Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:5]=[N:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=1.C[Si]([C:26]#[N:27])(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:11][CH:12]=2)[C:26]#[N:27])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1F
Product: COc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1F

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(3-fluoro-4-methoxybenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a slightly yellow powder (yield 98%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:32])[NH:21][C:22]3[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[CH:16][C:15]=1[CH3:33])[O:9][CH2:8][CH2:7][CH:6]2[C:34]([O:36]C)=[O:35])#[N:2].O[Li].O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:32])[NH:21][C:22]3[CH:23]=[N:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)=[CH:16][C:15]=1[CH3:33])[O:9][CH2:8][CH2:7][CH:6]2[C:34]([OH:36])=[O:35])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(C(F)(F)F)nc4)cc3C)c(C#N)cc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)Nc2ccc(C(F)(F)F)nc2)ccc1Oc1cc2c(cc1C#N)C(C(=O)O)CCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.3 %

Procedure:
To a solution of methyl 6-cyano-7-(2-methyl-4-(6-(trifluoromethyl)pyridin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.097 g, 0.190 mmol) in 2 mL of THF containing 200 μL methanol was added LiOH—H2O (0.379 mL, 0.379 mmol) and the solution was stirred at ambient temperature for 12 hours. The reaction was quenched with 1 drop of glacial acetic acid and then concentrated to dryness. The crude material was purified by silica gel column chromatography, eluting with 2-5% methanol/dichloromethane+0.1% acetic acid to provide the desired product (0.04 g, 42%). MS (APCI)=498.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[NH:14][CH2:13][C@@H:12]1C.F[C:20]1C=CC([N+]([O-])=O)=CC=1F.C[C@H]1CNC[C@@H](C)N1>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:12][C@H:13]([CH3:20])[NH:14][C@H:15]([CH3:17])[CH2:16]1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: C[C@@H]1CNC[C@H](C)N1
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)C[C@H](C)N1
Yield: 103 %

Procedure:
Crude 1-(2-fluoro-4-nitrophenyl)-cis-3,5-dimethylpiperazine (5.71 g, 103% recovery) is prepared according to the method described above for the synthesis of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,5-dimethylpiperazine by treatment of 1,2-difluoro-4-nitrobenzene (3.48 g, 21.8 mmol) with cis-2,6-dimethylpiperazine (2.50 g, 21.8 mmol). The crude product is used in the next step without chromatographic purification. LCMS-ESI (m/z): calcd for C12H16FN3O2, 253; [M+H]+ found, 254.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])=[O:4].[CH3:13][N:14](C)C=O>>[CH3:13][NH:14][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: CN(C)C=O
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
5 g of polifungin and 1.5 g of fructose were suspended in 50 ml of dimethyl formamide and next the procedure was carried out as in the Example IV. 4.4 g of N-methylglucamine salt of N-glycosyl polifungin of E1 cm1% =562 at 304 nm and IC50 =0.46 mcg/ml were obtained. Original antibiotic: E1 cm1% =660 at 304 nm and IC50 =0.16 mcg/ml.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[CH2:7][CH2:8][CH:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:33]=[C:32]([C:34]([NH:36][C:37]4[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=4[F:44])=[O:35])[CH:31]=[CH:30][C:29]=3[F:45])[CH:24]=[CH:23][N:22]=2)[NH:18][CH:17]=1)=[O:15])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:80]([NH2:82])[CH3:81].Cl>O1CCCC1.O>[CH2:80]([NH:82][C:10](=[O:11])[CH:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:33]=[C:32]([C:34]([NH:36][C:37]4[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=4[F:44])=[O:35])[CH:31]=[CH:30][C:29]=3[F:45])[CH:24]=[CH:23][N:22]=2)[NH:18][CH:17]=1)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:46])[CH3:81]
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)O)c[nH]4)c3)c2)c1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 5-tert-butoxy-2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-oxopentanoic acid (150 mg, 0.24 mmol) in 10 ml of anhydrous tetrahydrofuran were added HATU (109 mg, 0.29 mmol) and N,N-diisopropylethylamine (93 mg, 0.72 mmol). The mixture was heated at 60° C. for 15 minutes and cooled to room temperature, followed by addition of 2M ethylamine solution in THF (0.18 ml, 0.36 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% methanol in chloroform to give tert-butyl 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-oxopentanoate as white solid. Yield: 100 mg, 64%.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.[CH:12]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>O1CCCC1>[CH:12]1([NH:18][C:19]([NH:11][CH:7]2[C:4]3[CH:5]=[CH:6][S:2][C:3]=3[CH2:10][CH2:9][CH2:8]2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C=NC1CCCCC1
Reactant: NC1CCCc2sccc21
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCc2sccc21

Procedure:
In a similar manner, as described in Example 1, 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride is allowed to react with cyclohexyl isocyanate in dry tetrahydrofuran to afford 7 grams of 1-cyclohexyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, melting point 222° C. to 225° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>COCCOC.Cl>[CH2:13]([O:12][C:10](=[O:11])/[CH:9]=[C:8](/[C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)=[CH:3][CH:4]=1)\[CH3:15])[CH3:14]
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Tetrakis(triphenylphoshine)palladium(0) (0.26 g, 0.22 mmol, 4 mol %) was added, under nitrogen, to a stirred solution of (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (1.5 g, 5.57 mmol) {prepared as detailed in example 50 a} in DME (70 ml), and the resulting orange coloured solution stirred at room temperature for 10 min. Aqueous 2M sodium carbonate (16.7 ml, 33.4 mmol) was then added, the mixture stirred for 10 min, then 4-chlorophenyl boronic acid (1.3 g, 8.36 mmol) was added, and the reaction mixture heated to 80° C. for 18 h, under reflux. The reaction mixture was diluted with 1N HCl (100 ml) and the products extracted into ethyl acetate (2×100 ml). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give the crude product, which was purified by column chromatography on silica gel (20% ethyl acetate in n-heptane eluent) to give the product, (E)-ethyl-3-(4′-chloro-biphenyl-4-yl)-but-2-enoate as a colourless solid; 1.17 g (70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH:23]([Si:26]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[N:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[C:29]([CH:36]=[O:37])=[CH:28]1)([CH3:25])[CH3:24].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:36]([OH:37])[C:29]3[C:30]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[N:27]([Si:26]([CH:38]([CH3:40])[CH3:39])([CH:41]([CH3:43])[CH3:42])[CH:23]([CH3:24])[CH3:25])[CH:28]=3)=[CH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C=O)c2cccnc21
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cn1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(C(=O)Nc3ccc(Cl)cc3)nc2)c2cccnc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 14.4 %

Procedure:
To 5-Bromo-pyridine-2-carboxylic acid (4-chloro-phenyl)-amide (70, 0.50 g, 1.60 mmol) in tetrahydrofuran (20.0 mL), under an atmosphere of nitrogen at −78° C., tert-butyllithium (3.02 mL, 1.70 M in Hexane) was added. After 20 minutes, 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (47, 0.39 g, 1.3 mmol, prepared as described in Example 18) in tetrahydrofuran (10.0 mL) was added to the reaction. The reaction was stirred at −78° C. for 1 hour, then allowed to warm to room temperature for 10 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as colorless oil (71, 100 mg, 14%). MS (ESI) [M+H+]+=535.3.
Reaction SMILES: Cl[C:2]1[N:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.O.[NH2:26][NH2:27]>N1C=CC=CC=1>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][CH:23]=[CH:22][CH:21]=3)[NH:27][N:26]=2)[CH:7]=[C:8]([C:17]([CH3:19])([CH3:20])[CH3:18])[C:9]=1[OH:16])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(C(=O)c2cccnc2Cl)cc(C(C)(C)C)c1O
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Yield: 96.7 %

Procedure:
A solution of 69.1 g of 4-(2-chloronicotinoyl)-2,6-di-tertiary butylphenol and 45 g of hydrazine hydrate in 380 ml of pyridine is refluxed for 5 hours. After the pyridine is distilled off under reduced pressure, to the obtained residue is added water. The crude crystals precipitated are recrystallized from ethanol to give 62.5 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 216°-217° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][C@H:21]([CH3:33])[CH2:22][S:23][C:24]2[S:25][C:26]3[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=3[N:28]=2)[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[C:34](O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(C)=NC=2Cl)(=O)C.CC1N=C(N)C2N=CN(C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.C[O-].[Na+]>CO>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[S:23][CH2:22][C@H:21]([NH:20][C:4]1[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=[C:2]([CH3:34])[N:3]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])[CH3:33]
Reactant: C[C@H](CSc1nc2ccccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: [Na+]
Solvent: CO
Product: Cc1nc(N[C@H](C)CSc2nc3ccccc3s2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Yield: 22.9 %

Procedure:
The title compound was prepared according to general method A as described above in Example 1 by reacting 2-[(R)-2-amino-1-propylthio]benzothiazole hydrochloride (prepared as described in Example 5) (0.89 g, 3.0 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-methyl-9H-purine (1.07 g, 2.5 mmol) [prepared from 2-methylinosine (Journal of Organic Chemistry, 1967, 32, 3258-3260) by standard acylation and chlorination steps]. Deacylation of the purified 2',3',5'-tri-O-acetyl-N-[(R)-1-(2-benzothiazolyl)thio° 2-propyl]-2-methyladenosine using sodium methoxide in methanol to provide the desired N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-methyladenosine (0.28 g, 11%) (following column chromatography), 1H NMR (DMSO-d6) δ 1.40 (3H, d, --CHCH3), 2.30 (3H, S, --CH3), 3.50-3.77 (4H, m, H-5'a and H-5'b and --CH2 --), 3.98 (1H, d, H-4'), 4.13 (1H, d, H-3'), 4.63 (1H, q, H-2'), 4.86 (1H, br, --CHCH3), 5.19, 5.42 (2H, 2d, 2'- and 3'-OH), 5.70 (1H, t, 5'-OH), 5.85 (1H, d, H-1'), 7.36, 7.47 (2H, 2t, Ar-H), 7.80-7.96 (2H, m, Ar-H), 8.0 (1H, s, N--H), 8.26 (1H, s, H-8), 8.52 (1H, s, N--H). HPLC retention time 22.4 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)]. C21H24N6O4S2.H2O requires C, 49.8; H, 4.8; N, 16.6. Found: C, 49.9; H, 5.1; N, 16.4%.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:13](=[O:14])[C:12](O)=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:10]2(=[O:23])=[O:22])=[CH:6][CH:5]=1.CN(C=O)C.C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl>[Cl:35][C:12]1[C:13](=[O:14])[N:9]([CH2:8][C:7]2[CH:24]=[CH:25][C:4]([O:3][CH:2]([F:26])[F:1])=[CH:5][CH:6]=2)[S:10](=[O:23])(=[O:22])[C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1C(O)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1C(Cl)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Yield: 61.4 %

Procedure:
2-[4-(Difluoromethoxy)benzyl]-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.98 g, ca.60% purity, 1.80 mmol)) was dissolved in DCM (40 mL) and DMF (0.14 mL) was added. Under an atmosphere of nitrogen, oxalyl chloride (0.46 g 3.61 mmol) was dropped in. The mixture was then heated to reflux for 5 h and then evaporated to dryness. Water (20 mL) was added and the reaction mixture was extracted with DCM (20 mL×3). The extracts were combined and washed with water (50 mL×3) and brine (20 mL), dried (MgSO4) and evaporated. The residue was purified by column chromatography (ISOLUTE SI, 20 g/70 mL), eluting with DCM:heptane (30:70), to give the title compound (0.442 g, 62%) as a semi-solid; 1H NMR (400 MHz, CDCl3): δ 7.97 (d, 2H), 7.48-7.58 (m, 5H), 7.11 (d, 2H), 6.51 (t, 1H), 4.86 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 155.8, 151.2, 143.5, 132.5, 130.8, 130.5, 129.4, 128.8, 127.2, 123.2, 119.5, 115.7 (t), 43.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]2[C:6]=1[C:7]([CH3:25])=[C:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9](=[O:16])[NH:10]2.Br[CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]2[C:6]=1[C:7]([CH3:25])=[C:8]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9]([O:16][CH2:28][CH3:29])=[N:10]2
Reactant: COC(=O)Cc1cc(C)cc2[nH]c(=O)c(Cc3ccc(Cl)cc3)c(C)c12
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1nc2cc(C)cc(CC(=O)OC)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 40 °C

Procedure:
A mixture of [3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1,2-dihydroquinolin-5-yl]acetic acid methyl ester (1.0 g), bromoethane (0.24 mL), potassium carbonate (1.1 g) and N,N-dimethylformamide (10 mL) was heated at 40° C. for 17 hours. The mixture was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (0:1 to 1:5 by volume) gave title compound as a gum, 0.28 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH2:11][CH3:12])[C:9]#N)=[CH:4][CH:3]=1.[OH-:14].[K+].CCO.[OH2:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH2:11][CH3:12])[C:9]([OH:19])=[O:14])=[CH:4][CH:3]=1
Reactant: CCC(C)(C#N)c1ccc(Cl)cc1
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: CCO
Product: CCC(C)(C(=O)O)c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(4-chlorophenyl)-2-methylbutanenitrile-(6.5 g, 34 mmol) in 50 mL EtOH/H2O (5:1) was treated with KOH (3.8 g, 67 mmol). The mixture was stirred at 120° C. for 4 hours and then at 180° C. for 30 minutes. The mixture was cooled to room temperature. The mixture was extracted with EtOAc and the organic layer discarded. The water layer was acidified with concentrated HCl, extracted with EtOAc, washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give 1.16 g of the product as a pale yellow oil. MS m/e=213 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH:3]=1.C([Li])(C)(C)C.C[O:23][B:24](OC)[O:25]C.CO>C1COCC1.O>[CH:8]([Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[N:4]1[CH:5]=[CH:6][C:2]([B:24]([OH:25])[OH:23])=[CH:3]1)([CH3:10])[CH3:9]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Br)c1
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To −78° C. solution of 3-bromo-1-(triisopropylsilyl)-1H-pyrrole (0.619 g, 2.288 mmol) in 10 mL THF was added tert-butyllithium (2.83 mL of 1.7 M in Heptane, 4.80 mmol) dropwise. The reaction mixture was stirring at −78° C. for 45 minutes, then trimethylborate (2.38 g, 22.88 mmol) was added. The reaction was stirred for another 45 minutes at −78° C. To this was then added 0.9 mL methanol and water solution (V/V=1:1) and the reaction was allowed warm to room temperature. The reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo, and used in the next step without further purification.
Reaction SMILES: ClC1C=C[N:5]=[C:4]2C=C(C(N3CC[C@@H](OC)C3)=O)SC=12.[CH3:20][O:21][C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]([C:29]2[S:37][C:36]3[C:31](=[N:32][CH:33]=[CH:34][C:35]=3[O:38][C:39]3[CH:40]=[CH:41][C:42]4[C:46]([C:47]([OH:49])=O)=[C:45]([CH3:50])S[C:43]=4[CH:51]=3)[CH:30]=2)=[O:28])[CH2:23]1.C([O-])([O-])=[O:53].[Cs+].[Cs+]>>[CH3:4][NH:5][C:47]([C:46]1[C:42]2[CH:41]=[CH:40][C:39]([O:38][C:35]3[CH:34]=[CH:33][N:32]=[C:31]4[CH:30]=[C:29]([C:27]([N:24]5[CH2:25][CH2:26][CH:22]([O:21][CH3:20])[CH2:23]5)=[O:28])[S:37][C:36]=34)=[CH:51][C:43]=2[O:53][C:45]=1[CH3:50])=[O:49]
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)sc5c4)c3s2)C1
Reactant: O=C([O-])[O-]
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: [Cs+]
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(C(=O)N5CCC(OC)C5)sc34)ccc12
Yield: 57.6 %

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4b (144 mg, 0.5 mmole) with 6-hydroxy-2-methylbenzo[b]furan-3-carboxylic acid methylamide 11c (120 mg, 0.6 mmole) and Cs2CO3 (794 mg, 2.4 mmole) in a manner as previously described for example 1 to give 134 mg (59%) of an off-white solid. 1H NMR (DMSO-d6) δ 8.58 (1H, d, J=5.3 Hz), 8.07 (1H, s), 7.97 (1H, d, J=4.5 Hz), 7.83 (1H, d, J=8.6 Hz), 7.65 (1H, d, J=2.0 Hz), 7.24 (1H, dd, J=2.0, 8.6 Hz), 6.72 (1H, d, J=5.3 Hz), 4.25–3.75 (3H, m), 3.65–3.45 (2H, m), 3.27, 3.24 (3H, s), 2.82 (3H, d, J=4.3 Hz), 2.62 (3H, s), 2.15–1.95 (2H, m). Anal. Calcd for C24H23N3O5S.0.5H2O: C, 60.74; H, 5.10; N, 8.86; S, 6.76. Found: C, 60.89; H, 5.16; N, 8.69; S, 6.58.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[N:16][OH:17])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(Cc1ccc(Cl)cc1)C(F)(F)F
Yield: 110.7 %

Procedure:
A solution of 3-(p-chlorophenyl)-1,1,1-trifluoro-2-propanone (10.0 g, 0.045 mol) in ethanol (60 mL) is treated with a solution of hydroxylamine hydrochloride (4.68 g, 0.067 mol) in water (20 mL) and then with a solution of sodium acetate (5.53 g, 0.067 mol) in water (20 mL). The reaction mixture is refluxed for 2 hours, cooled, diluted with water, and extracted with ether. The combined ether extracts are washed sequentially with water and brine, dried (Na2SO4) and evaporated to a liquid which solidifies upon standing to give the title compound as white needles (11.84 g): IR (neat) 3300 cm-1 (broad); 1H NMR (CDCl3) δ3.86 (s, 2H, CH2), 7.23 and 7.30 (AB,JAB =8.6 Hz, ArH), 19F NMR δ-69.2; 13C NMR δ29.3 (s, CH2), 120.8 (q, 1JCF =274.5 Hz, CF3), 128.8, 130.3, 132.5, 133.1 (Aromatic C), 148.4 (q 2JCF =32.1 Hz, CO).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:15]=1[F:23].Cl>C1COCC1>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:15]=1[F:23])[C:3](=[O:4])[CH3:5])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=[N+]([O-])c1cccc(CBr)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1F)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
Ethyl acetoacetate (37.4 mL, 294 mmol) was added at 0° C. to a suspension of sodium hydride (65%, 10.8 g) in THF (600 mL), and the mixture was stirred at 0° C. for 30 minutes. It was added dropwise at 0° C. to a solution of 1-bromomethyl-2-fluoro-3-nitrobenzene (compound 1a-1) (68.7 g, 294 mmol) in THF (400 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into 0.5N hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. A crude product was obtained by vacuum concentration, and purified by column chromatography (ethyl acetate:hexane=1:3) to yield the title compound (52.2 g, 63%) as a yellow oil.
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:1])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: NN
Reactant: O=C1NC(=O)c2c(CCCCCCN3CCOCC3)cccc21
Solvent: CO
Product: NCCCCCCN1CCOCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 6-morpholinylhexylphthalimide (253 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[CH:33]=4)[CH:27]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(-c3cc(C)no3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1ccnc(-c3cc(C)no3)c1)=N2

Procedure:
The title compound was prepared from (4-chloro-5-[(2-methoxy-ethyl)-methyl-amino]-2-{3-[2-(3-methyl-isoxazol-5-yl)-pyridin-4-yl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert.-butyl ester (Example M12) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (106 mg).