Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][C:28](OC)=[O:29])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C.CCO>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:27]([CH2:26][CH2:25][C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)[C:28]2=[O:29])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CCCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=c1c(CCc2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 4-(pyridin-4-yl)butanoate (1.1 eq., prepared in Synthetic Example 8) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1,8-naphthyridin-2(1H)-one, mp 213 to 214° C./DMF-EtOH.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:11][N:12]([CH2:42][C:43]([OH:45])=[O:44])[CH:13]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=1)[CH2:14][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:16][CH:17]([CH3:27])[N:18]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][C:20]([OH:22])=[O:21])([OH:10])=[O:9].[H][H]>[Pd].O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:11][N:12]([CH2:42][C:43]([OH:45])=[O:44])[CH:13]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH2:14][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:16][CH:17]([CH3:27])[N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH2:23][C:24]([OH:26])=[O:25])([OH:10])=[O:9]
Reactant: CC(CN(CC(=O)O)CC(Cc1ccc([N+](=O)[O-])cc1)N(CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(CN(CC(=O)O)CC(Cc1ccc(N)cc1)N(CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O
Yield: 125.5 %

Procedure:
To a Parr flask was added 3.40 g (3.84 mmol) of N,N,N′,N″,N″-Pentakis(carboxymethyl)-2-[(4-nitrophenyl)methyl-]-6-methyldiethylenetriamine trifluoroacetic acid salt and 50 ml of water followed by the addition of 0.3 g of 5% palladium on carbon. The flask was pressurized to 30 psi hydrogen and vented twice. The vessel was then pressurized to 45 psi hydrogen and shaken. Once hydrogen uptake ceased, typically after 2 to 4 hours, the flask was vented and the mixture filtered through a pad of celite. The celite was washed with 20 ml of water. The filtrate was concentrated under reduced pressure to afford 3.02 g of product with a yield of 92.03%. The spectral data obtained for this product are consistent with those of a reference standard.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[CH:50]=[C:51]([CH:53]=[CH:54][CH:55]=2)[NH2:52])[CH:38]=[CH:37][N:36]=1.[F:56][C:57]1[CH:58]=[CH:59][C:60]([O:67][CH3:68])=[C:61]([S:63](Cl)(=[O:65])=[O:64])[CH:62]=1>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[CH:50]=[C:51]([NH:52][S:63]([C:61]3[CH:62]=[C:57]([F:56])[CH:58]=[CH:59][C:60]=3[O:67][CH3:68])(=[O:64])=[O:65])[CH:53]=[CH:54][CH:55]=2)[CH:38]=[CH:37][N:36]=1
Reactant: COc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: COc1ccc(F)cc1S(=O)(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1
Yield: 79 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (309 mg, 0.934 mmol) and 5-fluoro-2-(methyloxy)benzenesulfonyl chloride (210 mg, 0.934 mmol) the title compound of Step A was obtained as a white solid. (381 mg, 79% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 8.42 (d, J=5.3 Hz, 1H), 7.39-7.54 (m, 2H), 7.23-7.37 (m, 1H), 7.09-7.23 (m, 4H), 6.87 (d, J=5.3 Hz, 1H), 3.79 (s, 3H), 3.29-3.38 (m, 1H), 1.33 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.Cl.[CH:22]12[CH2:29][CH2:28][CH:25]([NH:26][CH2:27]1)[CH2:24][NH:23]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:22]12[CH2:29][CH2:28][CH:25]([NH:26][CH2:27]1)[CH2:24][N:23]2[C:10]1[C:11]([F:13])=[C:12]2[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: C1CC2CNC1CN2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCC3CN4)c(F)c21
Yield: 62.4 %

Procedure:
A solution of 0.81 g (3.0 mmole) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.74 g (4.0 mmole) of 2,5-diazabicyclo[2.2.2]octane dihydrochloride [P. A. Sturm et al., J. Med. Chem., 17, 481 (1974)], 1.65 ml (11 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 40 ml of acetonitrile was stirred at room temperature for 25 hours and heated under reflux for two hours. The reaction mixture was filtered and the solid was washed with methanol to give 0.68 g of the title compound, mp 255°-257°.
Reaction SMILES: [Na:1].[CH3:2][CH2:3][C@@H:4]([C:23]([C@H:25]([C@@H:27]([OH:43])[C@@H:28]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([OH:39])[C:33]=1[C:40]([OH:42])=[O:41])[CH3:29])[CH3:26])=[O:24])[C@H:5]1[O:9][C@@:8]([C@@H:12]2[O:17][C@@H:16]([CH3:18])[C@@:15]([OH:21])([CH2:19][CH3:20])[CH2:14][CH2:13]2)([CH2:10][CH3:11])[CH2:7][C@@H:6]1[CH3:22].[C:44](Cl)(=[O:47])[CH2:45][CH3:46].O>N1C=CC=CC=1>[CH3:38][C:35]1[C:34]([O:39][C:44](=[O:47])[CH2:45][CH3:46])=[C:33]([C:32]([CH2:31][CH2:30][CH:28]([CH3:29])[CH:27]([OH:43])[CH:25]([CH3:26])[C:23](=[O:24])[CH:4]([CH2:3][CH3:2])[CH:5]2[CH:6]([CH3:22])[CH2:7][C:8]([CH2:10][CH3:11])([CH:12]3[CH2:13][CH2:14][C:15]([CH2:19][CH3:20])([OH:21])[CH:16]([CH3:18])[O:17]3)[O:9]2)=[CH:37][CH:36]=1)[C:40]([OH:42])=[O:41].[Na:1]
Reactant: CCC(=O)Cl
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Agent: [Na]
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)Oc1c(C)ccc(CCC(C)C(O)C(C)C(=O)C(CC)C2OC(CC)(C3CCC(O)(CC)C(C)O3)CC2C)c1C(=O)O
Reaction time: 2 h

Procedure:
6.12 g. of the sodium salt of antibiotic X-537A was dissolved in pyridine (10 ml.) by warming slightly. The solution was cooled in an ice bath and treated with propionyl chloride, then allowed to stand at room temperature for 2 hours. The mixture was poured into water, extracted with ethyl acetate, and the organic phase washed in succession with 1N hydrochloric acid (several times) and sodium carbonate solution (twice). Evaporation of the ethyl acetate solution left a residue which was crystallized from methylene chloride/hexane to afford 3-methyl-2-propionyloxy-6-(7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-(5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl)heptyl)benzoic acid, sodium salt, m.p. 185°-186.5° [α]D25 -20.00° (C=1.00 in methanol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Sn](CCCC)(CCCC)CCCC.[CH2:20]([O:24][C:25]([N:27]([C:44]1[C:49]([O:50][CH3:51])=[N:48][C:47]([CH3:52])=[CH:46][N:45]=1)[S:28]([C:31]1[C:32]([C:37]2[CH:42]=[CH:41][C:40](I)=[CH:39][CH:38]=2)=[N:33][CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:26])[CH:21]([CH3:23])[CH3:22].O>C1(C)C(C)=CC=CC=1.C1C=CC([P]([Pd]([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>[CH2:20]([O:24][C:25]([N:27]([C:44]1[C:49]([O:50][CH3:51])=[N:48][C:47]([CH3:52])=[CH:46][N:45]=1)[S:28]([C:31]1[C:32]([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:39][CH:38]=2)=[N:33][CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:26])[CH:21]([CH3:23])[CH3:22]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(I)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(-c2ccccn2)cc1
Temperature: 125 °C
Yield: 31.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (45 mg) was added to a deoxygenated solution of (2-pyridyl)tributylstannane (294 mg) and N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-iodophenyl)pyridine-3-sulphonamide(465 mg) in xylene (15 ml). The mixture was stirred and heated under argon at 125° C. for 17 hours and then allowed to cool to ambient temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column, eluting with 0-65% ethyl acetate/hexane to give N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-(2-pyridyl)phenyl)pyridine-3-sulphonamide (135 mg) as a foam; 1H NMR (CDCl3): 0.7 (d, 6H), 1.7 (m, 1H), 2.5 (s, 3H), 3.8 (d, 2H), 4.0 (s, 3H), 7.5 (dd, 2H), 7.6-7.8 (m, 4H), 7.9 (s, 1H), 8.1 (dd, 2H), 8.7 (dd, 1H), 8.9 (dd, 1H), 9.0 (dd, 1H); mass spectrum (+ve ESP): 534 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(Cc1ccccc1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 137.8 %

Procedure:
Benzyl 4-hydroxyphenyl ketone (5.1 g; 24 mmol), 3.8 g (3.5 mL, 30 mmol) of benzyl chloride, and 16.6 g (120 mmol) of pulverized and flame dried K2CO3 were slurried in 75 mL dry Me2CO under Ar. The mixture was heated to reflux 16 h, cooled to room temperature, diluted with CH2Cl2 (100 mL), and filtered. The resulting filter cake was washed with C6H6 (50 mL) and EtOAc (50 mL). The combined filtrates were concentrated and the resulting orange oil was dissolved in C6H6, washed with 10% K2CO3 (100 mL), 5% NaOH (2×50 mL), and H2O (100 mL). The organic layer was dried (MgSO4), filtered, and concentrated to give 10 g of a light orange solid, which was purified on 60 g flash SiO2 (1:1 petroleum ether-CH2Cl 2) to give Benzyl 4-benzyloxphenyl ketone as a clear oil which was crystallized from C6H6 -EtOH to yield 3.1 g of white needles (43%). mp: 134.5°-136° C. NMR δ 8.03 and 7.03 (AA'BB', c, 4H, ArH), 7.43 (s, 5H, ArH), 7.31 (s, 5H, ArH), 5.15 (s, 2H, PhCH2O), 4.25 (s, 2H, COCH2).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])(=[O:3])[CH3:2].C(N(CC)CC)C.C[Si](C)(C)Cl.[C:22](Cl)([Cl:24])=[O:23]>C1C=CC=CC=1>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:22]([Cl:24])=[O:23])[C:5]1=[O:9])(=[O:3])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CC(=O)N1CCNC1=O
Agent: C[Si](C)(C)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C(=O)Cl)C1=O
Reaction time: 18 h

Procedure:
20 parts by weight of N-acetyl-imidazolid-2-one mixed with 25 parts by weight of triethylamine and 150 parts by volume of dry benzene were first taken and 27 parts by weight of trimethylchlorosilane in 40 parts by volume of benzzene were added dropwise at room temperature over the course of 30 minutes, with stirring. The mixture was subsequently boiled for 18 hours under reflux, moisture being excluded, and the triethylamine hydrochloride which precipitated (22 parts by weight = 100%) was filtered off after cooling and carefully rinsed with dry benzene. The benzene solution thus obtained was treated with a solution of 17 parts by weight of phosgene in 50 parts by volume of benzene at 5° C and left to stand overnight at 5° C. Thereafter the solvent was stripped off in vacuo and the residue was dried under an oil pump. It was recrystallized from acetone/pentane mixture.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5](N)=[N:6][CH:7]=1.[OH:11]S(O)(=O)=O.N([O-])=O.[Na+]>O>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5](=[O:11])[NH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1c(Br)cnc(N)c1C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(Br)c[nH]c(=O)c1C
Temperature: 31 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a mixture of 5-bromo-3,4-dimethylpyridin-2-amine (0.6 g, 3.0 mmol) and H2SO4 (98%, 1.62 mL) and H2O (18 mL) is added a solution of NaNO2 (243.6 mg, 4.2 mmol) in H2O (1.6 mL) drop-wise at 0° C. Then, it was stirred at 31° C. for 30 minutes and filtered. The resulting solid is washed with water to provide the title compound (375.0 mg, 62%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.48 (s, 1H), 2.32 (s, 3H), 2.19 (s, 3H). LCMS (M+H)+ 202.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:22]([O:24]CC2C=CC=CC=2)=[O:23])=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>CO>[CH2:1]([O:8][C:9]1[C:10]([C:22]([OH:24])=[O:23])=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ncnc(C(=O)OCc3ccccc3)c2OCc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2ncnc(C(=O)O)c2OCc2ccccc2)cc1
Temperature: 90 °C

Procedure:
To a solution of benzyl 5-(benzyloxy)-6-p-tolylpyrimidine-4-carboxylate P71 (90 mg, 0.22 mmol) in methanol (5 mL) was added lithium hydroxide monohydrate (46 mg, 1.10 mmol). The reaction mixture was heated in a microwave reactor at 90° C. for 10 minutes. The organic solvent was evaporated under reduced pressure. Ethyl acetate and 1 N hydrochloric acid were added. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The solid product was dried under reduced pressure to afford the desired 5-(benzyloxy)-6-p-tolylpyrimidine-4-carboxylic acid P72 (70 mg, 0.22 mmol).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[OH:21])[CH:16]=[O:17])([O-:12])=[O:11].C(N(CC)CC)C>C(Cl)Cl>[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:16]=[O:17])([O-:12])=[O:11]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc(OC(=O)c2ccccc2)c([N+](=O)[O-])c1

Procedure:
To a solution of benzoyl chloride (2.50 mL, 20.0 mmol) in methylene chloride (100 mL) cooled at 0° C. was added 3-nitro-4-hydroxybenzaldehyde (3.00 g, 19.0 mmol) and triethylamine (2.80 mL, 20.0 mmol). After 1 hour the mixture was washed with water and concentrated to an oil, in vacuo. The product was crystallized from ethyl acetate-hexane giving 1.70 g (33.0%); mp110.5-112° C. 1H NMR (CDCl3): 10.05 (s,1H,CHO), 8.59 (s,1H) 8.20 (m,3H), 7.62 (2,1H), 7.38 (m,3H). MS (DCl) 272 (MH+). C14H9NO5.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C@@:3]([O:8][Si](C)(C)C)([CH3:7])[C:4](Cl)=[O:5].[Cl:15][C:16]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].N1C=CC=CC=1>C(Cl)Cl>[Cl:15][C:16]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:4](=[O:5])[C@:3]([OH:8])([CH3:7])[C:2]([F:14])([F:13])[F:1]
Reactant: Cc1cccc(N)c1Cl
Reactant: C[C@@](O[Si](C)(C)C)(C(=O)Cl)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)[C@@](C)(O)C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.1 %

Procedure:
A solution of (S)-3,3,3-trifluoro-2-trimethylsilyoxy-2-methylpropanoyl chloride (prepared from (R)-(+)-2-Hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 3) as described in J Med. Chem., 1999, 42, 2741-2746)(17.4 g, 70 mmol) in DCM (50 ml) was added to a stirred mixture of 2-chloro-3-methyl-aniline (WO 9741846; 8.25 g, 141.6 mmol) and pyridine (7.1 ml, 87.5 mmol) in DCM (100 ml). The resultant mixture was stirred at ambient temperature for 24 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was dissolved in methanol (150 ml), treated with 2 M hydrochloric acid (130 ml) and the mixture stirred at ambient temperature for 18 hour. The methanol was evaporated, the aqueous layer was extracted with EtOAc (2×75 ml), the EtOAc extracts were combined and washed with saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with DCM as eluent to give the title compound as a solid (13.6 g, 48.4 mmol). NMR (CDCl3): 1.75 (s, 3H), 2.4 (s, 3H), 3.75 (s, 1H), 7.05 (d, 1H), 7.2 (dd, 1H), 8.2 (d, 1H), 8.85 (brs, 1H); m/z 280.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19](Cl)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:29][CH2:30][CH2:31][N:32]([CH3:43])[S:33]([C:36]1[C:37]([CH3:42])=[CH:38][CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:29][CH2:30][CH2:31][N:32]([S:33]([C:36]3[C:37]([CH3:42])=[CH:38][CH:39]=[CH:40][CH:41]=3)(=[O:35])=[O:34])[CH3:43])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1S(=O)(=O)N(C)CCO
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCN(C)S(=O)(=O)c2ccccc2C)cc1

Procedure:
According to Example 24d) 100 mg 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide was reacted with N-(2-hydroxyethyl)-N-methyl-toluenesulfonamide to give 14 mg 4-tert.-butyl-N-{6-[2-(toluene-sulfonyl-methyl-amino)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-benzenesulfonamide. LC-MS: tR=6.18 min, [M−1]−=607.54.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[OH:28][NH:29][C:30](=[NH:41])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37](=[O:40])(=[O:39])[NH2:38])[CH:32]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:28][N:29]=[C:30]([C:31]5[CH:32]=[C:33]([S:37]([NH2:38])(=[O:39])=[O:40])[CH:34]=[CH:35][CH:36]=5)[N:41]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5cccc(S(N)(=O)=O)c5)no4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) (195 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a light yellow solid (190 mg, 67%). MS (EI) 568.1 [(M)+]; mp 270° C.
Reaction SMILES: C([N:4]1[C:16]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=O)C.[C:18]1([CH3:32])[CH:23]=[CH:22][C:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1>[Cu]=O>[C:28]1([CH3:31])[CH:29]=[CH:30][C:25]([N:24]([C:8]2[CH:7]=[CH:6][C:5]3[NH:4][C:16]4[C:11]([C:10]=3[CH:9]=2)=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:21]2[CH:20]=[CH:19][C:18]([CH3:32])=[CH:23][CH:22]=2)=[CH:26][CH:27]=1
Reactant: CC(=O)n1c2ccccc2c2cc(Br)ccc21
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Agent: O=[Cu]
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc3[nH]c4ccccc4c3c2)cc1
Temperature: 170 °C
Yield: 79.5 %

Procedure:
A mixture of 1.2 g of 9-acetyl-3-bromocarbazole and 1.2 g of di-p-tolylamine were stirred together in 20 ml N,N′-dimethylacetamide. To this was added 0.8 g of copper oxide and heated to 170° C. for 24 h. The reaction was quenched with water and the solid was filtered, washed with methanol, and dried under vacuum. The solid was then taken up for further deprotection using 0.6 g KOH with THF (3 ml), methanol (6 ml) and water (6 ml) at reflux temperature. The reaction mixture was then extracted using ethyl acetate; and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Subsequent silica gel column chromatography using toluene/hexane (½) as eluent, yielded 1.2 g of 3-(N,N-di-p-tolylamino)-9H-carbazole.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[O:8]=[C:5]1[CH2:6][CH2:7][N:2]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 80 %

Procedure:
The mixture of 4-piperidone hydrochloride (0.851 mol), triethylamine (1.70 mol), 4-fluoronitrobenzene (0.851 mol) in 800 ml chloroform was heated under reflux for 16 hours. The solvent was removed under vacuum and to the residue water (1 liter) was added and the precipitate was filtered to afford 4-[4-oxo-piperidin-1-yl]-nitrobenzene in 80% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[C:38]1([CH2:44][C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CCO.C1(C)C=CC=CC=1>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:48]([NH:47][C:45](=[O:46])[CH2:44][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[S:49])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=3)[S:15][C:8]=12
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a solution of 46 (375 mg, 0.711 mmol) in a mixture of EtOH (5 mL) and toluene (5 mL) at RT was added phenylacetyl isothiocyanate (189 mg, 1.066 mmol) and the reaction mixture was stirred at RT for 3 hours. The mixture was concentrated to dryness then purified by column chromatography (eluent a gradient of 80% EtOAc in hexane to EtOAc), to afford 47 (400 mg, 80%) as a red solid. MS (m/z): 705.2 (M+H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][O:14][C:15]1[CH:16]=[C:17]([CH2:18][OH:19])[CH:20]=[CH:21][CH:22]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: OCc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 80 °C

Procedure:
2-Chloromethylquinoline hydrochloride (11.6 g, 54 mmol), 3-hydroxybenzyl alcohol (6.7 g, 54 mmol) and potassium carbonate (16 g, 116 mmol) are heated in DMF (45 mL) at 50° C. for 14 h. The temperature is increased to 80° C. and heated an additional 24 h. The reaction is cooled and added to water, filtered and the solid is washed with water to yield a semi-pure product. The residue is dissolved in ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The sample is then recrystallized from ethyl acetate and hexanes to provide the title compound. MS (ESI) 266 (M+H)+.