Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO[S:3]([O-:5])=O.[K+].S1[C:11]2[CH:12]=[C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:24]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH3:36])[CH:29]=5)=[N:25][NH:26][CH:27]=4)[CH:20]=[CH:19][N:18]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1>O.CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:24]2[C:23]([C:21]3[CH:20]=[CH:19][N:18]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]5[N:9]=[CH:8][S:3](=[O:5])[C:11]=5[CH:12]=4)[N:22]=3)=[CH:27][NH:26][N:25]=2)=[CH:29][C:30]=1[O:35][CH3:36]
Reactant: COc1cc(-c2n[nH]cc2-c2ccnc(Nc3ccc4ncsc4c3)n2)ccc1Cl
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(-c2n[nH]cc2-c2ccnc(Nc3ccc4c(c3)S(=O)C=N4)n2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of OXONE (=KHSO5; 141.4 mg, 0.23 mmoles) in water (2 mL) is added dropwise to a suspension of benzothiazol-6-yl-{4-[3-(4-chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-amine (Example 44) (20 mg, 0.046 mmoles) in methanol (2 mL) at rt. After stirring overnight at rt the suspension is diluted with water upon which the suspension turns to a clear yellow solution. The reaction mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, concentrated and chromatographed on SiO2 (5% MeOH/CH2Cl2) to yield the title compound as light yellow solid: ES-MS 451.0751 [M+H]; single peak at tR=4.93 min (System 3).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:16]2[CH:17]=[N:18][C:19]([Br:22])=[CH:20][CH:21]=2)O)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].O=S(Cl)[Cl:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:16]2[CH:17]=[N:18][C:19]([Br:22])=[CH:20][CH:21]=2)[Cl:26])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: OC(c1ccc(Br)nc1)c1ccc(OC(F)F)c(OC(F)F)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)Oc1ccc(C(Cl)c2ccc(Br)nc2)cc1OC(F)F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution [3,4-Bis(difluoromethoxy)phenyl]-(6-bromo-3-pyridyl)methanol (15.8 g,40.0 mmol) in 400 mL of CH2Cl2, was added 3.8 mL (52.0 mmol) of SOCl2. The solution was stirred 45 minutes at room temperature and poured into a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were dry over MgSO4 and concentrated under reduced pressure. The crude chloride was used directly for the next step without any purification.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][C:20]([CH3:22])=[O:21])=[C:9]([O:12][CH2:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.S(Cl)([Cl:25])=O>CN(C)C=O>[Cl:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][C:20]([CH3:22])=[O:21])=[C:9]([O:12][CH2:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc2ncnc(O)c2cc1OCC1CCCC1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2ncnc(Cl)c2cc1OCC1CCCC1

Procedure:
3.80 g of 4-hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline are suspended in 90 ml thionyl chloride and heated to boiling under a nitrogen atmosphere. After the addition of four drops of N,N-dimethylformamide the reaction mixture is refluxed for a further two hours. After cooling to ambient temperature the excess thionyl chloride is distilled off in a water jet vacuum. The brown residue is stirred with 30 ml toluene. The solvent is distilled off, leaving 4.30 g of a greyish-brown solid, which is reacted further without any more purification.
Reaction SMILES: CN1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[C:5](=O)N(C)C1=O.COC1N=C(OC)C(B2OC(C)(C)C(C)(C)O2)=CN=1.CCN(CC)CC.[CH3:46][O:47][C:48]1C=C(Br)C=[CH:50][C:49]=1[OH:55].COC1C=C(C=C(B2OC(C)(C)C(C)(C)O2)C=1OC)C=O.B([O-])([O-])[O-]>>[CH3:46][O:47][C:48]1[CH:5]=[C:6]([B:8]2[O:9][C:10]([CH3:15])([CH3:16])[C:11]([CH3:13])([CH3:14])[O:12]2)[CH:7]=[CH:50][C:49]=1[OH:55]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(=O)n(C)c1=O
Reactant: COc1cc(Br)ccc1O
Agent: COc1cc(C=O)cc(B2OC(C)(C)C(C)(C)O2)c1OC
Agent: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Agent: [O-]B([O-])[O-]
Solvent: CCN(CC)CC
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Solution 1 was transferred under N2 to a pressure-equalising dropping funnel and added to Solution 2 over 6 h. Stirred at RT overnight before heating at 40–50° C. for ˜8 h. After stirring overnight at RT a white ppt had formed. NEt3 (149 ml; 1.07 mol) was added followed by slow addition of 2-methoxy-4-bromophenol (91.6 g; 0.451 mol). Finally, the activated catalyst (Solution 3) was added and the resultant dark brown solution was stirred at 100° C. GC analysis after 20 hours showed the desired borate compound at 11.1 minutes (62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5](I)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.CN([CH:26]=[O:27])C.C([Li])CCC>COC1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=2[C:5]([CH:26]=[O:27])=[C:4]([CH3:22])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(C)cc(Cl)c32)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: COC1CCCC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C)cc(Cl)c32)cc1

Procedure:
To a solution of 7-chloro-4-iodo-5-methyl-1-tosyl-1H-indole (98 mg, 0.220 mmol) and DMF (34 μL, 0.440 mmol) in cyclopentyl methyl ether (2 mL) at −78° C., was added n-butyllithium (2.5 M in hexanes, 114 μL, 0.286 mmol). After 80 minutes additional n-butyllithium (2.5 M in hexanes, 0.11 mL, 0.286 mmol) was added. After 15 more minutes the reaction was quenched with MeOH (0.5 mL) and sat. aq. NH4Cl. The layers were separated and the aqueous layer was extracted with EtOAc, washed with brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-50% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 347.9 (M+H).
Reaction SMILES: [OH-].[K+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(O)(=O)C>C(O)C.O>[OH:22][C:11]1[CH:10]=[CH:9][C:8]2[CH:7]3[CH:16]([CH2:15][CH2:14][C:13]=2[CH:12]=1)[CH:17]1[C:4]([CH3:3])([C:20](=[O:21])[C:19](=[CH:30][C:29]2[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)[CH2:18]1)[CH2:5][CH2:6]3
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium hydroxide (2.0 9) was added to a suspension of estrone (1.352 g, 5.0 mmol) and 4-nitro-benzaldehyde (755 mg, 5.0 mmol) in ethanol (80 mL). The resulting dark brown solution was stirred for 4 hours at room temperature, then acetic acid (5 mL) and water (5 ml) were added (colour changes to orange). The product precipitated and was filtered off, washed with water (50 mL), ethanol (50 mL) and diethyl ether (50 mL) and dried under high vacuum. Yield: 1.682 g (83%) yellow solid. 1H-NMR (DMSO-d6, 400 MHz), δ: 0.93 (s, 3H, —CH3), 1.30-1.68 (m, 5H), 1.86-1.92 (m, 1H), 1.96-2.04 (m, 1H), 2.16-2.24 (m, 1H), 2.32-2.39 (m, 1H), 2.62-2.82 (m, 2H), 2.88-2.96 (m 1H), 6.46 (d, J=2.3 Hz, 1H), 6.52 (dd, J=8.6, 2.3 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.42 (s, 1H), 7.92 (d, J=8.6 Hz, 2H), 8.27 (d, J=8.6 Hz, 2H), 9.04 (s, 1H, —OH). LRMS (FAB+): 404.1 (100, [M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[F:20][C:21]1[CH:22]=[C:23]([C@H:28]([NH2:30])[CH3:29])[CH:24]=[CH:25][C:26]=1[F:27]>>[F:20][C:21]1[CH:22]=[C:23]([C@H:28]([NH:30][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:29])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: O=C(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1
Reactant: C[C@@H](N)c1ccc(F)c(F)c1
Agent: Cl
Product: C[C@@H](NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1ccc(F)c(F)c1
Yield: 90.8 %

Procedure:
Following a similar procedure to that described in Example (1a), 12.91 g of 4-fluorophenyl 3-nitrophenyl ketone and 10.19 g of (R)-1-(3,4-difluorophenyl)ethylamine hydrochloride were reacted, to obtain 18.47 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]([CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])C(=O)C(F)(F)F)[CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=1)=[O:5].O[Li].O>C1COCC1.O.CCOC(C)=O>[F:53][C:49]1[CH:50]=[CH:51][CH:52]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:36][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])[CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=1)=[O:5]
Reactant: CS(=O)(=O)CCN(Cc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)c1)C(=O)C(F)(F)F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCNCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a solution of 2,6-difluoro-N-[3-(3-{2-[(3-{[[2-(methylsulfonyl)ethyl](trifluoro-acetyl)amino]methyl}phenyl)amino]-4-pyrimidinyl}pyrazolo[1,5-a]pyridin-2-yl)phenyl]benzamide (102 mg, 0.14 mmol) in THF (3 mL) and water (0.5 mL) was added LiOH.H2O (12 mg, 0.28 mmol). The solution was stirred at 50° C. for 1 h, then diluted with 25 mL EtOAc and washed with 1 M aqueous Na2CO3. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and lyophilized to generate 42 mg of the title compound as a yellow powder (77 mg, 84% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.95 (s, 1H), 9.55 (s, 1H), 8.86 (d, J=6.6 Hz, 1H), 8.52 (d, J=8.2 Hz, 1H), 8.27 (d, J=5.0 Hz, 1H), 8.02 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.75 (s, 1H), 7.59 (d, J=7.3 Hz, 1H), 7.50 (bs, 2H), 7.37 (d, J=7.5 Hz, 1H), 7.27 (d, J=7.7 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H), 7.13-7.18 (m, 4H), 6.93 (d, J=6.9 Hz, 1H), 6.53 (d, J=5.5 Hz, 1H), 3.67 (s, 2H), 3.23 (bs, 2H), 3.01 (s, 3H), 2.87-2.91 (m, 2H). MS (ESI) m/z=654 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](Br)[C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:31])[C:22]=1[N:23]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH2:30])[CH2:25][CH2:24]1)=[O:16].[CH3:32]B(O)O>>[NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:32])[C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:31])[C:22]=1[N:23]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH2:30])[CH2:25][CH2:24]1)=[O:16]
Reactant: Cn1ncc(NC(=O)c2nc(-c3cccc(Br)c3F)sc2N)c1N1CCC[C@@H](N)CC1
Reactant: CB(O)O
Product: Cc1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC[C@@H](N)CC3)c(N)s2)c1F

Procedure:
Boc and Cbz protected intermediate of 373 from Example 373, was subjected to standard Suzuki conditions, following procedures in Example 141 with methyl boronic acid to give the methylated intermediate. Deprotection according to procedures for Example 373, gave 381. 1H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.07 (t, J=7.2 Hz, 1H), 7.52 (s, 1H), 7.40 (s, 2H), 7.32 (t, J=6.9 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 6.74 (s, 1H), 3.65 (s, 4H), 3.23-2.95 (m, 8H), 2.31 (s, 3H), 1.95-1.72 (m, 4H), 1.72-1.44 (m, 4H). MS (ESI) m/z: 444.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([CH3:15])[CH2:13][C:12]3[C:8]4[C:9](=[N:26][CH:27]=[CH:28][C:7]=4[C:6]=2[CH:29]=1)[N:10]([S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:11]=3.C([N-]C(C)C)(C)C.[Li+].[I:38]I>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([CH3:15])[CH2:13][C:12]3[C:8]4[C:9](=[N:26][CH:27]=[CH:28][C:7]=4[C:6]=2[CH:29]=1)[N:10]([S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:17])=[O:18])[C:11]=3[I:38]
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(ccnc42)-c2cc(F)ccc2N(C)C3)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)c3c4c(ccnc42)-c2cc(F)ccc2N(C)C3)cc1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
To a solution of Example 41C (26.6 g, 65.3 mmol) in tetrahydrofuran (326 mL) at −75° C. under nitrogen was added lithium diisopropylamide (49.0 mL, 98 mmol) dropwise. A solution of iodine (33.1 g, 131 mmol) in 250 mL tetrahydrofuran was added dropwise and the mixture was stirred at −75° C. for 2 hours. The reaction was quenched with saturated aqueous sodium thiosulfate and extracted with ethyl acetate (twice). The combined organics were dried over magnesium sulfate, filtered and concentrated. The residue was slurried in hot 40% ethyl acetate in heptanes, cooled to room temperature and filtered and dried in vacuo to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J=5.3 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.71 (d, J=10.3 Hz, 1H), 7.57 (d, J=5.4 Hz, 1H), 7.42 (d, J=8.3 Hz, 2H), 7.33-7.22 (m, 2H), 4.01 (s, 2H), 2.89 (s, 3H), 2.32 (s, 3H). MS (ESI+) m/z 534.0 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:26](Cl)(=[O:29])[O:27][CH3:28]>C(Cl)Cl>[C:1]1([CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][N:8]2[C:26]([O:27][CH3:28])=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CCNC(c2ccccc2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 107.4 %

Procedure:
Methyl 2-phenylpiperidine-4-carboxylate (4.33 g, 19.75 mmol) was dissolved in DCM (150 mL) and DIPEA (3.78 mL, 21.72 mmol), then methyl carbonochloridate (1.710 mL, 21.72 mmol) was added. The solution was stirred at room temperature for 1 h 45 min. More DIPEA (1.720 mL, 9.87 mmol) and methyl carbonochloridate (0.777 mL, 9.87 mmol) were added and the reaction continued at room temperature for another 30 min. The reaction mixture was washed with 0.1 M HCl and satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-phenylpiperidine-1,4-dicarboxylate (5.88 g, quant.) as a yellow oil. MS m/z 278 (M+H)+
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]=[C:10]=[O:11])[CH:4]=1)[CH3:2].[C:12]([NH:15][C:16]1[NH:17][CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:20]=1[C:21]([NH2:23])=[O:22])(=[O:14])[CH3:13]>O1CCCC1>[C:12]([NH:15][C:16]1[NH:17][CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=3)=[O:11])=[CH:26][CH:25]=2)[C:20]=1[C:21]([NH2:23])=[O:22])(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Reactant: CCc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: CCc1cccc(NC(=O)Nc2ccc(-c3c[nH]c(NC(C)=O)c3C(N)=O)cc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.061 cm3 (0.426 mmol) of 1-ethyl-3-isocyanatobenzene is added at room temperature to a suspension of 100 mg (0.387 mmol) of 2-acetylamino-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide in 5 cm3 of anhydrous tetrahydrofuran. The reaction medium is stirred at room temperature for 24 hours and then evaporated to dryness under reduced pressure. The crude product is purified by flash chromatography [eluent; dichloromethane/methanol (97/3 by volume)]. After concentrating under reduced pressure the fractions containing the expected product, 107 mg of 2-acetylamino-4-{4-[3-(3-ethylphenyl)ureido]phenyl}-1H-pyrrole-3-carboxamide are obtained in the form of a brown solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[CH3:3].CN(CCN(C)C)C.C([Li])CCC.[CH2:25]([Sn:29](Cl)([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>CCCCCC>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][N:7]1[C:11]([Sn:29]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:10][N:9]=[CH:8]1)[CH3:3]
Reactant: CN(C)CCCn1ccnc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cncn1CCCN(C)C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
1-(N,N-Dimethylaminopropyl)-imidazole (3 g) was added to a mixture of TMEDA (7 ml) and n-butyl lithium (29.4 ml, 1.6M) in n-hexane (25 ml) at −20° C. under nitrogen. After 30 minutes at −20° C. and 30 minutes at 20° C., the mixture was recooled to −20° C. and tri-n-butylstannyl chloride (13.05 ml) was added dropwise. The mixture was allowed to warm to 20° C. and stirred there for 20 hours. The mixture was partitioned between ethyl acetate and water, the aqueous phase was extracted with ethyl acetate and combined organic extracts were dried and concentrated. Purification by flash chromatography gave the title compound (2.10 g); δH CDCl3 7.70 (1H,s), 7.01 (1H,s), 3.98 (2H,t), 2.20 (6H,s), 2.20 (2H,t), 1.90 (2H, m) 1.55 (6H,m), 1.37 (12H,m), 0.92 (9H,m).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].F[C:18]1[CH:19]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:22][CH:23]=1.O>CN1C(=O)CCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Fc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Sodium hydride (0.9 g, 60% dispersion in mineral oil) was added to a solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (4 g) in NMP (40 ml) and the solution stirred for 1 h, then a solution of 3-fluorobenzotrifluoride (3.5 g) in NMP (10 ml) was added and the mixture was stirred for 2 h at 80 ° C. The mixture was added to water (200 ml) and extracted with diethyl ether (2×100 ml), the solvent washed with water, 1 M sodium hydroxide and brine, dried and evaporated to give the title compound as yellow oil (5.2 g) which was carried through to the next step without purification.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:20][C:19]3[CH:22]=[CH:23][CH:24]=[C:17]([Br:16])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Product: O=C(Nc1ccccc1)N1CCN(Cc2cccc(Br)c2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 3-bromobenzaldehyde. 1H NMR (400 MHz, CDCl3): 7.50 (br s, 1H), 7.43-7.17 (m, 7H), 7.05-7.00 (m, 1H), 6.47 (br s, 1H), 3.52-3.45 (m, 6H), 2.48-2.42 (m, 4H).
Reaction SMILES: [CH2:1]([CH:8]1[C:14]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10](=O)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCCC1>[CH2:1]([CH:8]1[C:14]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(Cc1ccccc1)NC(=O)CC2
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(Cc1ccccc1)NCCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.8 %

Procedure:
To a solution of 2.17 mmol of 1-benzyl-8-methoxy-4,5-dihydro-1H-benzo[c]azepin-3(2H)-one in tetrahydrofuran under nitrogen atmosphere was added 3.25 mmol of lithiumaluminumhydride as 1 M solution in tetrahydrofuran. The solution was heated to reflux and stirred for 1.5 h. The mixture was cooled to room temperature and water (1 ml) was carefully added. The mixture was concentrated and the residue was dissolved in ethyl acetate. The organic phase was extracted with acidified water (acidified with 1 M HCl, 4×). To the combined aqueous phase was added NaOH (50%) until basic and ethyl acetate. The suspension was filtered over celite. The residue was washed with water and ethyl acetate. Phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. Evaporation of the solvent gave 439 mg of crude material that was purified by flash chromatography to yield 399 mg of 1-benzyl-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine (69%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[Si](C)(C)[C:21]#[C:22][C:23]1[CH:24]=[C:25]2[CH2:31][C@:30]3([CH:36]4[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]4)[CH2:32]3)[O:29][C:26]2=[N:27][CH:28]=1>O1CCCC1>[C:22]([C:23]1[CH:24]=[C:25]2[CH2:31][C@:30]3([CH:36]4[CH2:35][CH2:34][N:33]([CH2:38][CH2:37]4)[CH2:32]3)[O:29][C:26]2=[N:27][CH:28]=1)#[CH:21]
Reactant: C[Si](C)(C)C#Cc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
Under an argon atmosphere, a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.3 mL, 1.3 mmol) was added at 0° C. to a solution of (R)-(−)-5′-(2-trimethylsilylethynyl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (265 mg, 0.85 mmol) in anhydrous tetrahydrofuran (5 mL), and stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (2 mL), extracted with ether (5×15 mL), dried (MgSO4), evaporated under reduced pressure, and purified by flash chromatography through silica gel (eluting with ammoniated chloroform/methanol, 95:5) to obtain the title compound (121 mg, 0.50 mmol, 59%): chemical ionization MS (m/z, relative intensity) 241 ([MH]+, 19).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([NH:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=S)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[O:9])[C:4](=[O:32])[CH2:3]1.CC1CCN(C(NCCC2C=CC(S(N)(=O)=O)=CC=2)=[O:41])C(=O)C1.C1(N=C=O)CCCCC1.C(=O)([O-])[O-].[K+].[K+].N([O-])=O.[Na+]>CC(C)=O.O.C(O)(=O)C>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([NH:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:41])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[O:9])[C:4](=[O:32])[CH2:3]1
Reactant: CC1CCN(C(=O)NCCc2ccc(S(N)(=O)=O)cc2)C(=O)C1
Reactant: CC1CCN(C(=O)NCCc2ccc(S(=O)(=O)NC(=S)NC3CCCCC3)cc2)C(=O)C1
Agent: O=C([O-])[O-]
Agent: O=C=NC1CCCCC1
Agent: O=N[O-]
Solvent: O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CC1CCN(C(=O)NCCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2)C(=O)C1
Reaction time: 2 h

Procedure:
1.2 g N-(4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl-thio-urea (m.p. 179°-181° C., prepared from 4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfonamide and cyclohexyl-isocyanate in acetone in the presence of potassium carbonate) are dissolved in 75 ml of acetone and 10 ml of water. At 0° C., a solution of 0.1 g of sodium nitrite in 5 ml of water is added to this solution, subsequently 0.8 ml of 5 N acetic acid is added dropwise, and agitation is continued for 2 hours at 0° C. Subsequently, the acetone is evaporated under reduced pressure, the product is suction-filtered and reprecipitated from dilute ammonia. After recrystallization from dilute acetone, N-(4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl urea has a melting point of 176°-178° C., and with the product prepared according to Example 8, shows no depression.