (25 mL) was added followed by Et3N (1.42 mL, 10.22 mmol). The solution was cooled to −78° C. Pivaloyl chloride (1.26 mL, 10.22 mmol) was added dropwise and the solution warmed to 0° C. and stirred for 1 h. In a separate flame-dried 50 mL round-bottom flask was added (R)-4-isopropyloxazolidin-2-one (1.0 g). THF (20 mL) was added and the solution cooled to −78° C. n-BuLi (6.83 mL, 9.29 mmol, 1.36 M) was added dropwise and the solution stirred at −78° C. for 15 min and then warmed to 25° C. where it was stirred for 15 min. The organolithium solution was transferred to the solution of the mixed anhydride via cannula at −78° C. The reaction was stirred at −78° C. for 15 min, warmed to 0° C., and stirred for 1 h. Water (10 mL) was added and the aqueous layer extracted with EtOAc (2×10 mL). The combined organics were washed with brine (10 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 30 g) using 25% EtOAc in hexanes as the eluent to afford trimethoxyphenyl)acetyl)oxazolidin-2-one as a colorless oil (2.30 g, 88%): Rf=0.28 (1:1, Hex:EtOAc); 1H NMR (CDCl3) δ 6.55 (s, 2H), 4.44-4.41 (m, 1H), 4.29-4.24 (m, 2H), 4.19 (dd, J) 9.0, 3.0 Hz, 1H), 4.12-4.07 (m, 1H), 3.82 (s, 6H), 3.80 (s, 3H), 2.36-2.30 (m, 1H), 0.87 (d, J) 6.8 Hz, 3H), 0.78 (d, J) 7.1 Hz, 3H); 13C NMR (CDCl3) δ 171.2, 154.1, 153.2, 129.4, 106.7, 63.4, 60.9, 58.6, 56.2, 41.6, 28.4, 18.0, 14.7, 14.3; HRFAB[M+Li]344.1686 (calculated C17H23NO6Li: 344.1686).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20](C(C)=C)[C:19]3=[O:30])[CH2:11][CH2:10]2)=[C:4]([N+:31]([O-:33])=[O:32])[CH:3]=1.CC1C=CC=CC=1.Cl>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:30])[CH2:13][CH2:14]2)=[C:4]([N+:31]([O-:33])=[O:32])[CH:3]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCC(Nc3ccc(Cl)cc3[N+](=O)[O-])CC2)c2ccccc21
Agent: Cl
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1
Yield: 75.5 %

Procedure:
A solution of 98.5 parts of 1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one in 360 parts of methylbenzene is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride. After boiling for a while, an oil precipitates. The supernatant phase is decanted and the residual oil is suspended in water. The suspension is alkalized with a concentrated ammonium hydroxide solution. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 68 parts (75.5%) of 1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}-propyl]-1,3-dihydro-2H-benzimidazol-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=4)[S:16][C:12]=3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=4)[S:16][C:12]=3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc(-c2cc3c(s2)CCCC3(O)c2ccc(Cl)cc2)ccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(=O)Nc1cc(-c2cc3c(s2)CCCC3c2ccc(Cl)cc2)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 100 mL round bottomed flask was placed crude N-{4-[4-(4-chlorophenyl)-4-hydroxy-4,5,6,7-tetrahydro-1-benzothien-2-yl]pyridin-2-yl}acetamide (410 mg, 1.0 mmol) prepared above and 1,2-dichloroethane (10 mL). The mixture was refluxed for 30 min to obtain a yellow solution. To the refluxing mixture were added triethylsilane (1 mL, 6 mmol) and trifluoroacetic acid (2 mL, 20 mmol), and refluxing was continued for an additional 3 hr. The mixture was allowed to cool to rt then concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) then washed with a saturated aqueous solution of NaHCO3 (50 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic phases were dried over anhydrous MgSO4.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[C:4]([Cl:10])[N:3]=1.Cl.[F:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][CH2:20][CH2:19][C@H:18]2[NH2:23].C(=O)(O)[O-].[Na+]>C(O)CCC>[Cl:10][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:23][C@H:18]2[C:17]3[C:22](=[C:13]([F:12])[CH:14]=[CH:15][CH:16]=3)[O:21][CH2:20][CH2:19]2)[C:5]=1[NH2:9]
Reactant: N[C@@H]1CCOc2c(F)cccc21
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Nc1nc(Cl)c(N)c(N[C@@H]2CCOc3c(F)cccc32)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.5 %

Procedure:
2,5-diamino-4,6-dichloropyrimidine (1.5 g, 8.37 mmol), (R)-8-fluorochroman-4-amine hydrochloride (see preparation below) (1.7 g, 8.37 mmol, 1 equiv.), sodium bicarbonate (2.46 g, 29.3 mmol, 3.5 equiv.) and 1-butanol (30 mL) were heated together at 150° C. in a sealed tube. After 3 days, when the reaction appeared to be complete (by HPLC), the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, elution with 1/1 ethyl acetate/methylene chloride) to give 2.01 g (78% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CD3OD) δ, ppm: 6.97-6.86 (m, 2H), 6.77-6.72 (m, 1H), 5.36 (m, 1H), 4.25 (m, 2H), 2.10 (m, 2H); MS (EI) m/z 310.1 (MH)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15](=[O:31])[CH2:16][CH:17]([N:21]1[C:29]2[C:24](=[CH:25][C:26](O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)[CH2:18][CH2:19][CH3:20])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:31])[CH2:16][CH:17]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([O:11][CH2:10][CH2:9][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([NH:2][CH3:1])[N:8]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)[CH2:18][CH2:19][CH3:20])[CH3:13]
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(O)ccc21
Reactant: CNc1cccc(CCO)n1
Product: CCCC(CC(=O)OCC)n1ccc2cc(OCCc3cccc(NC)n3)ccc21
Yield: 25 %

Procedure:
The title compound was synthesized from 2-(6-methylamino-pyridin-2-yl)-ethanol and 3-(5-hydroxy-indol-1-yl)-hexanoic acid ethyl ester using the procedure described in Example 14, step (c), in 25% yield. The crude product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:20]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:21]([C:23]2([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[OH:36][CH:37]1[C:41]2([CH2:43][CH2:42]2)[CH2:40][N:39]([CH2:44][CH2:45][CH2:46]CS([O-])(=O)=O)[CH2:38]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:36][CH:37]1[C:41]2([CH2:43][CH2:42]2)[CH2:40][N:39]([CH2:44][CH2:45][CH2:46][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([N:20]([C:29]5[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=5)[C:21]([C:23]5([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]5)=[O:22])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:38]1
Reactant: O=S(=O)([O-])CCCCN1CC(O)C2(CC2)C1
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(OCCCN5CC(O)C6(CC6)C5)ccc34)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.4 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxy-quinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (266 mg, 0.56 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propylmethanesulfonate (283 mg, 1.14 mmol) and Cs2CO3 (556 mg, 1.71 mmol). The reaction was then stirred at rt for 2 days. The solvent was then removed and the residue was partioned between saturated NaHCO3 aqueous solution (15 mL) and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v) EtOAc/CH3OH/Et3N) to afford the title compound as a white solid (290 mg, 82%).
Reaction SMILES: C([Li])CCC.[C:6]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:7][C:8]([OH:10])=O.N1C=CC=CC=1C1C=CC=CN=1.[F:27][C:28]1[C:36]([O:37][CH3:38])=[C:35]([F:39])[C:34]([F:40])=[CH:33][C:29]=1C(Cl)=O>O1CCCC1.C(OCC)(=O)C>[OH:10]/[C:8](/[C:29]1[CH:33]=[C:34]([F:40])[C:35]([F:39])=[C:36]([O:37][CH3:38])[C:28]=1[F:27])=[CH:7]\[C:6]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)O
Reactant: COc1c(F)c(F)cc(C(=O)Cl)c1F
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\O)c1cc(F)c(F)c(OC)c1F
Temperature: 25 °C

Procedure:
Compound B is prepared using the general method of Wierenga and Skulnick (Wierenga, W.; Skulnick, H. I. J. Org. Chem. (1979) 44: 310-311). n-Butyllithium (1.6 M in hexanes) is added to a cooled (−78° C.) solution of tetrahydrofuran (10 mL) containing ethyl hydrogen malonate (180 μL, 1.50 mmol) and 2,2′-bipyridyl (˜1 mg as indicator). The temperature of the reaction mixture is allowed to rise to ca. −5° C. during the addition of n-butyllithium. Sufficient n-butyllithium (2.8 mL, 4.48 mmol) is added until a pink color persists at −5° C. for 5-10 min. A solution of 2,4,5-trifluoro-3-methoxybenzoyl chloride (0.75 mmol, vide supra) in tetrahydrofuran (˜3 mL) is added in one portion to the reaction mixture that had been recooled to −78° C. The resulting mixture is allowed to warm to room temperature, diluted with ethyl acetate (50 mL), and quenched with a 1 M aqueous solution of hydrochloric acid. The organic layer is washed with a 5% aqueous solution of sodium bicarbonate (2×30 mL), followed by brine (2×50 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product. This material is purified by flash column chromatography (eluting with 20% v/v ethyl acetate in hexanes) to give pure B as a white solid. 1H NMR (300 MHz, CDCl3): (enol, predominant tautomer, ≧90%) 81.32 (t, JH-H=7.0 Hz, 3H, CO2CH2CH3), 4.02 (apparent t, JH-F=1.0 Hz, 3H, OCH3), 4.25 (q, JH-H=7.0 Hz, 2H, CO2CH2CH3), 5.79 (s, 1H, CH3C(OH)═CH—CO2CH2CH3), 7.39 (ddd, JH-F=11.0 Hz, 8.5 Hz, 6.5 Hz, 1H, aromatic), 12.68 (s, 1H, OH). 19F{1H} NMR (282 MHz, CDCl3): δ−146.8 (dd, JF-F=21.5 Hz, 10.5 Hz, 1F), −140.2 (dd, JF-F=21.5 Hz, 13.5 Hz, 1F), −131.3 (dd, JF-F=13.5 Hz, 10.5 Hz, 1F).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)=O.CC(O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=1)[C:31]([OH:33])=[O:32]>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:34]1[CH:35]=[N:36][CH:28]=[CH:29][C:30]=1[C:31]([OH:33])=[O:32]
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(O)c1ccnc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-fluoro-4-iodoaniline (20.0 g, 84.38 mmol) in dry THF (80 mL) was cooled to −67° C. (dry ice/IPA bath) under nitrogen, prior to slow addition of 1.0 M lithium bis(trimethylsilyl)amide (255 mL, 255 mmol) via addition funnel, at a rate that kept the internal temp below −59° C. (˜2 h). After final addition, the yellow-green slurry was stirred for 30 min and then treated with 2-fluoroisonicotinic acid (8.0 g, 56.69 mmol). The bath was not removed, but the contents were allowed to slowly warm to room temp. After 4 days, the dark slurry was poured into a biphasic mixture of aqueous 2.0 N sodium hydroxide (1000 mL) and ethyl acetate (150 mL). The aqueous layer was separated and the organics were again extracted with base (1000 mL). The pH of the two aqueous layers was adjusted to ˜2 with concentrated hydrochloric acid. A yellow solid precipitated, which was filtered. The resultant yellow cake was washed with water (2×400 mL) and dried under high vacuum at 40° C. (17-19 g). LC/MS [(5.2 min; 359 (M+1)].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]O)(=[O:14])[CH:12]=[CH2:13].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>ClCCl>[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)OCCCCO
Reactant: O=C(O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: C=CC(=O)OCCCCOC(=O)c1ccc(O)cc1
Reaction time: 4 h
Yield: 5.2 %

Procedure:
2000 g of dichloromethane, 40.0 g of 4-hydroxybenzoic acid, 39.6 g of 4-hydroxybutyl acrylate and 0.05 g of methoquinone were charged into a separable flask of the same type as used in Reference Example 3, and then a liquid mixture consisting of 54.0 g of N,N'-dicyclohexylcarbodiimide, 5.9 g of dimethylaminopyridine and 60 g of dichloromethane was dropwise added thereto at room temperature over 4 hours, while replacing the flask inside gas with a nitrogen gas. After the same treatment as in Reference Example 1, 3.8 g of p-hydroxybenzoyloxybutyl acrylate of the following chemical formula was obtained (yield: 5%): ##STR4##
Reaction SMILES: [CH2:1]([NH:4][NH2:5])[CH2:2][CH3:3].[CH3:6][O:7][C:8]1[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=1.NN>C(Cl)Cl>[CH2:1]([N:4]([C:14]([NH:13][C:11]1[S:12][C:8]([O:7][CH3:6])=[N:9][N:10]=1)=[O:15])[NH2:5])[CH2:2][CH3:3]
Reactant: CCCNN
Reactant: COc1nnc(N=C=O)s1
Agent: NN
Solvent: ClCCl
Product: CCCN(N)C(=O)Nc1nnc(OC)s1
Temperature: 25 °C

Procedure:
A solution of propylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-Methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-propyl-4-(5-methoxy-1,3,4-thiadiazol-2-yl)semicarbazide as the residue.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11].I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>>[Br:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:12]
Reactant: CCCCCCCI
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCOc1ccc(Br)cc1C(=O)O

Procedure:
5-Bromo-2-heptyloxy-benzoic acid was prepared by reacting 5-Bromo-2-hydroxy-benzoic acid methyl ester (1.0 g, 4.32 mmol) with Iodoheptane (1.46 g, 6.49 mmol) as per general procedure G with potassium carbonate (1.5 g, 10.8 mmol) added to it. The ester thus obtained was subjected to hydrolysis as per general procedure C to yield the 5-Bromo-2-heptyloxy-benzoic acid (0.950 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]([O:12]CC)=O)[CH:5]=[C:4]([CH3:15])[N:3]=1.[C:16]1([CH2:22][CH2:23][NH2:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]([NH:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])[CH:5]=[C:4]([CH3:15])[N:3]=1
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)CSc1cc(C)nc(N)n1
Solvent: CO
Product: Cc1cc(SCC(=O)NCCc2ccccc2)nc(N)n1
Yield: 76.7 %

Procedure:
A mixture of 7.50 g (33.0 mmol) of ethyl 2-[(2-amino-6-methylpyrimidin-4-yl)thio]acetate, 4.40 g (36.3 mmol) of 2-phenylethylamine and 25 ml of MeOH was heated at 120° for 18 hrs. in a steel bomb. The reaction mixture was evaporated to a residual solid which yielded crude solid product (7.65 g, 76.7%), m.p. 114°-121° upon trituration with Et2O. The analytically pure sample was obtained after one recrystallization from 2-propanol, m.p. 130°-132° (3.79 g, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:34]=[C:35]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1>>[Cl:32][C:33]1[CH:34]=[C:35]([N:39]2[CH2:44][CH2:43][N:42]([C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:31])([F:30])[F:29])[C:9]=5[CH:17]=4)[CH:19]=3)=[O:23])[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: Clc1cccc(N2CCNCC2)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2cccc(Cl)c2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(3-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=625.97 (M+H+); retention time=1.05 minutes.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@@H:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][N:5]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])(=O)[NH2:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:36]2)=CC=1>O1CCCC1>[CH3:13][S:10]([O:9][C@H:7]1[CH2:6][N:5]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:4]([C:1](=[S:36])[NH2:2])[CH2:8]1)(=[O:12])=[O:11]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=S)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 2 h
Yield: 152.4 %

Procedure:
To a solution of (2S, 4R) -2-carbamoyl-4-methane-sulfonyloxy-1- (4-nitrobenzyloxycarbonyl)pyrrolidine (7 g) in tetrahydrofuran (210 ml) was added 2,4-bis(4-methoxyphenyl) -1, 3-dithia-2,4-diphosphetane-2,4-disulfide (3.65 g) and the solution was stirred for 2 hours under refluxing. After the solvent was removed, the resulting oily residue was subjected to a column chromatography on silica gel (150 g) eluting with a mixture of n-hexane and ethyl acetate (2:3 V/V) to give (2S, 4R) -4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl) -2-thiocarbamoylpyrrolidine (5.55 g).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4]([OH:6])=O.[CH3:13][C:14]([NH2:17])([CH3:16])[CH3:15].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(=O)([O-])O.[Na+]>[C:14]([NH:17][C:4](=[O:6])[C:3]1[C:7]([F:12])=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[F:1])([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(F)c(C(=O)O)c1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)c(C(=O)NC(C)(C)C)c1F
Reaction time: 2 h
Yield: 55.3 %

Procedure:
To a stirred solution of 2,6-difluoro-3-methylbenzoic acid (8.75 mmol, 1.5 g), 2-methylpropan-2-amine (9.43 mmol, 1 mL, 0.690 g) and triethylamine (28.7 mmol, 4 mL, 2.90 g) in dichloromethane (20 mL) was added 1-propanephosphonic acid cyclic anhydride (13.50 mmol, 8 mL, 8.59 g, 50% solution In ethyl acetate). The reaction was stirred for 2 hours before being diluted with dichloromethane and aqueous sodium hydrogen carbonate. The organic layer was separated, dried and concentrated under vacuum to yield the title compound (1.1 g). MS (ESI) m/z 228.4 [M+H]+
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].O=[C:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)[CH2:12][CH2:13][C:14]([OH:16])=[O:15]>O.C(O)C>[OH:9]/[N:8]=[C:11](\[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)/[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCC(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)CC/C(=N/O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
Sodium carbonate (0.80 g, 5.76 mmol) was added to hydroxylamine hydrochloride (0.80 g, 11.5 mmol) in water (3 mL), and the mixture stirred for 15 minutes with ice cooling. The resulting mixture was added to 4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (2.99 g, 8.86 mmol) (Example 1) in ethanol (50 mL) and the resulting mixture refluxed for 6 hours, concentrated to one-third volume, and allowed to cool. The resulting precipitate was dissolved in hot sodium bicarbonate solution, filtered, and the filtrate acidified with 1M HCl to yield a slurry which was filtered, washed with water, and dried in vacuo to give the title compound as a white solid (1.17 g, %C,H,N found: 71.77, 6.79, 7.88).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.[Na+].CN(C)CCN.O>CS(C)=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S([O-])c1ccc(Br)cc1
Reactant: O=Cc1ccccc1Br
Agent: CN(C)CCN
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccccc1S(=O)(=O)c1ccc(Br)cc1
Temperature: 110 °C
Yield: 54.9 %

Procedure:
2-Bromobenzaldehyde (1.55 g, 8.4 mmol), sodium 4-bromophenylsulfinate (2.79 g, 10 mmol) and copper(I) trifluoromethanesulfonate benzene complex (500 mg, 1 mmol) were combined in dimethylsulfoxide (10 mL) under nitrogen and degassed. The suspension was heated to 110° C. and N,N-dimethylethylenediamine (176 mg, 2 mmol) was added. The reaction was heated until the colour became clear and pale yellow, then cooled and poured into water. The products were extracted into ethyl acetate. The organic layer was washed with water:brine (1:1, ×5), dried over MgSO4 and evaporated in vacuo. The residue was triturated with isohexane to give 2-[(4-bromophenyl)sulfonyl]benzaldehyde (1.5 g, 55%). δH (400 MHz, CDCl3): 10.76 (1H, s), 8.14-8.12 (1H, m), 7.98-7.96 (1H, m), 7.76-7.68 (4H, m), 7.64-7.62 (2H, m).