Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]C(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.C(N)CN.NC1C=CC=CC=1>>[NH2:1][CH2:30][CH2:29][NH:28][C:26](=[O:27])[NH:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]3=[C:13]([N:7]3[CH2:6][CH:5]4[O:12][CH:9]([CH2:10][CH2:11]4)[CH2:8]3)[N:18]=2)=[CH:20][CH:21]=1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: NC(N)=O
Solvent: NCCN
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)NCCN)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing ethylenediamine as the aniline component. (31%, MS=550.3 (M+H))
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CS([Cl:61])(=O)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][Cl:61])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(CO)cc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(CCl)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-bath cooled solution of Intermediate 106a (150 mg, 0.25 mmol) in DCM (3 mL) was added DIPEA (107 μL, 0.61 mmol) followed by methanesulfonyl chloride (29 μL, 0.37 mmol). The reaction mixture was stirred for 2 h. After warming to RT, additional amount of DIPEA (65 μL) and methanesulfonyl chloride (30 μL) were added and stirring was continued for 2 h. The reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.59 min, ink 653 [MH+].
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11]C)=[O:9])=[CH:5][CH:4]=1.[CH3:13][O-:14].[Na+].Cl>CO>[CH3:13][O:14][CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(C(=O)OC)o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82.7 %

Procedure:
In 20 ml of dry methanol was dissolved 5.0 g (26.5 mmol) of ethyl 5-chloromethyl-2-furancarboxylate, followed by addition of 20 ml of a 28% solution of sodium methoxide in methanol. The mixture was stirred at room temperature for 17 hours, at the end of which time it was neutralized with 1N-hydrochloric acid. The resulting precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform and the solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to give 3.73 g (82.7%) of methyl 5-methoxymethyl-2-furancarboxylate (Compound c) as light yellow oil.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH3:32][N:33]([CH3:61])[C:34]([C:36]1[CH:37]=[CH:38][C:39]2[CH:43]=[C:42]([C:44]3[C:49]([CH3:50])=[CH:48][N:47]=[C:46]([NH:51][CH2:52][CH2:53][CH:54]4[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]4)[N:45]=3)[S:41][C:40]=2[CH:60]=1)=[O:35]>>[ClH:3].[ClH:1].[CH3:61][N:33]([CH3:32])[C:34]([C:36]1[CH:37]=[CH:38][C:39]2[CH:43]=[C:42]([C:44]3[C:49]([CH3:50])=[CH:48][N:47]=[C:46]([NH:51][CH2:52][CH2:53][CH:54]4[CH2:55][CH2:56][N:57]([CH3:4])[CH2:58][CH2:59]4)[N:45]=3)[S:41][C:40]=2[CH:60]=1)=[O:35]
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Reactant: Cc1cnc(NCCC2CCNCC2)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1
Agent: Cl
Product: Cc1cnc(NCCC2CCN(C)CC2)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from crude product 2-[5-methyl-2-(2-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-6-carboxylic acid dimethylamide and isolated as yellow foam (307 mg, 42% yield). ES+(m/z) 438 [M(free base)+H].
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:7][C:6]2=1)=O.Cl.[O:23]([NH2:25])[CH3:24].[OH-].[Na+]>>[CH3:24][O:23][N:25]=[CH:1][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:7][C:6]2=1
Reactant: CON
Reactant: O=Cc1ccc2[nH]c3c(c2c1)CC(NC(=O)C1CC1)CC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CON=Cc1ccc2[nH]c3c(c2c1)CC(NC(=O)C1CC1)CC3

Procedure:
Prepare the title compound from cyclopropanecarboxylic acid(6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-amide (Preparation 72) (6.50 g, 57.3 mmol) methoxylamine hydrochloride (4.81 g, 57.6 mmol) and sodium hydroxide (1.84 g, 46.0 mmol), by essentially following procedures as described in Example 202 to obtain 6.00 g (84%) of product. MS (ES): m/z 312 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11]C)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br>>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(Cl)c1O
Agent: Br
Product: O=Cc1ccc(O)c(O)c1Cl

Procedure:
2-Chloro-3-hydroxy-4-methoxybenzaldehyde is treated with hydrogen bromide to give 2-chloro-3,4-dihydroxybenzaldehyde which is converted to the methylenedioxy derivative with dibromomethane as described above. The product is condensed with nitromethane and the resulting nitroethylene reduced to give the phenethylamine. This compound is condensed with p-methoxystyrene oxide to give the α-hydroxyphenethylamine intermediate which is reated with an excess of trifluoroacetic acid at room temperature for 18 hours to give 6-chloro-7,8-methylenedioxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine. This compound is split using boron trichloride as described above to give 6-chloro-7,8-dihydroxy-1-p-methoxyphenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: N1C=CC=C(CCC[CH2:10][C:11]([OH:13])=[O:12])C=1.[N:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22]Br)=[CH:16][CH:15]=1>>[N:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:10][C:11]([OH:13])=[O:12])=[CH:16][CH:15]=1
Reactant: O=C(O)CCCCc1cccnc1
Reactant: BrCCCc1ccncc1
Product: O=C(O)CCCCc1ccncc1
Yield: 24 %

Procedure:
4-Pyridinevaleric acid was prepared according to the procedure employed in the preparation of 3-pyridinevaleric acid. From 56.0 g of the hydrobromide salt of 3-(4-pyridyl)propyl bromide there was obtained 10.4 g (24%) of 4-pyridinevaleric acid, mp 195°-200° C. The analytical sample was obtained from isopropanol, mp 200°-201° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=O)([O-:3])=[O:2].[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1)([O-:3])=[O:2]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1
Yield: 94 %

Procedure:
The title compound was prepared from 5-nitro-1H-indole-2,3-dione (Gassman, et al., Journal of Organic Chemistry 1977, 42, 1344-8) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 94% yield: 1H NMR (DMSO-d6): δ7.14 (d, J=8.6 Hz, 1H), 7.33 (s, 2H), 7.75 (d, J=8.8 Hz, 2H), 7.84 (d, J=8.8 Hz, 2H), 8.23 (dd, J=2.2, 8.6 Hz,1H), 8.42 (d, J=2.2 Hz, 1H), 11.76 (s, 1H), 12.78 (s, 1H). Anal. Calcd for C14H11N5O5S: C, 46.54, H, 3.07; N, 19.38. Found C, 46.76, H, 3.13; N, 19.23.
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=O>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][O:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][C:8]([CH:6]=[CH2:1])=[CH:9][CH:10]=1
Reactant: [Li]CCCC
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of n-butyllithium (4 mL, 2,5 M solution in hexane, 10 mmol) (Aldrich) in ether (30 mL) was added methyltriphenylphosphonium bromide (3.57 g, 10 mmol) (Aldrich) over a period of 5 min. The reaction mixture was stirred for 4 h at room temperature. To the resulting orange solution was added methyl 4-formylbenzoate (1.54 mL, 10 mmol) dropwise. The solution became colorless, and a white precipitate separated. The mixture was then heated to reflux and immediately allowed to cool to room temperature. The precipitate was removed by filtration. The resulting precipitate was washed with ether, and the combined ethereal filtrates were washed with water until neutral and then dried over anhydrous MgSO4. The solvent was removed and the residue, 4-ethenyl-benzoic acid methyl ester, was used in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[C:21]([S:26]([O-:28])=[O:27])[CH:20]=[CH:19]3)=[CH:12][CH:11]=1.[Na+]>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[C:21]([S:26]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[CH2:7][OH:8])(=[O:28])=[O:27])[CH:20]=[CH:19]3)=[CH:12][CH:11]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: OCc1ccsc1Br
Agent: [Na+]
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1sccc1CO

Procedure:
Prepared according to the method of Example 6 Step 4 using (2-bromo-3-thienyl)methanol (itself prepared according to WO2004/065384A1) and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate. 1H NMR (400 MHz, d6-DMSO): δ 8.72 (1H, s), 8.36 (2H, d, J=7.9 Hz), 8.21 (1H, d, J=8.8 Hz), 8.04 (2H, dd, J=3.2, 8.4 Hz), 7.93-7.87 (3H, m), 7.38 (2H, t, J=8.9 Hz), 7.26 (1H, d, J=5.1 Hz), 5.47 (1H, t, J=5.9 Hz), 4.70 (2H, d, J=5.9 Hz). m/z (ES+) 384 [(M-OH)+].
Reaction SMILES: [CH:1]1([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][C:27]=1[O:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.C(Cl)(Cl)Cl.[I-].[K+]>[CH:1]1([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][C:27]=3[O:35][CH3:36])[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1ccc(C(C2CCCCC2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCCCO
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(c2ccc(F)cc2)C2CCCCC2)CC1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A mixture of 4-[cyclohexyl(4-fluorophenyl)methyl]piperidine (5.71 g, 0.0207 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.03 g, 0.207 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The reaction mixture was cooled to room temperature and filtered. The 1-butanol was removed by rotary evaporation to give a brown oil. This oil was dissolved in chloroform and the chloroform layer was extracted with 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a brown oil. This oil was subjected to flash chromatography on silica gel. Elution was performed using ethyl acetate, 5% methanol-ethyl acetate, and 10% methanol-ethyl acetate. Separate fractions of similar purity were combined and solvent was removed to give a yellow oil. This oil was dried in vacuo overnight at 80° C. to give 7.36 g (73.8%) of title compound.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(O)CC[N+]([F:20])(CC2)C1.[CH3:21][O:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][CH2:28][C:29]2=[O:32])=[CH:25][CH:24]=1>C(#N)C>[F:20][C:31]1[C:23]([O:22][CH3:21])=[CH:24][CH:25]=[C:26]2[C:30]=1[C:29](=[O:32])[CH2:28][CH2:27]2
Reactant: O[N+]12CC[N+](F)(CC1)CC2
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1ccc2c(c1F)C(=O)CC2

Procedure:
A solution of Accufluor™ fluorinating reagent (6.75 g, 9.00 mmol) and 6-methoxy-indan-1-one (500 mg, 3.00 mmol) in ACN (600 mL) was heated at 80° C. for six hours. The reaction was concentrated under reduced pressure, and the residue was purified by medium pressure chromatography (silica, 10 to 25% EtOAc:hexanes) to yield 38.1. 1H NMR (400 MHz, CDCl3) δ ppm 7.21-7.29 (m, 1H), 7.12-7.18 (m, 1H), 3.92 (s, 3H), 3.04-3.12 (m, 2H), 2.70-2.76 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[O:21]=[S:22]1(=[O:30])[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH:28]=O>>[O:21]=[S:22]1(=[O:30])[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH2:28][NH:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: O=CCN1CCCS1(=O)=O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN1CCCS1(=O)=O

Procedure:
This compound was prepared from ethyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate and (1,1-dioxido-2-isothiazolidinyl)acetaldehyde employing methods similar to those described in Example 265 and was obtained as a brownish oil. 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1 H), 7.89 (br, 1 H), 7.14 (dd, J=8.4, 5.4 Hz, 2 H), 6.98 (t, J=8.6 Hz, 2 H), 6.92 (s, 1 H), 4.41 (q, J=7.2 Hz, 2 H), 3.91 (s, 2 H), 3.41 (m, 2 H), 3.29-3.24 (m, 4 H), 3.13 (t, J=7.7 Hz, 2 H), 2.31 (m, 2 H), 1.41 (t, J=7.0 Hz, 3 H); MS m/z 422 (M+H)+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:13]=[C:12]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:11]=1.[C:36](=O)([O:39]C)[O:37][CH3:38]>>[CH3:38][O:37][C:36](=[O:39])[CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:13]=[C:12]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=2)[CH:11]=1
Reactant: COC(=O)OC
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A solution of LDA (1.8 M in THF/heptane/ethyl benzene, 4.4 mL, 7.92 mmol) was added slowly to a stirred solution of 4-methyl-2,6-bis-(4-trifluoromethylphenyl)-pyridine (1.37 g, 3.6 mmol) under N2 at −78° C. After 30 minutes, dimethyl carbonate (720 μL, 8.0 mmol) was added. After stirring at −78° C. for an additional 30 minutes, the solution was allowed to warm up slowly and stirred at 0° C. for 30 minutes The reaction was quenched with saturated aqueous NH4Cl (10 mL). The mixture was partitioned between CH2Cl2 and H2O. The aqueous layer was extracted with CH2Cl2 (2×). The combined extracts were washed with brine, then dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (10-50% CH2Cl2 in heptane) to give the product as a white solid (1.38 g, 87%). 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=7.91 Hz, 4H), 7.76 (d, J=7.91 Hz, 4H), 7.72 (s, 2H), 3.80 (s, 2H), 3.77 (s, 3H). MS m/e 440.2 (M+H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[C:10]([Br:16])[CH:9]=2)=[O:5])[CH3:2].[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C(P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:23]1[CH2:24][CH2:25][N:20]([CH:17]([CH3:19])[CH3:18])[CH2:21][CH2:22]1)=[C:10]([Br:16])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CCOC(=O)c1cc2cc(O)c(Br)cc2[nH]1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Br)cc2[nH]1
Temperature: 0 °C
Yield: 55.5 %

Procedure:
To the suspension of 0.25 g (0.88 mmol) 6-bromo-5-hydroxy-1H-indole-2-carboxylic acid ethyl ester in 5 mL tetrahydrofuran, 0.15 g (1.05 mmol) 1-isopropyl-piperidin-4-ol (commercially available) and 0.28 g (1.07 mmol) tributylphosphine were added. The suspension was cooled to 0° C., 0.244 g (1.06 mmol) di-tert-butyl azodicarboxylate was added and the reaction was allowed to reach room temperature. After 48 hours the suspension was filtered and the filtrate was evaporated. The residue was flash-chromatographed on silica gel with a gradient of dichloromethane:methanol (100:0 to 60:40 v/v) to give 0.20 g (55%) of the product as a light yellow foam. MS (m/e): 409.0 (M−H+, 100%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.[Na].[N:14]([CH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([NH:23]N)=O)=[N+:15]=[N-:16]>C(O)C>[N:14]([CH2:17][C:18]1[CH:19]=[C:20]([C:21]2[N:10]=[C:8]([C:7]3[CH:11]=[CH:12][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[NH:9][N:23]=2)[CH:25]=[CH:26][CH:27]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=NCc1cccc(C(=O)NN)c1
Reactant: COc1ccc(C(=N)N)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: COc1ccc(-c2nc(-c3cccc(CN=[N+]=[N-])c3)n[nH]2)cc1
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To an ethanolic suspension of 4-methoxybenzamidine hydrochloride salt (1:1) (2.01 g, 10.8 mmol, 1.5 eq.) was added sodium (331 mg, 14.4 mmol, 2 eq.) in ethanol (60 ml), stirring was then continued for 30 min. at r.t. 3-azidomethyl-benzoic acid hydrazide (1.37 g, 7.2 mmol) in ethanol was then added at 20° C. and the mixture heated at reflux for 18 hrs. Upon cooling the product mixture was filtered, the solvent was evaporated and the residue chromatographed over 20 g SiO2 (Merck 230-400 mesh) with CH2Cl2, affording a solid after evaporation of the solvent. The residue was dried under high vacuum overnight at 20° C. affording the title compound (1.25 g, 57% yield) as a white solid. MS: m/e=306 (M+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.O=[C:12]([CH3:28])[CH2:13][S:14][CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.Cl.CCOCC>C(O)(C)C>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]([CH3:28])=[C:13]2[S:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: CC(=O)CSC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1[nH]c2ccc(Br)cc2c1SC1CCNCC1
Reaction time: 4 h

Procedure:
4-Bromophenylhydrazine hydrochloride (11.5 g) is solubilized in a solution of 1,1-dimethylethyl 4-[(2-oxopropyl)thio]piperidine-1-carboxylate (prepared in Example 10) in isopropanol (100 ml) under nitrogen. The solution is cooled to 0° C. and saturated with gaseous hydrogen chloride. After 4 hours at room temperature, the precipitate is filtered off, taken up in sodium hydroxide and extracted with ether and then with methylene chloride. The organic phases are combined, dried over sodium sulfate and concentrated. The solid obtained is taken up in the minimum amount of ether and recrystallized from xylene to give 5-bromo-2-methyl-3-(piperidin-4-ylthio) -1H-indole (9.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[N:31]1([C@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:42])[CH:35]=[CH:34][N:33]=[CH:32]1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:42][C@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][C@@H:36]2[N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: O[C@H]1CCCC[C@@H]1n1ccnc1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3n3ccnc3)cc2F)c(OC)c1
Yield: 90.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide (260 mg, 0.592 mmol) prepared in Example 14b, (1S*,2S*)-2-(1H-imidazol-1-yl)cyclohexanol (Tetrahedron, 2007, 63, 469-473; 100 mg, 0.602 mmol), sodium hydride (63%; 50 mg, 1.31 mmol) and DMF (3.0 mL), to yield the title compound (315 mg, 91%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>[Cu]I.O>[CH:13]1[CH:18]=[CH:17][C:16]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])=[CH:15][CH:14]=1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Brc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1Nc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-2-nitroaniline (5.5 g), bromobenzene (20 ml), potassium carbonate (1.63 g) and copper(I) iodide (0.68 g) was heated to 180° for 36 h. The reaction mixture was cooled to room temperature, then ethyl acetate (200 ml) and water (300 ml) were added; the organic extracts were washed with brine (2×150 ml), dried and concentrated in vacuo to give the crude compound which was purified by flash chromatography (eluting with CH-EA 95:5) to give the title compound (3.67 g). T.l.c. CH-EA (1:1 ), Rf 0.71.