Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.CN.[CH:30]([N:33](CC)C(C)C)(C)C>ClCCl>[CH3:21][C:20]1([CH3:22])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=2)[N:12]=[C:11]1[C:8]1[CH:9]=[CH:10][C:5]([S:2](=[O:4])(=[O:3])[NH:33][CH3:30])=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(S(=O)(=O)Cl)cc1)=N2
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(C2=Nc3ccc(C(=O)OC)cc3CC2(C)C)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 49.2 %

Procedure:
To a round bottom flask, a mixture of methyl 2-(4-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (396 mg, 1.0 mmol) in dichloromethane (10 mL) was added dropwise to a mixture of methylamine hydrochloride (68 mg, 1.0 mmol) and N,N-diisopropyl ethylamine (0.54 mL, 3.0 mmol) in dichloromethane (10 mL). The resultant mixture was allowed to stir at room temperature for 10 hours. The reaction mixture was washed by water several times, dried over anhydrous magnesium sulfate. Filtered and concentrated to provide methyl 3,3-dimethyl-2-(4-(N-methylsulfamoyl)phenyl)-3,4-dihydroquinoline-6-carboxylate as a yellow oil (190 mg). MS (ES+APCI) M+1=389.1.
Reaction SMILES: [OH:1][C:2]1[C:11](C(O)=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C1C2C(=CC=CC=2)C=CC=1O.[H-].[Na+:27]>>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[O-:1].[Na+:27]
Reactant: O=C(O)c1cc2ccccc2cc1O
Agent: Oc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Product: [O-]c1ccc2ccccc2c1

Procedure:
2-hydroxynaphthalene-3-carboxylic acid is important as an intermediate for pigments or dyes. Generally, it is prepared by reacting β-naphthol with sodium hydride to give sodium β-naphtholate, reacting the resulting compound with carbon dioxide under pressure to give sodium 2-hydroxynaphthalene-3-carboxylate and then, isolating the desired compound by means of acid precipitation i.e. by adding a mineral acid to the salt.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:11]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15](OC)=[O:16])=[N:10][N:9]=[N:8]1.Cl.[H][H]>C1COCC1>[NH:10]1[C:11]([C:12]2[CH:13]=[C:14]([CH2:15][OH:16])[CH:19]=[CH:20][CH:21]=2)=[N:7][N:8]=[N:9]1
Reactant: COC(=O)c1cccc(-c2nnn[nH]2)c1
Reactant: [H][H]
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cccc(-c2nnn[nH]2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
438 mg (11.56 mmol) of lithium aluminum hydride are initially charged in 60 ml of dry THF and cooled to 0° C., and a solution of 1.18 g (5.78 mmol) of the compound from Example 48A in 40 ml of dry THF is added. The reaction mixture is allowed to warm to RT and stirred at this temperature for 2 h. At 0° C., 4 M hydrochloric acid is added carefully to the reaction mixture until the evolution of hydrogen has stopped. The solution is then extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases are washed in each case once with in each case 10 ml of water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After removal of the solvent on a rotary evaporator the residue is dried under reduced pressure. The product is used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:51])=[CH:38][C:39]([C:43]6[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: COc1ccc(-c2cc(C)c(Br)c(C)c2)nc1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccc(OC)cn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-5-methoxy-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.98 min; Mass spectrum (ESI+): m/z=554 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@@:12]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=3)([CH3:14])[O:11][C:10]2=[O:25])=[CH:5][CH:4]=1.C[O:27]C1C=CC(N2[C@@H](C)[C@@H](COC3C=CC(C#N)=CC=3)OC2=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@@:12]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:27])=[CH:19][CH:18]=3)([CH3:14])[O:11][C:10]2=[O:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2C(=O)O[C@H](COc3ccc(C#N)cc3)[C@@H]2C)cc1
Reactant: COc1ccc(N2C[C@](C)(COc3ccc(C#N)cc3)OC2=O)cc1
Product: COc1ccc(N2C[C@](C)(COc3ccc(C=O)cc3)OC2=O)cc1
Yield: 85 %

Procedure:
The same procedure of Example 16 was repeated except that 4-[(R)-(-)-3-(4-methoxyphenyl)-5-methyl-2-oxooxazolidin-5-yl]methoxybenzonitrile obtained in Reference Example 15 was used in lieu of 4-[(4S, 5S)-(-)-3-(4-methoxyphenyl)-4-methyl-2-oxooxazolidin-5-yl]methoxybenzonitrile to give the title compound (compound 44) as an oil (yield 85%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@@H:7]2[CH2:11][O:10][CH2:9][C@@H:8]2[NH2:12])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH3:26][CH:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28].O>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@@H:7]2[CH2:11][O:10][CH2:9][C@@H:8]2[NH:12][S:29]([CH:27]([CH3:28])[CH3:26])(=[O:31])=[O:30])=[CH:4][CH:3]=1
Reactant: N[C@H]1COC[C@H]1Oc1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: O
Product: CC(C)S(=O)(=O)N[C@H]1COC[C@H]1Oc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of (3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3-amine (65.6 g, 0.254 mol) in methylene chloride (500 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 53 mL, 0.35 mol). The reaction mixture was cooled to 0° C. and propane-2-sulfonyl chloride (31.2 mL, 0.28 mol) was added drop-wise. The mixture was then stirred at room temperature for 18 hours. The reaction was monitored by proton NMR: additional propane-2-sulfonyl chloride (2.8 mL, 25 mmol) was added and the mixture was stirred at room temperature for an additional 18 hours. Again the reaction was monitored by NMR and additional propane-2-sulfonyl chloride (2.8 mL, 25 mmol) was added. After 2.5 hours the reaction was complete according to NMR analysis. Water (500 mL) was added and the layers were separated. The aqueous layer was extracted with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in methylene chloride and washed with aqueous hydrochloric acid (1N, 2×300 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford N-[(3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide as an orange/brown oil. Yield: 92.5 g, 0.254 mol, 100%. 1H NMR (300 MHz, CDCl3) δ 1.36 (d, J=7 Hz, 3H), 1.38 (d, J=7 Hz, 3H), 3.15 (septet, J=7 Hz, 1H), 3.69 (dd, J=8.5, 8.5 Hz, 1H), 3.93 (dd, J=10.6, 1.5 Hz, 1H), 4.10-4.28 (m, 3H), 4.72-4.81 (m, 2H), 6.77 (d, J=9.1 Hz, 2H), 7.41 (d, J=9.1 Hz, 2H). The absolute configuration of this material was established via X-ray crystallographic analysis of a crystal of N-[(3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide grown from a heptane/ethyl acetate solution. The results are described below.
Reaction SMILES: C(OC([N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[N:14]=[C:15]([S:18][C:19]3[C@H:25]([CH3:26])[C@H:24]4[N:21]([C:22](=[O:30])[C@@H:23]4[C@H:27]([OH:29])[CH3:28])[C:20]=3[C:31]([O:33]CC=C)=[O:32])[S:16][CH:17]=2)[CH2:9][C@H:8]1[CH2:37][OH:38])=O)C=C.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC.P([O-])([O-])([O-])=O>ClCCl>[OH:29][C@@H:27]([C@H:23]1[C:22](=[O:30])[N:21]2[C@@H:24]1[C@@H:25]([CH3:26])[C:19]([S:18][C:15]1[S:16][CH:17]=[C:13]([C:10]3[CH2:9][C@@H:8]([CH2:37][OH:38])[NH:7][CH2:12][CH:11]=3)[N:14]=1)=[C:20]2[C:31]([OH:33])=[O:32])[CH3:28]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C(=O)OCC=C)[C@H](CO)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(Sc3nc(C4=CCN[C@H](CO)C4)cs3)[C@H](C)[C@H]12
Temperature: 0 °C
Yield: 17.8 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-({4-[(2S)-1-[(allyloxy)carbonyl]-2-(hydroxymethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-thiazol-2-yl}sulfanyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (28 mg, 0.05 mmol) in dichloromethane (4 ml) were added acetic acid (7.2 μl) and tributyltin hydride (135 ml, 0.50 mmol) and then was added at room temperature bis(triphenylphosphine)palladium chloride(II) (3.5 mg, 0.005 mmol). Ten minutes later the reaction mixture was poured into a mixture of ice (10 g) and phosphate buffer (pH7.0, 10 ml). After separation of the mixture with a separating funnel, the organic layer was extracted twice with water and the aqueous layer was washed twice with dichloromethane (3 ml). The organic solvent in the aqueous layer was evaporated under reduced pressure, and the residue was purified by polymer chromatography (CHP-20P). The fractions eluted with 1–3% aqueous THF solution were combined and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-({4-[(2S)-2-(hydroxymethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-thiazol-2-yl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (3.9 mg) as a white amorphous.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26].C(N(CC)CC)C.[N-]=C=S>CN(C)C=O>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26])=[O:15])=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C(=O)NCCCN
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Agent: [N-]=C=S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)C(=O)NCCCNC(=O)c1ccc(C(=O)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
N-[3-[(4-benzoylphenyl)formamido]propyl]methacrylamide (BPMA, C21H22O3N2, 350.4 g mol−1) monomer was synthesized via reaction of the succinimidyl ester of 4-benzoylbenzoic acid (BP-NHS, 323.3 g mol−1; 81577, Invitrogen) with N-(3-aminopropyl)methacrylamide hydrochloride (APMA, 178.7 g mol−1; 21200, Polysciences, Warrington, Pa.) in the presence of catalytic triethylamine (TEA) in dimethylformamide (DMF). A mixture of the reactants and TEA at 50 mM each in DMF was incubated overnight (18 hrs) at room temperature, centrifuged at 18,000 g for 5 minutes and the pellet discarded. The supernatant was incubated on a tube inverter for 24 hrs with 30 mg isothiocyanate-functionalized (primary amine-reactive) polystyrene beads (538604, Sigma) for every 100 μmol of APMA initially added to the reaction. The mixture was then spun at 18,000 g for 5 minutes and the supernatant passed through a 0.2 μm syringe filter. A 10-fold excess of acetone was added to the filtrate and the mixture dried in vacuo. The BPMA product (white powder) was verified by 1H NMR (400 MHz, d6-DMSO, δ 8.79 (t, 1H), 8.04 (t, 1H), 8.02 (d, 2H), 7.80 (d, 2H), 7.75 (d, 2H), 7.70 (t, 1H), 7.58 (t, 2H), 5.67 (s, 1H), 5.32 (s, 1H), 3.31 (q, 2H), 3.18 (q, 2H), 1.86 (s, 3H), 1.71 (quin, 2H)) and mass spectrometry (ESI, m/z 351.2, C21H22O3N2+H+). 100 mM stocks of BPMA in DMSO were stored at −20° C. until use, and were stable for at least 12 months.
Reaction SMILES: [F:1][C:2]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[CH2:3][N:4]([CH2:8][C:9]([N+:14]([O-:16])=[O:15])([N+:11]([O-:13])=[O:12])[F:10])[C:5](Cl)=[O:6].[F:23][C:24]([N+:30]([O-:32])=[O:31])([N+:27]([O-:29])=[O:28])[CH2:25][NH2:26]>>[F:1][C:2]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[CH2:3][N:4]([CH2:8][C:9]([N+:14]([O-:16])=[O:15])([N+:11]([O-:13])=[O:12])[F:10])[C:5]([NH:26][CH2:25][C:24]([N+:30]([O-:32])=[O:31])([N+:27]([O-:29])=[O:28])[F:23])=[O:6]
Reactant: O=C(Cl)N(CC(F)([N+](=O)[O-])[N+](=O)[O-])CC(F)([N+](=O)[O-])[N+](=O)[O-]
Reactant: NCC(F)([N+](=O)[O-])[N+](=O)[O-]
Product: O=C(NCC(F)([N+](=O)[O-])[N+](=O)[O-])N(CC(F)([N+](=O)[O-])[N+](=O)[O-])CC(F)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
A previous method for the preparation of N,N-bis(2-fluoro-2,2-dinitroethyl)carbamyl chloride (I) has been reported by W. H. Gilligan and M. J. Kamlet in U.S. Pat. No. 3,850,978, which issued on Nov. 26, 1974. However, that method suffers from the serious disadvantage that the carbamyl chloride (I) can not be separated from the reaction mixture and must be used in crude form for subsequent reactions. This drawback greatly hinders the preparation of derivatives of the carbamyl chloride (I) and heretofore certain derivatives of it could be prepared only in very low yield or not at all. For example, reaction of crude N,N-bis(2-fluoro-2,2-dinitroethyl)carbamyl chloride (prepared by the procedure of Gilligan and Kamlet, supra) with 2-fluoro-2,2-dinitroethyl amine gave none of the desired N,N,N'-tris(2-fluoro-2,2-dinitroethyl)urea. Less than a 5% yield of N,N-bis(2-fluoro-2,2-dinitroethyl)-O-(2,2,2-trinitroethyl)carbamate was obtain when the crude N,N-bis(2-fluoro-2,2-dinitroethyl)carbamyl chloride was reacted with 2,2,2-trinitroethanol.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:22][SiH:23]([Cl:25])[Cl:24]>>[CH2:14]([CH2:22][SiH:23]([Cl:25])[Cl:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: C[SiH](Cl)Cl
Agent: CCCCP(CCCC)CCCC
Product: Cl[SiH](Cl)CCc1ccccc1
Yield: 20.1 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.15 g (0.75 mmol) of tri-n-butylphosphine, 0.95 g (7.5 mmol) of benzyl chloride, and 4.31 g (37.5 mmol) of methyldichlorosilane were reacted at 200° C. for 2 hrs. The resulting mixture was distilled to give 0.31 g of benzylmethyldichlorosilane (bp; 214-215° C./740 mmHg, yield; 20%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][N:2]=1.S(=O)(=O)(O)O.[CH3:15]O>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:15])=[O:8])=[CH:3][N:2]=1
Reactant: O=C(O)c1ccnnc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccnnc1
Reaction time: 16 h

Procedure:
To a solution of pyridazine-4-carboxylic acid (Aldrich, 5.0 g, 40.3 mmol) in methanol (anhydrous, Aldrich, 100 mL) was added sulfuric acid (concentrated, Aldrich, 2 mL). The reaction mixture was then heated to reflux and stirred for 16 hours. The volatiles were removed under reduced pressure. The residue was basified to pH=8-9 with saturated sodium carbonate (20 mL) and then extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (2×20 mL) and dried over magnesium sulfate. The drying agent was filtered off and the organic solution was concentrated and dried to give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 3.34 (s, 3H), 8.10 (dd, J=5.2, 2.4 Hz, 1H), 9.52 (dd, J=5.2, 1.2 Hz, 1H), 9.58 (dd, J=2.2, 1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 139 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].C([O-])(O)=O.[Na+].[CH2:11]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:12]1[CH:20]=[CH:19][C:18]2[O:17][CH2:16][O:15][C:14]=2[CH:13]=1>CCO>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][N:24]1[CH2:25][CH2:26][N:21]([CH2:11][C:12]2[CH:20]=[CH:19][C:18]3[O:17][CH2:16][O:15][C:14]=3[CH:13]=2)[CH2:22][CH2:23]1
Reactant: ClCC1CO1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OC(CCl)CN1CCN(Cc2ccc3c(c2)OCO3)CC1
Reaction time: 16 h
Yield: 24.6 %

Procedure:
To a mixture of epichlorohydrin (3.9 mL, 50 mmol) in EtOH (25 mL) and anhydrous NaHCO3 (4.2 g, 50 mmol), 1-piperonylpiperazine (11.0 g, 50 mmol) in EtOH (125 mL) was added dropwise over 45 min at 0° C., under nitrogen. After 16 h and removal of the EtOH in vacuo, the crude material was passed through silica gel (vacuum, 5% MeOH:CH2Cl2) to give pure product (3.85 g, 26.4%) as an amber oil. DCI/MS (M+1) 313. 400 MHz 1H NMR (CDCl3) δ: 7.25 (s, 1H), 6.7-6.8 (m, 2H), 5.9 (s, 2H), 4.6 (m, 1H), 3.9 (m, 1H), 3.5 (m, 2H), 3.4 (s, 2H), 2.4-2.7 (m, 10H).
Reaction SMILES: [CH3:1][S-:2].[Na+].[NH2:4][C:5]1[C:6](Cl)=[N:7][C:8]([Cl:11])=[N:9][CH:10]=1>CO>[NH2:4][C:5]1[C:6]([S:2][CH3:1])=[N:7][C:8]([Cl:11])=[N:9][CH:10]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSc1nc(Cl)ncc1N
Yield: 35 %

Procedure:
Sodium methanethiolate (0.342 g) was added to a solution of 5-amino-2,4-dichloropyrimidine (1 g) in methanol (5 ml) and the mixture was heated at reflux for 2 hours. Volatile material was then removed by evaporation and water (1 ml) was added. The suspended solid was collected by filtration, washed with hexane (10 ml) and dried under vacuum to give 5-amino-2-chloro-4-methylthiopyrimidine (0.3 g); 1H NMR (CDCl3): 2.55 (s, 3H), 7.75 (s, 1H); mass spectrum (+ve CI): 175 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C@H:3]1[C:15]([OH:17])=[O:16].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.O[C@@H:41]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([O:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:45]=1)[C:42]#[N:43]>C(Cl)Cl>[CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])=[O:14])[C@H:3]1[C:15]([O:17][C@H:41]([C:42]#[N:43])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([O:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:45]=1)=[O:16]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.5 %

Procedure:
1.3 g of (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2, 2,2-trifluoroethoxy)-1-propenyl]-cyclopropane-carboxylic acid, 0.1 ml of pyridine and 15 ml of methylene chloride were mixed with agitation and then 1.05 g of dicyclohexylcarbodiimide were added thereto. A solution of 1.35 g of (S)α-hydroxy-3-phenoxy-benzene-acetonitrile in 5 ml of methylene chloride were then added to the mixture which was stirred for 5 hours at ambient temperature and then was filtered. The filter was rinsed with methylene chloride and 2N hydrochloric acid was added to the filtrate. The decanted organic phase was washed with water, dried and evaporated to dryness. The oil residue was chromatographed over silica gel and was eluted with 95-5 cyclohexane-ethyl acetate mixture to obtain 1.33 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-(2,2,2-trifluoroethoxy)-3-oxo-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+42°±2° (c=0.7% in benzene).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8]([CH3:24])=[C:9]2[C:13](=[C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]=1[CH3:16])[NH:12][CH:11]=[CH:10]2)=[O:5])[CH3:2].[H-].[Na+].I[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C=O)C>[CH2:28]([N:12]1[C:13]2[C:9](=[C:8]([CH3:24])[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:15]([CH3:16])[C:14]=2[NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[CH:10]=[CH:11]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCI
Reactant: CCOC(=O)Cc1c(C)c(NC(=O)C(C)(C)C)c2[nH]ccc2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCn1ccc2c(C)c(CC(=O)OCC)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
N-(5-Ethoxycarbonylmethyl-4,6-dimethylindol-7-yl)-2,2-dimethylpropanamide (1.45 g) was dissolved in DMF (10 ml) and NaH (P=60%, 132 mg) was added under a nitrogen atmosphere, which was followed by stirring at room temperature for 1 hr. Then, 1-iodooctane (1.06 g) was added and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was poured into ice water. The mixture was extracted with AcOEt (100 ml), washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt-1/0-1/1) to give 1.02 g of N-(1-octyl-5-ethoxycarbonylmethyl-4,6-dimethylindol-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:20]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCCc1ccc(Br)cc1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1
Yield: 85.1 %

Procedure:
In a manner similar to that described in Example 3, 4-(4-bromo-phenyl)-butyryl chloride (0.086 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.089 g of 4-{4-[4-(4-bromo-phenyl)-butyrylamino]-phenyl}-4-oxo-butyric acid as a yellow solid; MS-(AP+) MH+419.
Reaction SMILES: C(O[C@@H](C1C(C)=CC2N=C(C3C=C4C(C(C)=NN4C)=CC=3)SC=2C=1C1C=CC(Cl)=CC=1)C(O)=O)(C)(C)C.[CH2:38]([N:45]1[C:53]([CH3:54])=[C:52]2[C:47]([CH:48]=[CH:49][C:50]([C:55]3[S:56][C:57]4[C:63]([C:64]5[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=5)=[C:62]([C@H:71]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])[C:72]([O:74]CC)=[O:73])[C:61]([CH3:82])=[CH:60][C:58]=4[N:59]=3)=[CH:51]2)=[N:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([N:45]1[C:53]([CH3:54])=[C:52]2[C:47]([CH:48]=[CH:49][C:50]([C:55]3[S:56][C:57]4[C:63]([C:64]5[CH:65]=[CH:66][C:67]([Cl:70])=[CH:68][CH:69]=5)=[C:62]([C@H:71]([O:77][C:78]([CH3:80])([CH3:79])[CH3:81])[C:72]([OH:74])=[O:73])[C:61]([CH3:82])=[CH:60][C:58]=4[N:59]=3)=[CH:51]2)=[N:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nn(Cc5ccccc5)c(C)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: Cc1cc2nc(-c3ccc4c(C)nn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-c3ccc4nn(Cc5ccccc5)c(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
Prepared in a manner similar to (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-indazol-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid, but using (S)-ethyl 2-(2-(2-benzyl-3-methyl-2H-indazol-5-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate instead of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-indazol-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C35H33ClN3O3S: 610.2 (M+H+); found: 610.3 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.99 (dd, J=9.1, 1.6 Hz, 1H), 7.80 (s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.65 (d, J=9.1 Hz, 1H), 7.59 (t, J=3.4 Hz, 3H), 7.38-7.26 (m, 3H), 7.17 (d, J=7.0 Hz, 2H), 5.65 (s, 2H), 5.26 (s, 1H), 2.64 (s, 3H), 2.61 (s, 3H), 0.98 (s, 9H).