Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5](Cl)=[O:6])[CH3:3].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:15]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([NH2:32])=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[C:16]2[CH2:21][CH2:20][CH2:19][N:17]2[N:18]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:1][N:2]([CH3:3])[CH2:4][C:5]([NH:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([C:15]3[C:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=4)=[N:18][N:17]4[CH2:19][CH2:20][CH2:21][C:16]=34)=[CH:23][CH:24]=[N:25]2)=[CH:30][CH:29]=1)=[O:6]
Reactant: Nc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: CN(C)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CN(C)CC(=O)Nc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1

Procedure:
A mixture of dimethylamino-acetyl chloride (620.0 mg, 13.33 mmol), 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ylamine (75 mg, 0.23 mmol), and 4-N,N-dimethylaminopyridine (10.2 mg, 0.09 mmol) in dry pyridine (1 mL) is refluxed for 72 h. The mixture is treated with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer is washed with brine, dried (sodium sulfate), concentrated in vacuo, and the residue chromatographed on SiO2 ((5% to 20% methanol in dichloromethane) to yield a yellow oil, 62.3 mg (67%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[CH3:9][O:10][C:11](=[O:27])[CH2:12]P(OCC(F)(F)F)(OCC(F)(F)F)=O>>[CH3:9][O:10][C:11](=[O:27])[CH:12]=[CH:7][C:4]1[S:5][CH:6]=[C:2]([Br:1])[CH:3]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Product: COC(=O)C=Cc1cc(Br)cs1
Yield: 78 %

Procedure:
4-Bromo-thiophene-2-carbaldehyde (44 g, 0.23 mol) and [Bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic methyl ester (80.6 g, 0.253 mol) were treated by the method outlined in Example 34, step a) to afford the subtitle compound that was purified by column chromatography (SiO2) using a 0-60% ethylacetate-hexane gradient (46.22 g, yield: 78%). MS calculated for C8H7BrO2S+H: 247, observed: 247 249.
Reaction SMILES: [C:1]1(=O)O[C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1(=O)OC(=O)C=[CH:13]1>CC1C=CC=CC=1C>[CH:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:1]=[CH:13][CH:12]=1
Reactant: O=C1C=CC(=O)O1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1C
Product: c1ccc2ccccc2c1

Procedure:
We have found that in the continuous isolation of phthalic anhydride and maleic anhydride from the reaction gases obtained by catalytic oxidation of o-xylene or naphthalene with air, by treating the reaction gases with a solvent, the disadvantages mentioned are avoided if
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:30][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: NC1CCCCC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CNC2CCCCC2)cc1
Yield: 68.8 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-((cyclohexylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.070 g; 0.202 mmol), cyclohexanamine (0.105 mL; 0.907 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 2 to 10% methanol in dichloromethane) furnished 0.057 g (69%) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH:8]=[CH:9][C:10]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1.O>CN(C)C=O>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:8]([C:7]3[CH:23]=[CH:24][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH:9]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[NH:35]2)=[CH:30][CH:29]=1
Reactant: O=C(C=Cc1ccc([N+](=O)[O-])cc1)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2NC(C=Cc3ccc([N+](=O)[O-])cc3)=CC2c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A solution of bis (4-nitrobenzal)acetone (1.62 g; 0.005 m) and 4-methoxy-phenyl-hydrazine hydrochloride (0.87 g; 0.005 m) in dimethylformamide (25 ml.) was heated at 100° C. for 4 hours to give a dark red solution, which was drowned into water (100 ml.) The crude solid product was filtered, water washed and was recrystallised from butanol to give a dark red solid (1.0 g; 45% theory)
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[CH:12]=[CH:11][O:10][C:9]=1[C:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]([C:25]([O:27]C)=[O:26])(O)[O:15][N:14]=1.[ClH:29]>O.CO>[Cl:29][C:11]1[O:10][C:9]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:25]([OH:27])=[O:26])[O:15][N:14]=2)=[CH:8][CH:12]=1
Reactant: Cl
Reactant: COC(=O)C1(O)ON=C(c2occc2Cl)C1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1onc(-c2ccc(Cl)o2)c1-c1ccccc1

Procedure:
A solution of Na2CO3 (237 mg, 2.24 mmoles) in water (10 ml) was added to the methyl [3-(chlorofuran-2-yl)-4-phenyl-5-hydroxy-2-isoxazolin-5-yl]carboxylate (360 mg, 1.12 mmoles) in MeOH (10 ml). The reaction mixture was heated under reflux conditions for 2 h. It was then acidified with HCl and then the MeOH was distilled at a reduced pressure and CHCl3 was added. The two phases were separated and the aqueous phase was extracted three times with CHCl3. The combined organic phases were dried over anhydrous Na2SO4 and the solvent evaporated at a reduced pressure to give the crude [3-(5chlorofuran-2-yl)-4-phenylisoxazol-5-yl]carboxylic acid which is purified by crystallisation from CHCl3/hexane (300 mg, 93% yield). M.p. 168-170° C. FT-IR (KBr): 3500-2850, 1709, 1614, 1592, 1521, 1454, 1416, 1392, 1305, 1249, 1208, 1153, 1122, 1022, 1006, 981, 941, 899, 779, 696 cm−1. 1H NMR (300 MHz, CDCl3, δ): 7.48-7.42 (m, 3H, aromatic protons); 7.39-7.32 (m, 2H, aromatic protons); 7.00-6.50 (bs, 1H, OH: exchange with D2O); 6.14 (d, J=3.6 Hz, 1H, furyl proton); 6.12 (d, J=3.6Hz, 1H, furyl proton). 13C NMR (75 MHz, CDCl3, δ): 159.9, 154.8, 153.6, 141.6, 139.2, 129.4, 129.1, 128.3, 126.8, 123.9, 114.8, 107.9. LC-MS (ESI−): 288[(M−1)−, 69], 117 (100). Anal. Calc. for C14H8ClNO4: C, 58.05; H, 2.78; N, 4.83. Found: C, 58.07; H, 2.75; N, 4.80.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH:10]([OH:24])[CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[C:14]=2[C:15]#[N:16])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].C1CCCCC=1>C(O)C.[Pd]>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH:10]([OH:24])[CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:14]=2[C:15]#[N:16])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(O)COc2cccc([N+](=O)[O-])c2C#N)ccc(C(C)=O)c1O
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCCc1c(OCC(O)COc2cccc(N)c2C#N)ccc(C(C)=O)c1O
Temperature: 25 °C
Yield: 65.8 %

Procedure:
A solution of 10 g of 2-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-6-nitrobenzonitrile, 2.5 g 10% Pd on carbon and 10 g cyclohexene in 500 ml absolute ethanol is refluxed for 30 min. The reaction mixture is cooled to room temperature, filtered through Celite and freed of solvent. Trituration with diethyl ether and drying of the insolubles gives 6.1 g of the title compound as a white solid, m.p. 123°-125° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]2[C:8](=[O:20])[C@@H:9]([NH:10][C:11](=[O:19])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:5]2[S:4][CH2:3]1.C(OC(=O)C)(=O)C>CS(C)=O>[O:1]=[C:2]1[CH2:7][N:6]2[C:8](=[O:20])[C@@H:9]([NH:10][C:11](=[O:19])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:5]2[S:4][CH2:3]1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C[C@H](O)CS[C@H]12
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: O=C1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2C1
Reaction time: 16 h
Yield: 76.4 %

Procedure:
(3S,6R,7R)-3-Hydroxy-7-phenylacetamidocepham (29 mg.) in dimethylsulphoxide (1 ml.) was treated with acetic anhydride (0.2 ml.) After being kept at 24° for 16 hour the reaction mixture was partitioned between brine and ethyl acetate. Removal of the ethyl acetate gave (6R,7R)-3-keto-7-phenylacetamidocepham (22 mg.). T.1.c. and g.1.c. data were in agreement with those obtained on material prepared in Example 3a. EXAMPLE 3d
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21](C)[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])(C(C)(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].CCOCC>C1COCC1>[C:49]1(=[O:50])[N:45]([O:8][CH2:9][C@H:10]2[O:14][C@@H:13]([N:15]3[CH:23]=[CH:21][C:19](=[O:20])[NH:18][C:16]3=[O:17])[CH2:12][C@@H:11]2[OH:24])[C:46](=[O:55])[C:47]2=[CH:54][CH:53]=[CH:52][CH:51]=[C:48]12
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 5′-O-t-butyldimethylsilylthymidine (1, 21.36 g, 60 mmol, prepared according to the procedure of Nair, et al., Org. Prep. Procedures Int. 1990, 22, 57 in dry THF (750 ml)), triphenylphosphine (17.28 g, 66 mmol) and N-hydroxyphthalimide (10.74 g, 66 mmol) were added. The solution was cooled to 0° C. and diisoprbpylazodicarboxylate (15.15 g, 75 mmol) was added dropwise over a period of 3 hr while stirring under nitrogen. The reaction mixture was then stirred at room temperature for 12 hr. The solution was evaporated and the residue was dissolved in CH2Cl2 (750 ml), extracted with sat. NaHCO3 (200 ml), and water (200 ml), dried (MgSO4), filtered and concentrated to furnish yellow oily residue. Silica gel column chromatography (100% hexanes, and then hexanes:Et2O gradient to 90% Et2O) of the residue gave compound 2 as a colorless glass (18.68 g, 62%); 1H NMR (CDCl3) δ 0.05 [2s, 6, (CH3)2], 0.91 [s, 9, (CH3)3], 2.0 (s, 3, CH3), 2.5-2.65 (m, 2, 2′CH2), 4.05-4.2 (m, 2, 5′CH2), 4.25-4.35 (m, 1, 4′H), 5.0 (m, 1, 3′H), 6.15 (m, 1, 1′H), 8.6 (br s, 1, NH), and aromatic protons. Anal. Calcd. for C24H31N3O7Si: C, 57.46;H, 6.23; N, 8.37. found : C, 57.20; H, 6.26; N, 8.27.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[C:69]([C:70](O)=[O:71])=[CH:68][O:67][N:66]=1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:70]([C:69]5[C:65]([CH3:64])=[N:66][O:67][CH:68]=5)=[O:71])[CH2:50][CH2:51]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: Cc1nocc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)c2conc2C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 21.1 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 3-methyl-4-isoxazolecarboxylic acid (0.128 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(3-methylisoxazol-4-yl)carbonyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.068 g). 1H NMR Spectrum: (DMSO d6 373K) 1.86 (m, 2H), 2.02 (m, 2H), 2.30 (s, 3H), 3.52 (m, 2H), 3.82 (m, 2H), 3.96 (s, 3H), 4.79 (m, 1H), 7.22 (m, 1H), 7.22 (s, 1H), 7.40 (m, 1H), 7.58 (m, 1H), 7.89 (s, 1H), 8.39 (s, 1H), 9.00 (s, 1H), 9.25 (br s, 1H); Mass Spectrum: (M+H)+ 512
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][O:20][CH3:21])=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[CH2:41]([O:48][C:49](=[O:52])[CH2:50][NH2:51])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)Cl>[CH2:41]([O:48][C:49](=[O:52])[CH2:50][NH:51][C:22]([C:10]1[N:11]=[C:12]([CH2:19][O:20][CH3:21])[C:13]2[C:18]([C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:23])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: COCc1nc(C(=O)O)c(OCc2ccccc2)c2ccccc12
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1nc(C(=O)NCC(=O)OCc2ccccc2)c(OCc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To a mixture of 4-benzyloxy-1-methoxymethyl-isoquinoline-3-carboxylic acid (120 mg, 0.37 mmol), NEt3 (109 μl, 0.78 mmol), and CH2Cl2 (7 ml) cooled with an ice bath was added ClCO2iBu (52 μl, 0.39 mmol) with stirring. After stirring for 15 min glycine benzyl ester hydrochloride (79 mg, 0.39 mmol) was added and the mixture was stirred for another 15 min before the ice bath was removed. Stirring was then continued at ambient temperature for additional 1.5 h. Subsequently the mixture was concentrated in vacuo. To the residue was added water (10 ml) and a few drops of aqueous 6N HCl. The mixture was extracted with EtOAc (15 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give a yellowish gum. Purification by flash column chromatography on silica gel using hexanes:EtOAc=7:3 as the eluent gave the title compound as a yellow oil (141 mg); MS-(+)-ion: M+1=471.1.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:25]([O:42][C@@H:43]1[CH2:60][CH2:59][C@@:58]2([CH3:61])[C@@H:45]([CH2:46][CH2:47][C@@H:48]3[C@@H:57]2[CH2:56][CH2:55][C@@:53]2([CH3:54])[C@H:49]3[CH2:50][CH2:51][C@@H:52]2[CH:62]=O)[CH2:44]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]([Br:5])=[CH:62][C@H:52]1[CH2:51][CH2:50][C@H:49]2[C@H:48]3[C@H:57]([CH2:56][CH2:55][C@:53]12[CH3:54])[C@:58]1([CH3:61])[C@H:45]([CH2:44][C@H:43]([O:42][Si:25]([C:38]([CH3:39])([CH3:41])[CH3:40])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:60][CH2:59]1)[CH2:46][CH2:47]3
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C=C(Br)Br)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of tetrabromomethane (1.99 g, 6 mmol) in anhydrous methylene chloride (31 mL) was added at 0° C., triphenylphosphine (3.14 g, 6 mmol) and the resulting mixture is stirred for 10 min. Subsequently, a solution of 3α-(t-butyidiphenylsilyloxy)-5α-androstan-17β-carboxaldehyde (540 mg, 1 mmol) in methylene chloride (6 mL) was added and the mixture was stirred at 0° C. for an additional 10 min. The reaction mixture was diluted with ethyl acetate and the organic layer is washed with water, saturated aqueous NaCl solution and was dried with anhydrous Na2SO4. The solvent was evaporated in vacuo and the residue was purified with flash column chromatography using petroleum ether/ether 95/5 as eluent afforded the desired compound named.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]1[CH:12]=[N:13][NH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:10][C:11]1[CH:12]=[N:13][N:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH:15]=1
Reactant: O=Cc1ccccc1F
Reactant: Cc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cnn(-c2ccccc2C=O)c1
Temperature: 100 °C

Procedure:
2-Fluorobenzaldehyde (250 mg, 2.01 mmol), 4-methyl-1H-pyrazole (260 mg, 3.17 mmol) and potassium carbonate (820 mg, 5.93 mmol) are combined in DMSO (15 mL) and warmed to 100° C. for 18 hours. The reaction mixture is cooled to room temperature and the potassium carbonate is removed via filtration. The solids are washed with EtOAc and the combined filtrates are poured into water. Separate the layers and extract the aqueous phase with EtOAc (1×). The combined organics are washed with water and brine and dried (MgSO4), filtered, and concentrated. Purification via flash chromatography (12 g silica gel, 0-15% EtOAc/heptane) gives 2-(4-methyl-pyrazol-1-yl)-benzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([CH3:35])[C:29]=1[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:5][NH:6][C:7](=[O:26])[CH:8]=[CH:9][C:10]1[C:11]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([CH3:35])[C:29]=1[NH:30][S:31]([CH3:34])(=[O:32])=[O:33])[CH2:5][NH:6][C:7](=[O:26])[CH2:8][CH2:9][C:10]1[C:11]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1
Reactant: Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2N2CCOCC2)cc(F)c1NS(C)(=O)=O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(CNC(=O)CCc2ccc(C(F)(F)F)nc2N2CCOCC2)cc(F)c1NS(C)(=O)=O
Yield: 61.5 %

Procedure:
A suspension of N-(3-fluoro-4-methanesulfonylamino-5-methyl-benzyl)-3-(2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (32 mg, 0.069 mmol) and 10% Pd/C (3 mg) in MeOH was reacted under hydrogen of 40 psi pressure. The reaction mixture was filtered through celite and then concentrated under reduced pressure to give N-(3-fluoro-4-methanesulfonylamino-5-methyl-benzyl)-3-(2-morpholin-4-yl-6-trifluoromethyl-pyridin-3-yl)-propionamide (22 mg, 69%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:28]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])[NH:29][NH2:30].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[C:33]([O:32][C:28]([NH:29][NH:30][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([O:18][C@H:15]2[CH2:16][CH2:17][C@H:12]([C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]3)=[O:11])[CH2:13][CH2:14]2)=[CH:27][CH:26]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)O)cc3)CC2)CC1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)NNC(=O)OC(C)(C)C)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 420 mg (0.93 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid, 156 mg (1.18 mmol) of tert-butyl carbazate, 272 mg (1.42 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 192 mg (1.42 mmol) of 1-hydroxybenzotriazole, and 574 mg (5.67 mmol) of N-methylmorpholine in 10 ml of dichloromethane was stirred for 3 h at room temperature. After evaporation, the mixture was diluted with AcOEt, washed with water and saturated NaHCO3 solution, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica eluting with dichloromethane and methanol=from 98:2 to 19:1. The combined product fractions were evaporated to dryness to yield 0.46 g (quant.) of the title compound. MS (m/e): 489.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][C:40]1[S:44][CH:43]=[N:42][C:41]=1[CH3:45])[CH2:24][NH:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:27]1=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:25]([CH2:24][C:23]2[CH:34]=[CH:35][C:36]([O:37][CH2:38][CH2:39][C:40]3[S:44][CH:43]=[N:42][C:41]=3[CH3:45])=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:27]2=[O:33])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(CNC2CCCCNC2=O)ccc1OCCc1scnc1C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)ccc1OCCc1scnc1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-chlorobenzenesulfonylchloride (0.26 mmol) was added to a methylene chloride (0.2 M) solution of triethylamine (1.0 mmol) and 3-{3-Methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzylamino)-azepan-2-one (7) (0.26 mmol), and stirred at room temperature for 12 h. The product (8) was obtained by purification upon reverse phase HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[C:10]([NH:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1)#[N:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:18]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]2=[N:12][C:10]#[N:11])=[CH:4][N:3]=1
Reactant: N#CNc1ncccn1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CN=c1ncccn1Cc1ccc(Cl)nc1
Yield: 38.1 %

Procedure:
A mixture of 2-chloro-5-chloromethylpyridine (3.24 g), 2-cyanaminopyrimidine(2.4 g), anhydrous potassium carbonate (3.04 g) and acetonitrile (100 ml) was refluxed for 5 hours under stirring. About 50 ml of the acetonitrile were evaporated under reduced pressure, and the residue was poured into ice water. The precipitated crystals were collected by filtration, and recrystallized from ethanol to give 1-(2-chloro-5-pyridylmethyl)-2-cyanoimino-1,2-dihydropyrimidine (1.87 g) as colorless crystals. mp. 218°-220° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=2)[CH2:4]1.Cl[C:24]1[N:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[N:27]1[CH:26]=[CH:25][CH:24]=[N:29][C:28]=1[N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=2)[CH2:4]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCNC2)cn1
Reactant: Clc1ccncn1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(c3ncccn3)C2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
To a solution of ethyl (2E)-3-{5-[(3R)-3-piperidinylamino]-2-pyrazinyl)acrylate dihydrochloride (300 mg, 0.86 mmol) in DMF (6 mL) were added diiopropylethylamine (366 mg, 2.84 mmol) and 6-chloropyrimidine (128 mg, 1.11 mmol) at ambient temperature and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH=95-5/hexane-EtOAc=1/4) to give ethyl (2E)-3-(5-{[(3R)-1-(2-pyrimidinyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate (141 mg, 46%) as an amorphous powder.