Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])I.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOCC.C1C=CC([P]([Ni]([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>[Cl:8][C:9]([F:15])([F:14])[C:10]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)([F:13])[F:12]
Reactant: Nc1ccccc1
Reactant: FC(F)(Cl)C(F)(F)I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Ni]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1ccc(C(F)(F)C(F)(F)Cl)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Ni(PPh3)4 (222 mg, 0.2 mmol) was added to a mixture of aniline (745 mg, 8 mmol) and 1-chloro-1,1,2,2-tetrafluoro-2-iodoethane (1049 mg, 4 mmol) in DMF (10 mL) in a MW vial under an argon atmosphere. The vial was sealed and the RM was stirred for two days at 80° C. After cooling at RT, the RM was dissolved in Et2O, washed with NaHCO3 10% and brine, dried over MgSO4 and the solvent was evaporated off under reduce pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 0 to 25% EtOAc) and further by reverse phase chromatography (MPLC, Lichroprep® 15-25 μm column, eluents: water+0.1% formic/MeCN+0.1% formic acid, gradient 10 to 50% MeCN+0.1% formic acid). The fractions containing pure product were combined and the MeCN was evaporated off under reduced pressure to give an aq. phase which was neutralized with NaHCO3 and extracted with Et2O. The combined extracts were dried over MgSO4 and the solvent was evaporated off under reduced pressure to afford the title compound as a red oil. HPLC (Condition 4) tR=5.48 min, UPLC-MS (Condition 3) tR=1.04 min, m/z=269 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[CH2:7]([Li])CCC.[C:12](=[O:14])=[O:13]>O1CCCC1.CCCCCC>[CH3:1][C:2]1[N:3]=[C:4]([C:12]([O:14][CH3:7])=[O:13])[S:5][CH:6]=1
Reactant: Cc1cscn1
Reactant: O=C=O
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1nc(C)cs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methylthiazole (10 g) in anhydrous tetrahydrofuran (200 ml) was added n-butyl lithium in hexane (34.65 ml of 1.6M solution) dropwise at −78° C. The solution was stirred at −78° C. for 1 hour, at which point carbon dioxide gas was passed through the solution for 20 mins at −78° C. The solution was then allowed to warm to room temperature over 2 hours, the precipitate was filtered off, dissolved in methanol (200 ml) and added to methanolic hydrogen chloride (200 ml). The solution was stirred at room temperature overnight. The solvent was removed under vacuum and diethyl ether was added to the residue. The resultant solid was filtered off to yield the title compound as a white solid (2.2 g). 1H NMR (250 MHz, DMSO) δ 2.44 (3H, s), 3.89 (3H, s), 7.74 (1H, s).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=1)=[O:28]>CC#N>[Cl-:25].[C:36]([C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([CH2:26][N+:1]23[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[O:28])=[N:31][CH:32]=1)#[N:37]
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: N#Cc1ccc(NC(=O)CCl)nc1
Solvent: CC#N
Product: N#Cc1ccc(NC(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)C2(c4ccccc4)CCCCCC2)C3)nc1
Product: [Cl-]
Yield: 38.2 %

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (Example 14e) (0.30 mmol) and 2-chloro-N-(5-cyano-pyridin-2-yl)-acetamide (Example 51a) (0.36 mmol) in MeCN (1.5 mL) were stirred together at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue purified by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to give the title compound as a white solid (60 mg).
Reaction SMILES: [OH:1]P(O)(O)=O.[ClH:6].[N:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1.C[C:14]#[N:15]>>[ClH:6].[N:7]1[CH:12]=[CH:11][CH:10]=[N:9][C:8]=1[C:14]([NH2:15])=[O:1]
Reactant: O=P(O)(O)O
Reactant: c1cncnc1
Reactant: CC#N
Agent: Cl
Product: NC(=O)c1ncccn1
Reaction time: 0.08 h

Procedure:
HPLC conditions: Column: Zorbax, Rx C8 250×4.6 mm; Temperature: 30° C.; Detection at 210 nm; Mobile Phase: 0.1% aq H3PO4 (A)/MeCN (B); Gradient: 90:10 (A)/(B) to 10:90 over 15 min, 10:90 hold for 5 min, 10:90 to 90:10 (A)/(B) over 10 seconds; Flow Rate: 1 mL/min. Retention time: the seven-membered ring-pyrimidine hydrochloride salt 11—8.118 minutes.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:16](=[O:18])[CH3:17])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.[NH:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:20]([C:25]([OH:27])=O)[CH2:21][CH:22]([CH3:24])[CH3:23].CCN=C=N[CH2:40][CH2:41][CH2:42]N(C)C.Cl>ClCCl.CN(C1C=CN=CC=1)C>[C:16]([C:5]1[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:14])([CH3:13])[CH3:15])[CH:7]=[C:3]([CH2:2][O:1][C:25](=[O:27])[C@@H:20]([NH:19][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:21][C:22]2[CH:23]=[CH:42][CH:41]=[CH:40][CH:24]=2)[N:4]=1)(=[O:18])[CH3:17]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(=O)c1nc(CO)cn1COCC[Si](C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)c1nc(COC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cn1COCC[Si](C)(C)C
Reaction time: 24 h

Procedure:
The compound (2.00 g) obtained in (3) was dissolved in dichloromethane (10 mL), and Boc-Leu-OH (2.21 g), EDC.HCl (2.13 g), and DMAP (0.99 g) were added while stirring. After the stirring was continued for 1 day, the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/chloroform=0%→25%) using silica gel column (product name: Hi-Flash Column 3 L, manufactured by Yamazen Corporation) to afford the title compound (3.20 g).
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH:12]2[C:21]3[C:16](=[C:17]([C:22]#[N:23])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][O:13]2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[N:9]1([CH2:11][CH:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([C:22]#[N:23])[C:16]=3[CH2:15][CH2:14][O:13]2)[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)C1CN(CC2OCCc3c(C#N)cccc32)CCN1C(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1cccc2c1CCOC2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,1-dimethylethyl-4-[(5-cyano-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine-1-carboxylate (150 mg, 0.42 mmol) in 10 mL of DCM was added 5 mL of 4N HCl/dioxane, and the mixture was stirred at room temperature for 2 hours. The solvents was removed off under vacuum to afford 1-(piperazin-1-ylmethyl)-3,4-dihydro-1H-isochromene-5-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)=[CH:15][C:6]1=2.[N:30]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:37][CH2:36][CH2:35][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:22])=[CH:18][CH:17]=3)=[CH:15][C:6]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2c(Cl)cccc2Cl)C(=O)CN3)cc1
Reactant: NCCN1CCCC1
Product: O=C(NCCN1CCCC1)c1ccc(-c2cnc3c(c2)N(Cc2c(Cl)cccc2Cl)C(=O)CN3)cc1
Yield: 26 %

Procedure:
4-[1-(2,6-Dichlorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (40 mg) was coupled to 2-pyrrolidin-1-yl-ethylamine as in General Procedure 8 to give the title compound as an off-white solid (26% yield). M.p.>200° C., LCMS: m/z=524.11 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.82 (4H, m), 2.60 (4H, m), 2.74 (2H, m), 3.59 (2H, m), 4.26 (2H, s), 4.85 (1H, bs), 5.56 (2H, s), 7.16 (1H, m), 7.32 (2H, d, J=8.1 Hz), 7.39 (2H, d, J=8.3 Hz), 7.82 (2H, d, J=8.3 Hz), 7.96 (1H, d, J=1.8 Hz).
Reaction SMILES: [Mg:1].II.C([Cl:8])CCC.[CH3:9][CH:10]([CH2:13][CH2:14][CH3:15])[CH2:11][OH:12]>CCCCCCCCC(C)C>[CH3:9][CH:10]([CH2:13][CH2:14][CH3:15])[CH2:11][O:12][Mg:1][Cl:8]
Reactant: CCCCCl
Reactant: [Mg]
Reactant: CCCC(C)CO
Agent: CCCCCCCCC(C)C
Agent: II
Product: CCCC(C)CO[Mg]Cl

Procedure:
Following the procedure of Example 1, 24.3 gm of magnesium metal chips were placed in a 3 necked 3 liter reactor with 0.25 g I2 crystals and 1500 ml of Isopar G solvent. A fraction of isoparaffinic hydrocarbons (Isopar G) having a boiling range of 157° to 176° C. The magnesium was iodine-activated by heating under argon and at reflux for 90 minutes. The activated magnesium metal slurry in Isopar G was then reacted with 104 ml of n-butyl chloride (lM) at the solvent reflux temperature. After two hours of reaction, 125 ml of 2-methyl-1-pentanol was added slowly with good agitation. The thick reaction slurry was agitated at reflux for two hours. Because of the viscous nature of the thick slurry, it was difficult to filter when it was hot. Therefore, the solvent was removed under reduced pressure at 90°-100° C. The dried solid obtained was not a powder, but sticky gray flakes. Dried product was analyzed and found to contain 15.21% Mg; 58.95%
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14](O)=O)=[C:7]2[N:6]=[N:5]1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>C(Cl)(Cl)Cl>[S:24]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:14]1[C:13]1[N:12]=[CH:11][N:8]2[C:9](=[O:10])[N:4]([CH2:3][O:2][CH3:1])[N:5]=[N:6][C:7]=12
Reactant: Nc1ccccc1S
Reactant: COCn1nnc2c(C(=O)O)ncn2c1=O
Solvent: ClC(Cl)Cl
Product: COCn1nnc2c(-c3nc4ccccc4s3)ncn2c1=O
Temperature: 70 °C

Procedure:
To a mixture of polyphosphate ester (see, e.g., Yalpn et al., Eur. J. Med. Chem., 1992, Vol. 27, pp. 401-406) (1 g) and chloroform (3 mL) was added 3-(methoxymethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (225 mg; 1 mmol) and 2-aminothiophenol (107 μL; 1 mmol). The mixture was carefully heated to 70° C. for 3.5 hours, then cooled and the chloroform removed under reduced pressure. The residue was added to water (100 mL), which was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4) and concentrated. The crude product was washed with ether/hexane, and purified by column chromatography to give a pale yellow powder (0.007 g; 3%). δH (DMSO d6): 9.03 (1H, s), 8.22 (1H, d, J=7.9), 8.17 (1H, d, J=7.9), 7.61 (1H, td, J=7.7, 1.3), 7.53 (1H, td, J=7.6, 1.2), 5.65 (2H, s), 3.46 (3H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl.O>[CH3:19][S:20]([O:11][CH2:10][CH2:9][CH2:8][C:7]#[C:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:22])=[O:21]
Reactant: OCCCC#Cc1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC#Cc1cccs1
Reaction time: 0.5 h

Procedure:
To a solution of 145 mg of 2a and 200 μl of triethyl amine in 2 ml of dichloromethane was added dropwise at 0° C. 80 μl of methanesulfonyl chloride in 1 ml of dichloromethane. The reaction mixture was stirred for ½ hr and then diluted with 10 ml of water and extracted with dichloromethane. The organic layer was washed with 1M K2CO3, dried and concentrated, to provide 210 mg of essentially pure 2b as an oil; Rf (heptane/ethyl acetate 1/1) 0.55. NMR (CDCl3): δ 2.03 (m, 2, CH2), 2.60 (t, 2, CH2), 4.40 (t, 2, CH2), 3.03 (s, 3, CH3SO2), 6.95, 7.13, 7.20 (3×m, 3, thiophene-H).
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:13]3[CH:16]([S:17][CH:18]=2)[C:15]([CH:20](OC(=O)C)[C:21]2[CH:32]=[CH:31][C:24]4[N:25]=[C:26]5[N:30]([C:23]=4[CH:22]=2)[CH2:29][CH2:28][S:27]5)(Br)[C:14]3=[O:37])=[O:11])=CC=1)([O-])=O.[H][H]>C1COCC1.P([O-])([O-])([O-])=O>[S:27]1[C:26]2=[N:25][C:24]3[CH:31]=[CH:32][C:21](/[CH:20]=[C:15]4\[C@@H:16]5[N:13]([C:14]\4=[O:37])[C:12]([C:10]([OH:11])=[O:9])=[CH:18][S:17]5)=[CH:22][C:23]=3[N:30]2[CH2:29][CH2:28]1
Reactant: CC(=O)OC(c1ccc2nc3n(c2c1)CCS3)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CSC21
Reactant: [H][H]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3ccc4nc5n(c4c3)CCS5)C(=O)N12
Yield: 8.1 %

Procedure:
6-[Acetoxy-(2,3-dihydro-benzo[4,5]imidazo[2,1-b]thiazol-6-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (690 mg, 1.1 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous phosphate buffer. The mixture was then subjected to 45 psi hydrogen for two hours. Then it was filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution was then cooled to zero degree and basified to pH=8 with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1 liter of water followed by 5%-25% acetonitrile and water. Water was then removed through concentrate in vacuo and 32 mg of product (Yield 3%) was collected. MP: >250° C.; H-NMR (D2O): □ 7.08 (m, 6H), 7.36 (s, 1H), 4.05 (m, 2H), 3.90 (b, 1H); MS: 358.3 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24]2[S:25][CH:26]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:27][N:28]=2)=[CH:14]3)=[CH:6][CH:5]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24]2[S:25][CH:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][N:28]=2)=[CH:14]3)=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC(C)C)c3[nH]2)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COCc1ccc(Oc2cc(OC(C)C)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A mixture of ethyl {2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (680 mg), tetrahydrofuran (5 mL), ethanol (5 mL) and 1M aqueous sodium hydroxide solution (5 mL) was stirred at 50° C. for 30 min, and then cooled to room temperature. Water and 1M hydrochloric acid (5 mL) were added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the title compound (600 mg, 94%) as a yellow amorphous solid. MS 456 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:67]([N:70]1[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1)(=[O:69])[CH3:68]>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]([N:73]3[CH2:74][CH2:75][N:70]([C:67](=[O:69])[CH3:68])[CH2:71][CH2:72]3)=[O:11])=[CH:19][CH:18]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Reactant: CC(=O)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N3CCN(C(C)=O)CC3)cc2)cc1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
The hydrogenated compound 4 (2.0 g, 4.6 mmol) was dissolved in CH2Cl2 (20 mL) and stirred at room temperature under an atmosphere of argon. Triethylamine (0.75 mL, 5.4 mmol) and BOP reagent (2.19 g, 4.96 mmol) were added and the reaction mixture was stirred for 15 min. 1-Acetylpiperazine (1.16 g, 9.02 mmol) was added and the resulting solution was stirred at room temperature for about 2 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (75 mL). The organic layer was extracted with 1.0 N NaOH (1×10 mL), water (2×30 mL) and brine (1×30 mL). Drying and concentration of the organic layer gave the desired amide 18 (2.4 g, ˜96%). 1H NMR (400 MHz, DMSO-d6): 7.24 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 6.87 (d, J=7.6 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 4.58 (m, 1H), 3.50 (s, 3H), 3.27-3.46 (m, 8H), 3.08-3.13 (m, 1H), 2.77-2.83 (m, 3H), 2.61 (t, J=7.2 Hz, 2H), 1.99 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: C[C@H:2]1[CH2:33][C:32](C)=[CH:31][C@@H:30](CC=C)[C:28](=[O:29])[CH2:27][C@H:26](O)[C@@H:25](C)[C@@H:24](/[C:40](/C)=[CH:41]/[C@H:42]2[CH2:47][C@@H:46](OC)[C@H:45](O)[CH2:44][CH2:43]2)OC(=O)[C@H]2N(CCCC2)C(=O)C(=O)[C@]2(O)[O:10][C@@H:5]([C@@H:6](OC)C[C@H]2C)[C@@H:4]([O:56]C)[CH2:3]1.N(CCCC(OCC[Si](C)(C)C)=O)=C=[O:60].[CH:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1>C(N(CC)CC)C>[CH3:6][C:5](=[O:10])[C:4](=[O:56])[CH2:3][CH2:2][CH2:33][CH2:32][CH2:31][CH2:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:40][C:41](=[O:60])[CH2:42][CH:43]=[CH:44][CH2:45][CH2:46][CH2:47][CH2:73][CH2:78][CH2:77][CH2:76][CH2:75][CH3:74]
Reactant: C[Si](C)(C)CCOC(=O)CCCN=C=O
Reactant: c1ccccc1
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: CCN(CC)CC
Product: CCCCCCCCCC=CCC(=O)CCCCCC(=O)CCCCCCC(=O)C(C)=O
Reaction time: 2 h

Procedure:
A solution of the FR-900506 substance (310 mg), 2-trimethylsilylethyl 4-isocyanatobutyrate (350 mg) and triethylamine (6 drops) in anhydrous benzene (4 ml) was heated at 50° C. with stirring for 2 hours. The reaction mixture was allowed to stand at room temperature overnight. The mixture was concentrated to dryness under reduced processure to leave a residue, which was chromatographed on silica gel in chloroform. Elution was carried out with chloroform to give 17-allyl-12-[2-[3-methoxy-4-{3-(2-trimethylsilylethoxycarbonyl) propylcarbamoyloxy)cyclohexyl]-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11, 28-dioxa-4-azatricyclo[22.3.1.04,9 octacos-18-ene-2,3,10,16-tetraone (99 mg). This product was treated with tetra(n-butyl)ammonium fluoride (0.12 m mole) in tetrahydrofuran (2.5 ml) at room temperature for 20 minutes. The reaction mixture was concentrated to dryness under reduced pressure to leave a residue, which was purified with preparative thin layer chromatography on silica gel. Elution with a mixture of chloroform and methanol (5:1) gave 17-allyl-12-[2-{4-(3-carboxypropylcarbamoyloxy)-3-methoxycyclohexyl}-1-methylvinyl]-1, 14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (18.1 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.Cl[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=1.[C:31]([O-:34])(O)=[O:32].[Na+]>CN1C(=O)CCC1>[F:28][C:27]([F:30])([F:29])[C:31]([OH:34])=[O:32].[Cl:1][C:2]1[N:3]=[C:4]([C:14]2[CH2:15][CH2:16][N:17]([C:21]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:18][CH:19]=2)[NH:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1
Reactant: Fc1ccc(-c2[nH]c(C3=CCNCC3)nc2Cl)cc1
Reactant: O=C([O-])O
Reactant: FC(F)(F)c1cccnc1Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Fc1ccc(-c2[nH]c(C3=CCN(c4ncccc4C(F)(F)F)CC3)nc2Cl)cc1
Product: O=C(O)C(F)(F)F
Temperature: 180 °C

Procedure:
A mixture of 4-[4-chloro-5-(4-fluoro-phenyl)-1H-imidazol-2-yl]-1,2,3,6-tetrahydro-pyridine from step (c) above, 2-chloro-3-trifluoromethyl-pyridine (125 mg, 0.689 mmol, TCI America) and NaHCO3 (84 mg, 1.0 mmol) in NMP (3 mL) was heated at 180° C. in a microwave synthesizer for 0.5 h. The reaction mixture was cooled to RT and was filtered. The filter cake was washed with NMP (2×2 mL) and the combined filtrates were concentrated in vacuo. The residue was dissolved in DMSO (2 mL) and purified by preparative HPLC [gradient 10-85% MeCN (0.1% TFA)/H2O (0.1% TFA)] to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 423 (M+1).
Reaction SMILES: Cl[CH2:2][CH:3]=O.[NH2:5][C:6]1[C:11]([Br:12])=[CH:10][C:9]([CH3:13])=[CH:8][N:7]=1>C(#N)C>[CH3:13][C:9]1[CH:10]=[C:11]([Br:12])[C:6]2[N:7]([CH:2]=[CH:3][N:5]=2)[CH:8]=1
Reactant: O=CCCl
Reactant: Cc1cnc(N)c(Br)c1
Solvent: CC#N
Product: Cc1cc(Br)c2nccn2c1

Procedure:
Add chloroacetaldehyde (2.51 g, 32.08 mmol) to a solution of 2-amino-3-bromo-5-methylpyridine (2.0 g, 10.69 mmol) in acetonitrile (200 ml). Reflux the reaction for 4 hours and then cool. Filter the reaction mixture and partition the white solid between saturated aqueous sodium bicarbonate (300 ml) and ethyl acetate. Separate the organic layer, wash with saturated aqueous sodium bicarbonate, dry over magnesium sulfate, and concentrated under reduced pressure to give the title compound as a tan solid.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].Cl[CH2:31][C:32]([NH2:34])=[O:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCCCCC.O>[CH3:1][N:2]([S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:5])[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][N:27]([CH2:31][C:32]([NH2:34])=[O:33])[CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2
Reactant: NC(=O)CCl
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C3=NCC4(CCN(CC(N)=O)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A mixture of N-methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (100 mg), chloroacetamide (30 mg), potassium carbonate (40 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with ethyl acetate:hexane=1:1 from a fraction to give the title compound (62 mg, yield 56%) as white crystals. melting point 226° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[C:27]1[O:31][C:30]([CH3:32])=[N:29][C:28]=1[C:33](O)=[O:34]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:21]3[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=3[CH3:19])=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1ccc(C)c(-c2oc(C)nc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cc(C)ccc3C)cn2)o1

Procedure:
Following general procedure B followed by either C or D, 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(2,5-dimethyl-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.01 min; [M+H]+=419.00.