Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[NH2:12].C12CC3CC(CC(C3)C1N=[C:24]=[O:25])C2.ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[N:12]=[C:24]=[O:25]
Reactant: Cc1cccc(C(F)(F)F)c1N
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C(F)(F)F)c1N=C=O

Procedure:
This compound was made from 2-methyl-6-trifluoromethyl-phenylamine in analogy to Eur. J. Med. Chem. 28 (1), 1993, 37-45 by treatment with bis-(trichloromethyl)-carbonate (627 mg) and triethylamine (1.58 mL) in DCM (16 mL). (2-Methyl-6-trifluoromethylphenyl)isocyanate was obtained as a colorless solid (1.17 g). 1H-NMR (δ, CDCl3): 7.49 (d, J=7.8 Hz, 1H), 7.41 (d, J=7.5 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 2.40 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[C:37]1([O:45][CH3:46])[CH2:42][CH2:41][CH:40]([C:43]#[N:44])[CH2:39][CH2:38]1.Cl>C1COCC1.O>[F:18][C:17]([F:19])([F:20])[C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:16]=1)[CH2:6][N:7]([CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:28]=1[C:37]1([O:45][CH3:46])[CH2:38][CH2:39][CH:40]([C:43]#[N:44])[CH2:41][CH2:42]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: COC1(c2ccc(C(F)(F)F)cc2CBr)CCC(C#N)CC1
Reactant: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CCC(C#N)CC1
Reaction time: 0.08 h
Yield: 119.4 %

Procedure:
To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazole-5-amine (285 mg, 0.877 mmol) in anhydrous THF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 105 mg, 2.63 mol) and the mixture was stirred for 5 minutes then a solution of 4-(2 (bromomethyl)-4-(trifluoromethyl)phenyl)-4-methoxycyclohexanecarbonitrile (330 mg, 0.877 mmol) in anhydrous THF (5 mL) was added. A further aliquot of sodium hydride (52 mg, 1.3 mmol) was added. The solution was stirred at room temperature for 72 hours. Water and 2 N HCl (5 mL) were added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organics were dried with anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow oil (0.65 gm). This material was initially purified by flash chromatography on a 40 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-75% ethyl acetate in heptane) and finally purified on 1 mm silica gel rotor (Chromatotron, Harrison Research) (eluted with 20-70% dichloromethane in heptane) to yield the title compound as a colorless foam (134 mg, 24.6%). 1H NMR (400 MHz, CDCl3) δ 7.74 (s, H) 7.67(s, 2H) 7.44 (d, J=5.81 Hz, 2H) 7.29 (d, J=8.72 Hz, 1H) 5.01 (s, 2H) 4.76 (s, 2H) 4.15 (s, 3H) 2.87(s, 3H) 2.43(m, 1H) 2.20(d, J=12.45 Hz, 2H) 1.99(m, 2H) 1.55(m, 4H). LC-MS calc. 620, found 621.5 (M+H)
Reaction SMILES: C(O)C.[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>C(N(CC)CC)C>[N+:21]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[NH:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH:5]=[CH:6]2)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1Nc1ccc2[nH]ccc2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To 150 ml of absolute ethanol were added 1H-indol-5-amine (8.06 g), 4-chloro-3-nitropyridine (10.0 g) and triethylamine (8.5 ml), and this mixture was heated to 60° C. and stirred for 2 hours. The mixture was cooled, the ethanol evaporated, and the residue taken up in a water/ethyl acetate mixture. This was treated with Na2CO3 (aq) to adjust the pH to 10. The organic layer was collected, the aqueous layer extracted again with ethyl acetate, and the organics were combined, washed with water and dried (sat. NaCl, anh. MgSO4).
Reaction SMILES: C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:5](C)=O.[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]2)=[O:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCCl.C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][N:33]2[CH3:5])=[O:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCCCN2)CC1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCCCC1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
0.54 ml of 37% aqueous formaldehyde and then 1.41 g of NaBH(OAc)3 are added to a solution of 0.99 g of the compound obtained in step 5.2, in 11 ml of DCE, and the medium is stirred at AT for 12 h. The medium is diluted in DCM and filtered through cotton wool. The organic phase is washed twice with a saturated NaHCO3 solution, and then with a saturated NaCl solution. After drying over MgSO4 and evaporation of the solvents, 0.84 g of the expected product is recovered.
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@H:17]2[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[O:23])[CH2:18]2)=[C:14]([CH3:41])[CH:13]=1>>[N:4]1[N:3]([CH2:7][C:8]([N:20]2[CH2:21][C@H:17]([CH2:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[CH:13][C:14]=3[CH3:41])[CH2:18][C@H:19]2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: Cc1cc(F)ccc1C[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Reactant: O=C(O)Cn1nccn1
Agent: Cl
Product: Cc1cc(F)ccc1C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2nccn2)C1
Yield: 34 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4R)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 7, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (106.7 mg, 34%). Major isomer: 1H-NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 7.72 (s, 2H), 7.43-7.38 (m, 2H), 7.09-6.81 (m, 9H), 5.29 (d, 2H), 4.84 (d, 1H), 3.59-3.53 (m, 1H), 3.19 (t, 1H), 2.96-2.87 (m, 1H), 2.82 (dd, 1H), 2.72-2.59 (m, 2H), 2.32 (s, 3H). MS (EI) for C29H28F2N5O3 found 532 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]([CH3:16])[N:6]=[C:7]([O:13][CH2:14][CH3:15])[C@H:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:35][CH2:36]I>>[Cl:17][C:18]1[CH:23]=[C:22]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:35][CH2:36][C@:5]1([CH3:16])[C:4]([O:3][CH2:1][CH3:2])=[N:9][C@@H:8]([CH:10]([CH3:11])[CH3:12])[C:7]([O:13][CH2:14][CH3:15])=[N:6]1
Reactant: CCOC1=N[C@@H](C(C)C)C(OCC)=NC1C
Reactant: FC(F)(F)c1cccc(Sc2ccc(CCI)c(Cl)c2)c1
Product: CCOC1=N[C@](C)(CCc2ccc(Sc3cccc(C(F)(F)F)c3)cc2Cl)C(OCC)=N[C@H]1C(C)C

Procedure:
(5S)-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine and 2-chloro-1-(2-iodoethyl)-4-(3-trifluoromethylphenylthio)benzene were reacted in the same manner as in Example 1 to obtain the target product as a colorless oil.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:12])[C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=1.[F:13][C:14]([F:28])([F:27])[C:15]1[C:16]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1>>[Cl:12][C:8]1[C:9]([Cl:11])=[CH:10][C:4]2[NH:3][C:2]([N:24]3[CH2:25][CH2:26][N:21]([C:16]4[C:15]([C:14]([F:28])([F:13])[F:27])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:22][CH2:23]3)=[N:6][C:5]=2[CH:7]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Product: FC(F)(F)c1cccnc1N1CCN(c2nc3cc(Cl)c(Cl)cc3[nH]2)CC1

Procedure:
The benzoimidazole from step (b) above (0.110 g, 0.5 mmol) and 1-(3-trifluoromethylpyridin-2-yl)piperazine (0.231 g, 1 mmol, Maybridge) reacted under the conditions Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 416 (M+1).
Reaction SMILES: C(O[C:6](=[O:23])[CH2:7][CH:8]([NH:16][C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH:9]([O:13]CC)[O:10][CH2:11][CH3:12])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:20]([O:19][C:17](=[O:18])[NH:16][CH:8]1[CH2:7][C:6](=[O:23])[O:13][CH:9]1[O:10][CH2:11][CH3:12])[CH:21]=[CH2:22]
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOC(=O)NC1CC(=O)OC1OCC
Yield: 85 %

Procedure:
A solution of the crude 3-Allyloxycarbonylamino-4,4-diethoxy-butyric acid tert-butyl ester, 103, obtained in the procedure above, in CH2Cl2 (50 mL) is treated with triflouroacetic acid (50 mL). After the consumption of starting material, the organics are reduced under vacuum. The residual triflouroacetic acid is removed with ethyl acetate by azeotroping conditions. The final residue is purified over silica (hexanes/ethyl acetate 80:20) to afford 10.1 g (85% yield) of the desired product as a slightly yellow oil. 1H-NMR, (300 MHz, CDCl3): δ 1.23 (m, 3H), 2.41–2.54 (m, 1H), 2.82–3.06 (m, 2H), 3.61–3.73 (m, 1H), 3.82–3.98 (m, 1H), 4.06–4.25 (m, 1H), 4.61 (br s, 2H), 5.24–5.53 (m, 3H), 5.86–6.01 (m, 1H); MS (ESI): m/e=230.03 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+]>C(O)C>[Cl:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[CH:14][N+:11]([O-:13])=[O:12])=[CH:3][C:2]=1[Cl:1]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1ccc(Cl)c(Cl)c1
Yield: 73.1 %

Procedure:
Using an analogous reaction procedure and workup as described in Example 1, 3,4-dichloro-benzaldehyde (5.6 g, 41.481=01) in ethanol (56 mL) was reacted with nitro methane (2.3 mL, 41.481 mmol), 10N NaOH solution (1.65 g, 41.481 mmol) at 0° C. for 1 hour to afford 5.1 g of the product (75% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)=[O:33])=[CH:4][N:3]=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][N:37]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:36]2)=[O:33])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(-c2csc3c(C(=O)NC4CCCNC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2csc3c(C(=O)NC4CCCN(S(C)(=O)=O)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)-N-piperidin-3-ylthieno[3,2-c]pyridine-7-carboxamide (150 mg, 0.270 mmol), methanesulfonyl chloride (26 μL, 0.32 mmol) and N,N-diisopropylethyl amine (0.15 mL, 0.81 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. Saturated sodium bicarbonate (2 mL) was added. The layers were separated and the organic solvent was removed. The residue was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (28–30% solution) (90:10:0.05) mixture as the mobile phase to give the title compound. 1H NMR (DMSO, d6) δ 1.58 (m, 2H), 1.91 (m, 2H), 2.58 (m, 1H), 2.71 (m, 1H), 3.50(m, 1H), 3.73 (m, 1H), 3.91 (s, 3H), 3.99 (m 1H), 4.04 (m, 3H), 7.07 (d, 1H), 7.15 (t, 1H), 7.19 (s, 1H), 7.33 (t, 1H), 7.35 (s, 1H), 7.58 (m, 2H), 7.71 (d, 1H), 7.99 (d, 1H), 8.34 (d, 1H), 8.61 (s, 1H), 9.50 (s, 1H). LCMS (Conditions a) Rt=3.22 min., 633.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:1][C:2]2[CH:14]=[CH:13][C:5]([CH2:6][N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=2)[CH2:18][CH2:17]1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCC(Nc2ccc(CN3CCOCC3)cc2)CC1
Reaction time: 8 h

Procedure:
A flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22 (0.48 g) is treated with tetrhydrofuran (10 mL) and N-methyl-4-piperidone (0.37 mL) under an argon atmosphere. The solution is treated with acetic acid (0.20 mL) followed by sodium triacetoxyborohydride (0.80 g). After stirring overnight, the mixture is partitioned between diethyl ether and saturated aqueous sodium bicarbonate containing sodium hyroxide. The aqueous is back-extracted with additional portions of dichloromethane. The combined organic layer is washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel eluting with 2% to 5% methanol saturated with ammonia in dichloromethane to afford 0.52 g of 1-methyl-N-[4-(4-morpholinylmethyl)phenyl]-4-piperidinamine as a tan solid.
Reaction SMILES: [C:1]([O:4][CH:5]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]([O:36][C:37]1[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[CH:42][C:38]=1[CH2:39][NH:40][CH3:41])([CH3:35])[CH3:34]>ClCCl>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([N:40]([CH3:41])[CH2:39][C:38]2[CH:42]=[CH:43][CH:44]=[C:45]([O:46][CH3:47])[C:37]=2[O:36][CH:33]([CH3:34])[CH3:35])=[O:8])[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(C(OC(C)=O)C(=O)O)cc(OC)c1OC
Reactant: CNCc1cccc(OC)c1OC(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1cccc(CN(C)C(=O)C(OC(C)=O)c2cc(OC)c(OC)c(OC)c2)c1OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A solution of α-acetoxy-3,4,5-trimethoxyphenyl-acetic acid (5.0 g) in dichloromethane (40 ml) was reacted with 1,1′-carbonyldiimidazole (2.92 g) at room temperature for 30 minutes. The solution was refluxed for 30 minutes, after which 2-isopropoxy-3-methoxy-N-methylbenzylamine (3.26 g) dissolved in dichloromethane (10 ml) was added. The mixture was stirred at room temperature for 2 hours, after which it was washed with aqueous hydrochloric acid (20 ml, is 1M) followed by aqueous sodium hydrogen carbonate (20 ml, 0.5 M). The organic phase was dried and concentrated to dryness, leaving crude 2-(3,4,5-trimethoxyphenyl)-2-acetoxy-N-methyl-N-(2-isopropoxy-3-methoxybenzyl)acetamide (7.27 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[OH:7].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.N1C=CC=CC=1>O>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH:3]2[CH2:4][CH2:5][CH2:6][CH:2]2[CH3:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1CCCC1O
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2CCCC2C)cc1
Reaction time: 10 h
Yield: 93 %

Procedure:
2-Methylcyclopentanol (21.06 g, 0.210 mol) and p-toluenesulfonyl chloride (48.3 g, 0.252 mol) were charged into a 500 cc three-necked flask equipped with a stirrer, and then pyridine (170 ml) was added dropwise thereto under ice-cooling. The mixture was stirred for 10 hours while gradually elevating the temperature to room temperature. After completion of the reaction, cold water (500 ml) was added to the reaction mixture, and the mixture was extracted with ether (200 ml×3). The organic layers were combined, washed successively with 2N hydrochloric acid, water and a saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. The drying agent was separated by filtration, and the solvent was distilled off under reduced pressure to obtain substantially pure 2-methylcyclopentyl p-toluenesulfonate as a colorless transparent oily substance (49.7 g, 0.195 mol, 93% yield).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([N:62]=[C:63]=[O:64])[CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:63]([NH:62][C:58]2[CH:59]=[CH:60][CH:61]=[C:56]([F:55])[CH:57]=2)=[O:64])[CH2:49][CH2:48]1
Reactant: O=C=Nc1cccc(F)c1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)Nc2cccc(F)c2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 39 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-fluoro-3-isocyanatobenzene as starting materials in 39% yield. LCMS for C31H31ClFN8O2 (M+H)+: m/z=601.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([O:17]C)=[O:16])[CH:9]=2)=[CH:4][CH:3]=1.Cl.C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([OH:17])=[O:16])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1-c1cc(-c2ccc(Cl)cc2)on1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1-c1cc(-c2ccc(Cl)cc2)on1
Yield: 95.3 %

Procedure:
A mixture of 2.8 g of methyl 2-[5-(4-chlorophenyl)3-isoxazolyl]benzoate, 12 ml of concentrated HCl, and 14 ml of acetic acid was held at reflux for 4 hours, cooled, diluted with water, and filtered to give 2.55 g (95%) of white solid, mp 174-176° C. Recrystallization of the solid gave 2.18 g of solid, mp 175.5-177.5° C.
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:7][C:8]([CH3:10])=[O:9]>>[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][CH2:7][C:8](=[O:9])[CH3:10]
Reactant: CC(C)CC=O
Reactant: CC(C)=O
Product: CC(=O)CCCC(C)C

Procedure:
To aid comprehension, the reaction will be explained here by the example of the reaction of acetone with isovaleraldehyde to produce 6-methylheptan-2-one. The reaction takes place “in situ” via the stage of aldol condensation with the formation of the corresponding β-hydroxyketone, which is not isolated. Dehydration to 6-methylhept-3-en-2-one takes place under the reaction conditions, and this is hydrogenated selectively to the corresponding methylketone with the hydrogenation catalyst distributed homogeneously in the aqueous catalyst phase.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([B:28]4[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:7])(C)(C)C.Cl.[CH3:38][O:39][C:40]([NH:42][CH:43]([CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)C(O)=O)=[O:41].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:38][O:39][C:40](=[O:41])[NH:42][CH:43]([CH:47]1[CH2:48][CH2:49][O:50][CH2:51][CH2:52]1)[C:6](=[O:7])[N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([B:28]4[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:35])([CH3:36])[O:29]4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1
Reactant: COC(=O)NC(C(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C1CCOCC1
Temperature: 25 °C

Procedure:
2-{5-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (350 mg, 0.717 mmol) was dissolved in DCM (8 mL) at room temperature. HCl (4N in dioxane, 8 mL) was added and stirring at room temperature was continued. After all starting material was consumed, the volatiles were removed in vacuo and the crude material was dissolved in DMF. Methoxy carbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (155 mg, 0.715 mmol), DIEA (276.6 mg, 2.1 mmol), and HATU (272 mg, 0.715 mmol) were added. After all starting material was consumed, the reaction was diluted with EtOAc and was washed with brine/aqueous bicarbonate. The organic layer was dried over sodium sulfate. Filtration and evaporation of solvents in vacuo gave the crude product, which was purified via flash chromatography on silica gel (eluent: EtOAc/hexanes) to yield 355 mg.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].S(Cl)([Cl:14])=O>N1C=CC=CC=1.ClCCl>[Cl:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCCCCCCCCCl
Yield: 95.3 %

Procedure:
To 26.0 g of 9-decene-1-ol was added 10-drops of pyridine and the mixture was placed into an eggplant flask. To the eggplant flask was added dropwise 24.0 g of thionyl chloride during cooling with ice. After dropping, the mixture was reacted for 8.5 hours at 70° C. After the conclusion of the reaction, the reaction product was diluted with dichloromethane and then washed with an aqueous potassium carbonate solution. The reaction solution was then dried over magnesium sulfate and subsequently concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain 27.7 g of 10-chloro-1-decene. (Yield: 95%)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][CH:6]1[CH3:20])=[O:4].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([C:37]2[O:41][N:40]=[CH:39][CH:38]=2)[CH:31]=1>C(#N)C.O1CCCC1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:32]([C:37]2[O:41][N:40]=[CH:39][CH:38]=2)[CH:31]=1
Reactant: CC1CN(C(=O)CCl)C(C)CN1Cc1ccc(F)cc1
Reactant: Oc1ccc(Cl)cc1-c1ccno1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1-c1ccno1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
To a solution of (2-chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.30 g, 1.0 mmol) in acetonitrile (10 mL) was added potassium carbonate (0.207 g, 1.5 mmol), potassium iodide (0.033 g, 0.20 mmol) and 4-chloro-2-isoxazol-5-yl-phenol (0.215 g, 1.1 mmol). The resulting mixture was stirred for 18 hours at ambient temperature. The reaction was diluted with tetrahydrofuran (10 mL), filtered and concentrated in vacuo to give the title compound (0.465 g).