Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:10])[C:4]=2[CH:3]=[CH:2]1.[N:11]1C=CC=C2CCC(=O)C=12>>[N:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[CH2:5][CH2:4][CH:3]([NH2:11])[C:2]=12
Reactant: NC1CCCc2occc21
Reactant: O=C1CCc2cccnc21
Product: NC1CCc2cccnc21

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but 5,6-dihydro-7H-cyclopenta[b]pyridin-7-one and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, DMSO) δ) 8.49, 7.79, 7.36, 4.65, 3.38, 3.01–2.90, 2.55, 1.93; (MS/CI) calcd for C8H10N2+H 135.2, found 135.2.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24](O)=[O:25])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:27]1[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29][CH2:28]1>>[C:1]([N:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([NH:34][CH2:33][CH:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)=[O:25])[N:22]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: NCC1CCOCC1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1Cc1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1Cc1ccc(F)cc1

Procedure:
Using the compound obtained in step 4 and (tetrahydro-2H-pyran-4-yl)methanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1.CB(C)C.[OH:17]O.[OH-].[Na+]>C1COCC1.O>[CH:10]1([CH2:9][O:8][C:5]2[N:6]=[CH:7][C:2]([OH:17])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: OO
Reactant: Brc1ccc(OCC2CC2)nc1
Agent: CB(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(OCC2CC2)nc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-bromo-2-(cyclopropylmethoxy)pyridine (1.88 g) in THF (15 mL) was added 1.6M n-butyllithium-hexane solution (7.25 mL) at −78° C., and the mixture was stirred at the same temperature for 20 min. Trimethylborane (1.29 mL) was added to this solution, and the mixture was stirred at −78° C. for 30 min. The reaction mixture was heated to 0° C., aqueous hydrogen peroxide (30%, 5 mL) and 8M aqueous sodium hydroxide solution (1.55 mL) were added thereto, and the mixture was stirred for 15 min. Water was added to the reaction mixture, the mixture was extracted twice with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (855 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OC2C=CC([N+]([O-])=O)=CC=2)=[O:9])=[C:6]([S:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:9])=[C:6]([S:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)nc(Sc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1
Reactant: CS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(Sc2cccc(Cl)c2C(=O)NS(C)(=O)=O)n1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, Step I, using equimolar amounts of 4-nitrophenyl 6-chloro-2-(4,6-dimethoxypyrimidin-2-ylthio)benzoate, methanesulfonamide, and potassium carbonate in acetonitrile to yield 2-[3-chloro-2-(methylsulfonylaminocarbonyl)phenylthio]-4,6-dimethoxyprimidine, Compound 40 of Table 1.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][O:8][C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[C:21]([O:27][CH2:28]Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>C1COCC1.[Na+].[I-]>[CH3:7][O:8][C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:28][O:27][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18]
Reactant: COC(=O)CCCCCCCC(=O)O
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCC(=O)OCOC(=O)C(C)(C)C
Temperature: 60 °C
Reaction time: 48 h
Yield: 67.2 %

Procedure:
A heterogeneous solution of Cs2CO3 (1.30 g, 4.0 mmol), NaI (30 mg, 0.20 mmol) and nonanedioic acid monomethyl ester (0.95 g, 4.0 mmol) in THF (15 ml) was stirred for ½ hour at 60° C. Chloromethyl pivalate (0.60 g, 4.0 mmol) in THF (5 ml) was added dropwise to the solution and stirred at 60° C. for 48 hours. The reaction mixture was cooled to room temperature and evaporated in vacuo. Diethyl ether (25 ml) was added, and the residue was washed with saturated NaHCO3 (3×15 ml), dried with MgSO4 and filtered. Evaporation in vacuo gave the product as a colourless oil (0.85 g, 67.5%). 1H-NMR (CDCl3) δ 5.74 (s, 2H), 3.66 (s, 3H), 2.38-2.26 (m, 4H), 1.63-1.56 (m, 4H), 1.31 (s, 6H), 1.21 (s, 9H). 13C-NMR (CDCl3) δ 177.05, 174.06, 172.23, 79.19, 51.33, 38.63, 33.90. 33.82, 28.78, 28.72, 28.64, 26.74, 24.73, 24.47.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[C:10]([CH3:17])[N:9]=1>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:1])=[O:15])[CH:11]=[C:10]([CH3:17])[N:9]=1
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(C)nc(Cl)c1
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Oxalyl chloride (1.9 g, 15 mmol) was added to 2-chloro-6-methyl-pyridine-4-carboxylic acid (1.7 g, 10 mmol) in methylene chloride (30 ml) and the mixture stirred for 2 hours. The volatiles were removed by evaporation and methanol (20 ml) added to the residue. The mixture was stirred for 1 hour and the volatiles removed by evaporation to give methyl 2-chloro-6-methyl-pyridine-4-carboxylate (1.85 g, 100%) as an off-white solid.
Reaction SMILES: CS([C:4]1[C:5]2[CH:28]=[CH:27][NH:26][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[N:9]=1)=O.[NH2:29][CH:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:29][CH:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:4]2[C:5]3[CH:28]=[CH:27][NH:26][C:6]=3[N:7]=[C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:9]=2)[CH2:32][CH2:31]1
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(S(C)=O)c4cc[nH]c4n3)cc2)CC1
Reactant: NC1CCC(N)CC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(Nc3nc(NC4CCC(N)CC4)c4cc[nH]c4n3)cc2)CC1
Temperature: 116 °C
Yield: 13.1 %

Procedure:
To a solution of 1-(4-(4-(4-(methylsulfinyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (34 mg, 0.085 mmol) in DMSO (1 mL), 1,4-diaminocyclohexane (cis and trans mixture, 35 mg, 0.31 mmol) and diisopropylethylamine (0.060 mL, 0.35 mmol) were added. The mixture was heated at 116° C. overnight. It was then purified by HPLC to give the titled compound (5 mg). MS 449.3 (M+H); UV 208.5, 265.1, 305.5 nm.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:7][N:6]=[C:5]([CH2:8]O)[CH2:4]1.C(N(S(F)(F)[F:16])CC)C>C(Cl)Cl>[Cl:1][CH2:2][CH:3]1[O:7][N:6]=[C:5]([CH2:8][F:16])[CH2:4]1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCC1=NOC(CCl)C1
Solvent: ClCCl
Product: FCC1=NOC(CCl)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
To a solution of (5-(chloromethyl)-4,5-dihydroisoxazol-3-yl)methanol (1.58 g, 10.56 mmol, 6a rac, Tetrahedron 1986, 42, 5267) in DCM (30 mL) at −78° C. was added (diethylamino)sulfur trifluoride (1.60 ml, 12.11 mmol). The reaction mixture was stirred at −78° C. for 10 min, warmed from −78° C. to room temperature over 15 min, stirred at room temperature for 1 h and quenched with saturated aq. saturated NaHCO3 solution. The reaction mixture was diluted with diethyl ether and water. The aqueous phase was extracted with diethyl ether (4×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated in vacuo to give a dark red oil. Purification by flash column chromatography on silica gel (20% diethyl ether in pentane) gave the title compound (0.79 g, 49% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.Br[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: BrC1CCCC1
Reactant: Oc1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1cc(OC2CCCC2)ccn1
Temperature: 120 °C
Yield: 82.2 %

Procedure:
To a solution of 2-bromopyridin-4-ol (1.6 g, 9.2 mmol) and bromocyclopentane (1.28 mL, 12.0 mmol) in DMF (12 mL) in a microwave vial was added cesium carbonate (4.19 g, 12.9 mmol). The vial was sealed and heated in a microwave reactor at 120° C. for 2 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc (3×). The combined organics were washed with sat'd LiCl and sat'd NaCl then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (20-30% EtOAc/heptane) to give 1.83 g (73%) of 2-bromo-4-cyclopentyloxy-pyridine as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH3:27])[CH:22]=[C:21]2[CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH3:27])[CH:22]=[C:21]2[CH2:28][CH2:29][NH:30][C:11]([C:8]1[CH:7]=[C:6]([CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)[O:10][N:9]=1)=[O:13]
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
Reactant: Cn1cc(CCN)c2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1cc(CCNC(=O)c2cc(Cc3cccc(F)c3)on2)c2cc(Cl)ccc21
Yield: 36.8 %

Procedure:
A solution of 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g; 0.257 mmol), 2-(5-chloro-1-methyl-1H-indol-3-yl)ethanamine (0.060 g; 0.284 mmol), HATU (0.108 g; 0.284 mmol) and N,N-diisoprpylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.039 g (36%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4]>C1COCC1>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
A solution of 3-(methoxycarbonyl)benzoic acid (1.05 g, 5.83 mmol) in THF (25 mL) was cooled to 0° C., and then treated with the dropwise addition of 2.0 M borane-methylsulfide complex in THF (14.57 mL, 29.1 mmol) at a rate which did not allow the temperature to exceed 5° C. The mixture was stirred at 0° C. for 15 minutes, and then allowed to warm to room temperature where it stirred for 4 hours. After this time, the reaction was cooled to 0° C. and then quenched with the addition of small pieces of ice, causing vigorous gas evolution. When gas evolution had ceased, the mixture was diluted with brine and extracted 3× with ethyl acetate. The combined organic phases were washed 3× with diluted bleach to remove residual methyl sulfide, 3× with saturated sodium carbonate to remove any unreacted acid, 1× with water, 1× with brine, dried over sodium sulfate and then concentrated in vacuo to yield the methyl 3-(hydroxymethyl)benzoate (845 mg, 5.09 mmol, 87% yield) as a colorless oil.
Reaction SMILES: C(OCCCC)CCC.[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C.[C:22]1([C:28]2[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:32][CH:31]=[CH:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[C:22]1([C:28]2[C:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[N:32][C:31]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [Li]c1ccccc1
Reactant: c1ccc(-c2nccnc2-c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCCOCCCC
Solvent: O
Product: c1ccc(-c2cnc(-c3ccccc3)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
First, 5.5 mL of a dibutyl ether solution of phenyl lithium (manufactured by Wako Pure Chemical Industries, Ltd., 2.1 mol/L) and 50 mL of diethyl ether were mixed under a nitrogen atmosphere. Then, 2.43 g of 2,3-diphenylpyrazine was dropped into this solution while the solution was being cooled with ice, and the mixture was stirred at room temperature for 24 hours. Water was added to the mixture, and the organic layer was extracted with diethyl ether. The extracted organic layer was washed with water and dried with magnesium sulfate. After the drying, an excess amount of activated manganese dioxide was added to the organic layer, and the mixture was filtered. After the solvent of the solution was distilled off, the obtained residue was recrystallized with ethanol to give a pyrazine derivative, Htppr (a yellow powder, 56% yield). The synthetic scheme of Step 1 is represented by (a-1) below.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][CH2:11][C:12](=[O:59])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][N:22]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:23][C@@H:24]([C:33]2[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[C:39]3[C:34]=2[CH:35]=[CH:36][C:37](=[O:51])[NH:38]3)[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:15]=1)C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:52]([N:22]([CH2:23][C@@H:24]([C:33]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:39]2[C:34]=1[CH:35]=[CH:36][C:37](=[O:51])[NH:38]2)[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[CH2:21][CH2:20][C:16]1[CH:15]=[C:14]([NH:13][C:12](=[O:59])[CH2:11][CH2:10][CH2:9][NH:7][CH3:6])[CH:19]=[CH:18][CH:17]=1)[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: CN(CCCC(=O)Nc1cccc(CCN(Cc2ccccc2)C[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCCC(=O)Nc1cccc(CCN(Cc2ccccc2)C[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.6 %

Procedure:
To a stirred solution of {3-[3-(2-{benzyl-[(R)-2-(8-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilanyloxy)ethyl]amino}ethyl)-phenylcarbamoyl]propyl}methylcarbamic acid tert-butyl ester (276 mg, 0.331 mmol) in DCM (3 mL) at room temperature was added trifluoroacetic acid (2 mL, 20 mmol) and the resulting mixture was stirred at room temperature overnight. LC-MS (Method 2-90) showed product was present (Rt 2.69 min; m/z 7.33.4 [M+H]−). The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DCM. This solution was washed with aqueous saturated sodium bicarbonate solution (2×), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (249 mg, 100% yield) as a yellow-brown oil, which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]([CH2:19][CH2:20][CH2:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:14]([O:16]CC)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(OCC)(=O)C>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH2:12][CH:13]([CH2:19][CH2:20][CH2:21][S:22]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)(=[O:24])=[O:23])[C:14]([OH:16])=[O:15])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(CCCS(=O)(=O)c1ccc(OC)cc1)CS(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)CCCC(CS(=O)(=O)c2ccc(OC)cc2)C(=O)O)cc1

Procedure:
A mixture of 2-[(4-methoxybenzenesulfonyl)methyl]-5-(4-methoxybenzenesulfonyl)-pentanoic acid, ethyl ester (0.70 g, 1.4 mmol) in 6N hydrochloric acid (20 ml) is refluxed overnight. The mixture is transferred to ethyl acetate which is extracted with aqueous sodium bicarbonate. The combined aqueous extract is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. This organic extract is concentrated in vacuo to yield the title compound as a white solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][OH:24])[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC(Cl)(Cl)C(=N)O[C:29]([C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=1)([CH3:31])[CH3:30]>C1COCC1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][OH:24])[C:20]([O:22][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:34][CH:33]=3)([CH3:31])[CH3:30])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CC(C)(OC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.3 %

Procedure:
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxypropanoic acid (Compound SP827, Fmoc-Ser-OH) (96.0 g, 292 mmol) was azeotropically distilled with THF (100 ml) eight times. This was dissolved in dehydrated THF (200 ml) under a nitrogen atmosphere, 2-(4-(trifluoromethyl)phenyl)propan-2-yl 2,2,2-trichloroacetimidate (Compound SP853) (67.9 g, 195 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was directly purified by amino silica gel column chromatography (DCM) and concentrated under reduced pressure. The residue was further purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=95/5→0/100) to afford (S)-2-(4-(trifluoromethyl)phenyl)propan-2-yl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxypropanoate (Compound SP826, Fmoc-Ser-OPis(4-CF3)) (38%, 38.4g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[C@@H:16]([NH:17][C:18](=O)[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=3)[CH2:15][CH2:14][N:13]([CH3:28])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)(=O)/C=C\C(O)=O>>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C@H:11]3[C@H:16]([CH2:15][CH2:14][N:13]([CH3:28])[CH2:12]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=3)[C:6]=2[CH:7]=1
Reactant: COc1ccc([C@@H]2CN(C)CC[C@@H]2NC(=O)c2ccc(C)c(C)c2)cc1OC
Agent: O=C(O)/C=C\C(=O)O
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(C)c(C)c1

Procedure:
cis-3-(3,4-Dimethoxyphenyl)-1-methyl-4-(3,4-dimethylbenzoylamino)-piperidine is cyclized in analogy to the process described in Example 1 b). The bis-hydrogen maleate of the title compound has a M.P. of 182°-184° (from ethanol).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:10](=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:22])[CH:8]=2)[N:3]1[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].[CH2:53](Br)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.O>CN(C)C=O>[CH2:53]([O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH:34]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:29][CH2:28]1)[C:2](=[O:1])[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]2=[O:21])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCCCn1c(=O)c2cc(O)ccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCCCn1c(=O)c2cc(OCc3ccccc3)ccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 30.6 %

Procedure:
To a suspension of ethyl 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-6-hydroxy-1,2,3,4-tetrahydroquinazoline-3-valerate (1.34 g, 2.13 mmol) obtained in Example 105 and potassium carbonate (354 mg, 2.56 mmol) in N,N-dimethylformamide (50.0 ml), benzyl bromide (305 ml, 2.56 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18.5 hours. The reaction mixture was combined with water and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO4) the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluting with n-hexane-ethyl acetate (5:1, v/v) to give the ethyl ester of the title compound (450 mg, 29%) as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][NH:25][CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38](O)[CH2:37][CH2:36]1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][N:25]([CH:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)[CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(O)CC1
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1
Product: Cc1ccc(-c2nn(C3CCN(C)CC3)cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1

Procedure:
The title compound is prepared as described in Example 55 starting from [4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 60) and 1-methyl-piperidin-4-ol.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[Br:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:42]([C:39]2[CH:40]=[CH:41][C:36]([Br:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: CC(C)OC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Br)cc1)nc(-c1ccccc1)n2-c1ccccc1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted according to general operating instructions 13 with 4-bromobenzenesulfonic acid chloride.