Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH:9]([CH3:20])[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[C:17]([OH:19])=O)=[O:11])=[O:7])=[CH:4][C:3]=1[Cl:23].C(OC(=O)[NH:29][CH:30]1[CH2:34][C:33](=[O:35])[O:32][CH:31]1[O:36][CH:37]([CH3:39])[CH3:38])C=C.O=C1OC(OCCC2C=CC=CC=2)C(NC(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)C1>>[CH:37]([O:36][CH:31]1[CH:30]([NH:29][C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][N:12]2[C:10](=[O:11])[CH:9]([NH:8][C:6](=[O:7])[C:5]2[CH:21]=[CH:22][C:2]([NH2:1])=[C:3]([Cl:23])[CH:4]=2)[CH3:20])=[O:19])[CH2:34][C:33](=[O:35])[O:32]1)([CH3:39])[CH3:38]
Reactant: C=CCOC(=O)NC1CC(=O)OC1OC(C)C
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(C)OC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1ccc(N)c(Cl)c1
Yield: 66 %

Procedure:
Prepared from 97a and (2-isopropoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 200 mg of title compound (66% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.05-1.35 (m, 6H), 1.35-1.50 (m, 3H), 1.70-2.45 (m, 4H), 2.45-3.05 (m, 2H), 3.55-4.10 (m, 3H), 4.15-4.88 (m, 4H), 5.48 (s, 0.4H), 5.58 (s, 0.1H), 5.64 (d, 0.4H), 5.70 (d, 0.1H), 6.78 (d, 1H), 7.58 (d, 1H), 7.80 (s, 1H). Analytical HPLC: 12.19, 12.40 min. LC-MS (ES+): m/e=581.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[S:12][C:11](Br)=[C:10]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2[CH3:23])[CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].C([Li])CCC>O>[CH2:1]([NH:4][S:5]([C:8]1[S:12][CH:11]=[C:10]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2[CH3:23])[CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNS(=O)(=O)c1cc(-c2sc(NC(C)=O)nc2C)c(Br)s1
Agent: [Li]CCCC
Solvent: O
Product: C=CCNS(=O)(=O)c1cc(-c2sc(NC(C)=O)nc2C)cs1
Temperature: -70 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
N-(5-{5-[(allylamino)sulfonyl]-2-bromo-3-thienyl}-4-methyl-1,3-thiazol-2-yl)acetamide obtained in Step I as described above (35 mg; 0.08 mmol; 1 eq), is dissolved in dry TBF (5 ml) at −70° C. under an inert atmosphere. n-Butyllithium (0.18 ml; 1 M; 0.18 mmol; 2.20 eq) is added slowly and reaction stirred at −70° C. for 1 hour before being hydrolyzed with water (0.3 ml). Reaction is warmed up to room temperature before being concentrated to dryness. Residue is taken up with water (2 ml) and EtOAc (10 ml). The organic phases are decanted, dried over MgSO4, filtrated and evaporated. Title compound is purified by reverse preparative HPLC, affording Compound (49) as a white powder (3 mg; 10%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:32])([F:31])[S:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([S:21]([C:20]([F:32])([F:19])[F:31])(=[O:23])=[O:22])=[CH:25][CH:26]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Product: O=S(=O)(c1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cc1)C(F)(F)F

Procedure:
The title compound was prepared substantially according to the procedure given for Compound 4A, using 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.2 g, 0.77 mmol), and 4-(trifluoromethylsulphonyl)aniline (0.27 g, 1.2 mmol) to give the desired N-benzyl intermediate as a brown solid (278 mg. 82%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Li]CCCC>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)C=CCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(CCCCc1ccccc1)Sc1ccccc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
t-butyl 7-phenylhept-2-enoate (2 g; 7.7 mmol) and thiophenol (1.2 g; 11 mmol) are dissolved in THF (25 mL) and cooled to 0° C. n-BuLi (2.5 M in hexane; 0.3 mL; 0.7 mmol) is added dropwise and the reaction is allowed to warm and stir at 20° C. for 3 hours. The reaction is concentrated in vacuo and purified by column chromatography using 5% Et2O/petroleum ether to obtain t-butyl 7-phenyl-3-phenylsulfanylheptanoate.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][C:19](O)=[O:20]>>[C:1]([C:5]1[C:6]([NH:14][C:19](=[O:20])[CH2:18][CH2:17][C:16]([CH3:23])([CH3:22])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CCC(=O)O
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)CCC(=O)Nc1nn2cccnc2c1C(C)(C)C

Procedure:
The product from Example 105B and 4,4-dimethylpentanoic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89 (s, 9H), 1.44 (s, 9H), 1.48-1.53 (m, 2H), 2.23-2.27 (m, 2H), 6.99 (dd, J=7.1, 4.0 Hz, 1H), 8.48 (dd, J=4.0, 2.0 Hz, 1H), 8.92 (dd, J=6.9, 1.8 Hz, 1H), 9.69 (s, 1H); MS (DCI) m/z 303 (M+H)+.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:22]([CH:24]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[CH2:25][C:26]([O:28]C)=[O:27])#[N:23]>>[C:22]([CH:24]([C:30]1[CH:35]=[CH:34][C:33]([O:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5]/[C:4](/[C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)=[N:3]\[O:2][CH3:1])=[CH:12][CH:11]=2)=[CH:32][CH:31]=1)[CH2:25][C:26]([OH:28])=[O:27])#[N:23]
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccc(F)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)c1ccc(F)cc1
Yield: 15.46 %

Procedure:
Compound 34 was synthesized from (1Z)-1-(4-fluorophenyl)-2-[4-(hydroxymethyl)phenoxy]ethanone O-methyloxime (0.4 g, 1.46 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.3 g, 1.46 mmol) by following the procedure described in scheme 18 (0.06 g, yield: 15.46%); Purity: 95.29%.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=3)=[CH:10][C:4]=2[O:3]1.CN(C)C=O.C(N(CC)CC)C.[CH3:33][O:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>O>[CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:16]([NH:17][C:36]([N:35]([O:34][CH3:33])[CH3:39])=[O:37])=[CH:15][CH:14]=3)=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)Cc2ccc(COc3ccc(N)cc3)cc2O1
Reactant: CON(C)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Nc1ccc(OCc2ccc3c(c2)OC(C)(C)C3)cc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
6.9 g of 4-(2,3-dihydro-2,2-dimethyl-6-benzofuranylmethyloxy)aniline was dissolved into 70 ml of N,N-dimethylformamide, and 2.8 g of triethylamine was added thereto. 3.8 g of N-methoxy-N-methylcarbamoyl chloride was slowly added dropwise thereto. After the mixture was stirred at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off and the residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/2) as a developer to obtain 6.0 g of Compound No. 4 shown in Table 1.
Reaction SMILES: [N:1]1[N:9]2[C:4]([CH2:5][O:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[NH2:10].Br[C:12]1[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16]([Br:18])[CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:18][C:16]1[CH:17]=[C:12]([NH:10][C:2]2[CH:3]=[C:4]3[CH2:5][O:6][CH2:7][CH2:8][N:9]3[N:1]=2)[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Nc1cc2n(n1)CCOC2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2cc3n(n2)CCOC3)c1=O
Temperature: 25 °C
Yield: 30.9 %

Procedure:
A 50-mL three-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (20 mL), 129b (600 mg, 4.31 mmol), 3,5-dibromo-1-methylpyridine-2(1H)-one (1.44 g, 5.40 mmol) and cesium carbonate (3.08 g, 9.48 mmol). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (300 mg, 0.52 mmol) and tris(dibenzylideneacetone)dipalladium(0) (320 mg, 0.35 mmol) were added, and the reaction mixture was heated at reflux for 2 h. After this time the reaction was cooled to room temperature, partitioned between ethyl acetate (75 mL) and water (75 mL) and filtered. The aqueous layer was separated and extracted with ethyl acetate (2×25 mL). The organic layers were combined and washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue was purified by column chromatography using 500 cc of silica gel and eluting with 1% methanol in methylene chloride. The fractions containing 129c were collected to afford, after concentrating under reduced pressure, a 31% yield (433 mg) of 129c as a green solid: mp 195-197° C.; 1H NMR (300 MHz, CDCl3) δ 7.92 (d, 1H, J=2.4 Hz), 7.44 (s, 1H), 6.90 (d, 1H, J=2.4 Hz), 5.65 (s, 1H), 4.80 (s, 2H), 4.13 (s, 2H), 3.61 (s, 5H); MS (ESI+) m/z 324.9 (M+H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f21) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: I.[NH2:2][NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[NH:5].C(OCC)C.[OH-].[Na+].[CH2:21]([O:23][C:24]1[CH:31]=[C:30]([O:32][CH2:33][CH3:34])[CH:29]=[C:28]([O:35][CH2:36][CH3:37])[C:25]=1[CH:26]=O)[CH3:22]>C(Cl)Cl.CCCCCC>[CH2:7]([NH:6][C:4]([NH:3][N:2]=[CH:26][C:25]1[C:24]([O:23][CH2:21][CH3:22])=[CH:31][C:30]([O:32][CH2:33][CH3:34])=[CH:29][C:28]=1[O:35][CH2:36][CH3:37])=[NH:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOc1cc(OCC)c(C=O)c(OCC)c1
Reactant: N=C(NN)NCc1ccccc1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: CCOc1cc(OCC)c(C=NNC(=N)NCc2ccccc2)c(OCC)c1

Procedure:
A mixture of 10.0 g. of 1-amino-3-benzylguanidine hydroiodide and 100 ml. each of diethyl ether, n-hexane and methylene chloride is shaken with 10 ml. of 5N NaOH. To this is added 8.15 g. of 2,4,6-triethoxybenzaldehyde and the mixture is shaken for 15 minutes. The organic layer is washed with saturated aqueous sodium chloride, passed through hydrous sodium magnesium silicate and concentrated to dryness under reduced pressure. The residue is crystallized from aqueous ethanol, giving the desired product as nearly colorless crystals, m.p. 140°-141° C.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20]C([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:58][C:59]([CH3:61])=[O:60])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][CH2:8]1)=[O:6]>C(Cl)Cl.CO>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:58][C:59]([CH3:61])=[O:60])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][CH2:8]1)=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@]2(C)CC[C@H]3OC[C@@]3(OC(C)=O)[C@H]2[C@H](OC(=O)c2ccccc2)[C@]2(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c3ccccc3)c3ccccc3)C(C)=C1C2(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(=O)O[C@H]1C(=O)[C@]2(C)CC[C@H]3OC[C@@]3(OC(C)=O)[C@H]2[C@H](OC(=O)c2ccccc2)[C@]2(O)C[C@H](O)C(C)=C1C2(C)C
Reaction time: 24 h
Yield: 79.3 %

Procedure:
(2) To a solution of 7-deoxy paclitaxel (461 mg, 0.55 mmol) in 20 mL of methylene chloride and 0.4 mL of methanol was added Bu4NBH4 (283 mg, 1.1 mmol) and the solution stirred for 24 hours. The solution was quenched with saturated NH4Cl and extracted with ethyl acetate. The solution was dried over MgSO4 and concentrated. The residue was chromatographed over silica gel using hexane-ethyl acetate (1:1) to give 249 mg of product (79%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH:11]([NH:18][C:1](=[O:3])[CH3:2])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ncsc1C(N)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(c1ccccc1)c1scnc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride was added to a solution of the product from Example 56 and triethylamine in dry dichloromethane. The mixture was stirred at room temperature overnight and then washed with aqueous sodium hydrogen carbonate solution. The organic phase was separated, dried and evaporated and the residue was purified by flash chromatography to give the title compound.
Reaction SMILES: COC1C=CC(C[NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=CC=1.[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>>[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:36][CH:35]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: O=C(NCCNCc1ccc(OC(F)(F)F)cc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 4-(trifluoromethoxy)benzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 476 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.25 (1H, s) 8.04 (1H, t, J=5.52 Hz) 8.01 (1H, d, J=5.42 Hz) 7.77 (1H, d, J=5.47 Hz) 7.46 (1H, d, J=5.42 Hz) 7.42 (2H, d, J=8.69 Hz) 7.29 (1H, d, J=2.54 Hz) 7.23 (2H, d, J=8.44 Hz) 6.79 (1H, d, J=5.42 Hz) 6.43 (1H, dd, J=3.47, 1.90 Hz) 3.70 (2H, s) 3.35 (2H, q, J=6.49 Hz) 2.63 (2H, t, J=6.52 Hz)
Reaction SMILES: [NH2:1][C:2]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24](F)[CH:23]=1)([C:16]1[N:17]([CH3:21])[CH:18]=[N:19][CH:20]=1)[CH2:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:1][C:2]1([C:16]2[N:17]([CH3:21])[CH:18]=[N:19][CH:20]=2)[C:22]2=[CH:29][C:28](=[C:25]([C:26]#[N:27])[CH:24]=[CH:23]2)[O:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cn1cncc1C(N)(CCCNCCc1cccc(O)c1)c1ccc(C#N)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cncc1C1(N)CCCNCCc2cccc(c2)Oc2cc1ccc2C#N
Reaction time: 18 h

Procedure:
4-[1-Amino-4-[2-(3-hydroxy-phenyl)-ethylamino]-1-(3-methyl-3H-imidazol-4-yl)-butyl]-2-fluoro-benzonitrile (0.058 g, 0.142 mmol) was dissolved in DMF (15 mL) and treated with Cs2CO3 (0.324 g, 0.994 mmol). After 18 h at 60° C., the reaction mixture was concentrated in vacuo, dissolved in H2O: 0.1% TFA (3 mL) and purified by RP LC on a Delta PrepPak eluting with 95:5 to 5:95 H2O (0.1% TFA): CH3CN(0.1% TFA) to give the title compound as an 80:20 mixture of enantiomers.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.O>CN(C)C=O>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][C:16]([F:30])([F:31])[F:15])=[CH:19][CH:20]=3)[CH2:29][CH2:28]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCN(c2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 7 h
Yield: 104.2 %

Procedure:
Mixture of (R)-2-chloro-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole (2.50 g, 11.5 mM) obtained in example 7 and 4-(4-trifluoromethoxyphenyl) piperazine (3.11 g, 12.6 mM) in N,N-dimethylformamide (25 ml) was stirred at 70° C. for 7 hours. The temperature of reaction mixture was turned back to a room temperature, water was added and extracted twice with ethyl acetate. The organic layers were combined, washed with water three times, dried on anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure, there was obtained (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]propan-2-ol (5.55 g, yield: 100%) of slightly yellow oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>CN(C=O)C.C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:31]([C:27]5[S:26][CH:30]=[CH:29][CH:28]=5)=[O:32])[N:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Nc1nccc(-c2ccc3noc(-c4cccc(Br)c4)c3c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1nccc(-c2ccc3noc(-c4cccc(Br)c4)c3c2)n1)c1cccs1
Temperature: 25 °C
Yield: 24.6 %

Procedure:
4-[3-(3-bromophenyl)-benzo[c]isoxazol-5-yl]-pyrimidin-2-ylamine (100 mg; 0.272 mmol) was dissolved in 3 mL of a mixture (2:1) of dry DMF/THF and stirred under a nitrogen atmosphere at ambient temperature. Sodium hydride (15 mg, 0.375 mmol, 60% oil dispersion) was added To the reaction and stirred for 30 minutes. Thiophenecarbonylchloride (32 μL; 43.7 mg; 0.299 mmol) in 500 μL of dry DMF was added dropwise over 2 minutes and the reaction was stirred for 18 hours at ambient temperature. Workup was affected by removing the solvents under reduced pressure and the resulting residue was triturated with methyltertbutyl ether. The crude solid was purified via silica column chromatography with 5% ethanol in methylenechloride to yield 32 mg of a tan powder; 24% yield. 1H NMR (500 MHz, DMSO-d6) δ 11.2 (s, 1H), 8.92 (s, 1H), 8.88 (d, 1H), 8.39 (d, 1H), 8.35 (s, 1H), 8.3 (d, 1H), 8.23 (d, 1H), 8.15 (d, 1H), 7.95 (d, 1H), 7.9 (d, 1H), 7.87 (d, 1H), 7.65 (t, 1H), 7.24 (t, 1H) in ppm. LC-MS (ES+) m/e=477/479 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[NH:7][CH:6]=1)=[O:4].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:7]([CH3:21])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c(-c2ccccc2C(F)(F)F)c1C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1cn(C)c(-c2ccccc2C(F)(F)F)c1C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of 4-methyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester (2.9 g, 10.2 mmol) in anhyd THF (40 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 12.3 mL, 12.3 mmol) slowly at 20° C. After stirring 0.5 h, iodomethane (0.96 mL, 15.4 mmol) was added and the mixture was stirred for 3 h at 20° C. After quenching with water, the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined extracts were washed with water, dried (anhyd Na2SO4) and concentrated under reduced pressure to yield 1,4-dimethyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester as an oil (2.8 g, 92%), which was used in the next step without purification. MS (ES): 298 (MH+). To a solution of 4-methyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester (2.9 g, 10.2 mmol) in anhyd THF (40 mL) was added lithium bis(trimethylsilyl)amide C. To a solution of 1,4-dimethyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester (2.5 g, 8.4 mmol) in MeOH (20 mL) was added 4N NaOH (10 mL) and the mixture was heated to reflux overnight. Evaporation of solvent gave a solid, which was re-dissolved in water. The solution was acidified with formic acid. The resulting solids were collected by filtration, washed with water and then dried under high vacuum to afford the title compound as an off-white solid (2.15 g, 90%). MS (ES): 284 (MH+).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([N+:17]([O-])=O)=[CH:12][C:11]=1[OH:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[C:1]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH2:17])=[CH:12][C:11]=1[OH:20])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl

Procedure:
In 100 ml of ethanol was dissolved 28 g (96×10-3 mole) of 2-benzamido-4-chloro-5-nitrophenol and hydrogenation was effected by using 1.5 g of Pd-C as a catalyst. The color of the nitro derivative disappeared in 2 hours, and the Pd-C was removed by filtration and ethanol was evaporated from the filtrate, followed by extraction of the residue with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium hydrogen carbonate solution and then with water, and after drying over magnesium sulfate, ethyl acetate was evaporated. 26 g of the crude product was used as such for the following reaction.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH:15]2[CH2:24][CH2:23][CH:22]3[CH:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:16]2)/[C:8]([O:10]CC)=[O:9])[N:6]=1.[K+].[Br-]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH:15]2[CH2:24][CH2:23][CH:22]3[CH:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:16]2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OC1CCC2CCCCC2C1)c1csc(N)n1
Agent: [Br-]
Agent: [K+]
Product: Nc1nc(/C(=N/OC2CCC3CCCCC3C2)C(=O)O)cs1
Yield: 79.2 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(decahydronaphth-2-yloxyimino)acetate (0.48 g) was hydrolysed as described in Example 4e to give the title compound (0.35 g), νmax (KBr) 3118, 2920, 1625, and 1013 cm-1, δH [(CD3)2SO]0.8-2.1 (16H, m), 4.06 (1H, m), 6.82 (1H, s), and 7.26 (3H, br s).