Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C([Si]([O:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][C@@H:52]2[CH2:54][O:53]2)=[CH:46][CH:45]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>ClCCl.C(Cl)(Cl)Cl.CO>[C:20]1([NH:19][C:17]([N:14]2[CH2:15][CH2:16][CH:11]([S:10][C:7]3[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:54][C@H:52]([OH:53])[CH2:51][O:50][C:47]4[CH:48]=[CH:49][C:44]([OH:43])=[CH:45][CH:46]=4)=[CH:9][CH:8]=3)[CH2:12][CH2:13]2)=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NCCc1ccc(SC2CCN(C(=O)Nc3ccccc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCC(Sc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 26 %

Procedure:
4-{[4-(2-Aminoethyl)phenyl]sulfanyl}-N-phenyl-1-piperidinecarboxamide (0.45 g, 1.27 mmol) was reacted with tert-butyl{4-[(2S)oxiranylmethoxy]phenoxy}diphenylsilane (0.512 g, 1.27 mmol) according to Procedure G (eluant: 12:3:1 dichloromethane-chloroform-methanol) to give the title compound (0.25 g, 0.33 mmol).
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:22]1[N:23]=[N:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][CH:27]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:22]3[N:23]=[N:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][CH:27]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(Cl)nn1
Reactant: CCCCCCCCC1Cc2ccc(B(O)O)cc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: CCCCCCCCc1ccc(-c2ccc3c(c2)CC(CCCCCCCC)C3)nn1
Temperature: 0 °C
Yield: 73.1 %

Procedure:
Then, 0.82 g (3.0 mM) of 2-octylindan-5-boronic acid, 0.68 g (3.0 mM) of 3-chloro-6-octylpyridazine, 2 ml of ethanol, 4 ml of benzene, 4 ml of 2M-sodium carbonate aqueous solution and 0.12 g of tetrakis (triphenylphosphine) palladium (O) were mixed and heat-refluxed for 2 hours under stirring. After the reaction, the reaction mixture was poured into ice water to precipitate a crystal. The crystal was recovered by filtration under reduced pressure and purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene/methanol) to obtain 0.92 g (2.19 mM) of 2-octyl-5-(6-octylpyridazine-3-yl)indan (Yield: 73%). ##STR318##
Reaction SMILES: Cl[C:2](=[O:8])[C:3](OCC)=[O:4].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:27])=[C:14]([CH:26]=1)[NH:15][C:16]([NH:18][O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[S:17]>C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:27])=[C:14]([N:15]2[C:3](=[O:4])[C:2](=[O:8])[N:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]2=[S:17])[CH:26]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCOC(=O)CONC(=S)Nc1cc(Cl)ccc1C
Solvent: ClCCl
Product: CCOC(=O)CON1C(=O)C(=O)N(c2cc(Cl)ccc2C)C1=S
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
Ethyl chlorooxoacetate (11.1 mL; 0.1 mol) was added dropwise to the solution of ethyl 2-({[(5-chloro-2-methylanilino) carbothioyl]amino}oxy)acetate (15.1 g; 0.05 mol) in methylene chloride (200 mL). The mixture was heated at reflux for 1 hour then evaporated to dryness. The residue was stirred in ether for 15 minutes and the solids were filtered. The solids were washed with fresh ether and dried to give 13.1 g of ethyl 2-{[3-(5-chloro-2-methylphenyl)-4,5-dioxo-2-thioxo-1-imidazolidinyl]oxy}acetate as a solid, m.p. 157–159° C. Mass spectrum; FAB (M+H)+ m/z 357. 1H-NMR (DMSO-d6; 300 MHz): δ 7.50 (d, 1H), 7.42 (m, 2H), 4.90 (q, 2H), 4.20 (q, 2H), 2.17 (s, 3H), and 1.24 ppm (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([CH2:9][O:10][CH2:11]Cl)=[CH:7][CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19](=[O:22])[NH:20][CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([CH2:9][O:10][CH2:11][N:20]2[CH:21]=[C:16]([Cl:15])[CH:17]=[N:18][C:19]2=[O:22])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(COCCl)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Product: COC(=O)c1ccc(COCn2cc(Cl)cnc2=O)cc1
Yield: 62 %

Procedure:
was prepared as described in Example 3 from chloromethyl 4-methyloxycarbonylbenzyl ether (see Preparation 13) (8.8 mmol) and 5-chloropyrimidin-2-one (8.8 mmol) in 62% yield, m.p. 172° C. 1H NMR (CDCl3): δ3.92 (OMe), 4.77 (CH2Ph), 5.38 (CH2O), 7.2-8.2 (Ph), 7.78 asnd 8.50 (H-4, H-6, J 4 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+:28]>CO>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O-:22])=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1.[Na+:28]
Reactant: CCOC(=O)c1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 2 h

Procedure:
A stirred suspension of the product of Example 131 (353 mg) in methanol (5 ml) was treated with a 1 molar sodium hydroxide solution (3 ml). After 2 hours, the cream coloured solid was collected, washed with a little methanol and dried to give the title compound, 240 mg, m.p. >300° C.; NMR (d6DMSO) δ8.15 (2H, d) 8.05 (4H, t, AB pattern), 6.85 (2H, d), 3.97 (2H, s), 3.38 (4H, t), 2.65 (4H, t), m/e 348 (M+H)+ ; calculated for C18H18N3NaO3. 0.25H2O: C, 61.4; H, 5.3; N, 11.9. found: C, 61.3; H, 5.2; N, 11.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:7]([CH3:16])[C:6]([N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1.C=O.C[C:23](C)([O-:25])C.[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:7]([CH2:16][CH2:23][OH:25])[C:6]([N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc([N+](=O)[O-])c(C)c1N1CCN(C)CC1
Agent: C=O
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc([N+](=O)[O-])c(CCO)c1N1CCN(C)CC1
Temperature: 72.5 °C
Yield: 111.9 %

Procedure:
A mixture of 1-(6-methoxy-2-methyl-3-nitrophenyl)-4-methylpiperazine (D30) (360 mg, 1.36 mmol), dry dimethylsulfoxide (3 ml), paraformaldehyde (82 mg, 2.72 mmol) and potassium tert-butoxide (52 mg, 0.46 mmol) was heated at 70-75° C. for 30 h. After cooling, the mixture was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) evaporated under reduced pressure and purified by chromatography on silica gel, eluting with methanol and dichloromethane, to give the title compound (D31) as a yellow solid (152 mg, 38%) MH+=296.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[C:4]([OH:12])=[N:3][CH:2]=1.F[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=1.CCN(C(C)C)C(C)C.C(O)(CC)(C)C>>[F:21][C:20]([F:23])([F:22])[C:19]1[C:14]([N:9]2[CH2:10][CH2:11][C:5]3[C:4]([OH:12])=[N:3][CH:2]=[N:1][C:6]=3[CH2:7][CH2:8]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1ncnc2c1CCNCC2
Reactant: Fc1ncccc1C(F)(F)F
Solvent: CCC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ncnc2c1CCN(c1ncccc1C(F)(F)F)CC2
Yield: 33.9 %

Procedure:
A solution of 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (353 mg, 1.76 mmol), 2-fluoro-3-trifluoromethyl-pyridine (582 mg, 3.53 mmol), iPr2NEt (0.9 mL, 5.28 mmol), and t-amyl alcohol (5 mL) was heated in a microwave at 180° C. for 5 h. The mixture was concentrated, diluted with water, and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated to give the title compound (185 mg, 34%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7](I)=[C:6]([O:11][CH2:12][C:13]([CH3:15])=[CH2:14])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]1(B(O)O)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[C:13]([CH3:15])([CH2:14][C:31]3[C:32]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:28]=[CH:29][CH:30]=3)[CH2:12][O:11][C:6]=2[CH:5]=1)=[O:16]
Reactant: C=C(C)COc1cc(C(=O)OC)ccc1I
Reactant: OB(O)c1cccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)OCC2(C)Cc1cccc2ccccc12
Reaction time: 0.25 h
Yield: 43 %

Procedure:
A solution of 4-Iodo-3-(2-methyl-allyloxy)-benzoic acid methyl ester (455 mg, 1.37 mmol) in DMF (15 mL) were added Potassium carbonate (379 mg, 2.74 mmol), Tetrabutylammonium chloride (380 mg, 1.37 mmol), Palladium acetate (25.6 mg, 0.136 mmol) in DMF (5 mL) and 1-Naphthylboronic acid, (282 mg, 1.64 mmol) was submitted to microwave irradiation at 100° C. for 10 minutes and as the reaction was not completed at 150° C. for 15 minutes. The resulting mixture was filtered over silica, washed with water, dried over MgSO4 and concentrated. Column chromatography (silica gel, heptane/CH2Cl2: 4/6) afforded 196 mg (43%) of the title compound as a slightly brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([O:18][Si](C(C)(C)C)(C)C)[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([OH:18])[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(Br)ccc32)cc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1sc(-n2cnc3cc(Br)ccc32)cc1O

Procedure:
In an alternative procedure, to a solution of methyl 5-(5-bromo-1H-benzimidazol-1-yl)-3-{[tert-butyl(dimethyl)-silyl]oxy}thiophene-2-carboxylate (12 g, 25 mmol) in 250 mL of THF cooled to 0° C. was added a 1M solution of tetrabutylammonium fluoride in THF (28 ml, 28 mmol). The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4 and concentrated onto silica gel. The crude material was purified by flash column chromatography (0-5% MeOH/DCM) to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:29][CH:28]([NH:30]C(=O)OC(C)(C)C)[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:26]3[CH2:29][CH:28]([NH2:30])[CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CC(N)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 26-1 in Scheme 7 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and tert-butyl azetidin-3-ylcarbamate. MS obsd. (ESI+) [(M+H)+] 409, 1H NMR (400 MHz, CD3OD) δ ppm 8.03-8.00 (d, J=7.6 Hz, 1 H), 7.87 (s, 1 H), 7.80-7.78 (d, J=7.6 Hz, 1 H), 7.67-7.62 (m, 2 H), 7.56-7.50 (m, 2 H), 6.00 (s, 1 H), 5.29 (s, 2 H), 4.47 (s, 2 H), 3.97-3.89 (m, 3 H), 3.82-3.69 (m, 4 H), 2.40 (s, 3 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[C:15](=O)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[CH2:15][O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(Cc3ccccc3)CC2)c2ccc(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)COC21CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of 1′-benzyl-5-chloro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (1.1 g, 3.35 mmol) in THF (12 mL) was added 1 M solution of borane complex in THF (7 mL, 7.0 mmol) slowly at 0° C. After addition was complete reaction mixture was kept at room temperature for 30 min, then kept at reflux overnight, cooled to 0° C. and 6M aqueous HCl (3.5 mL) was added slowly. The reaction mixture was kept at reflux for 5 h, cooled to 0° C., pH of the reaction mixture was adjusted to 10 by addition of aqueous NaOH (6M) and the whole was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-30% ethyl acetate in petroleum ether) to give the subtitled compound (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].Cl[C:11]1[NH:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.Cl>C(O)C>[ClH:1].[NH:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[NH:4][C:3]1[C:5]([F:9])=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1c(F)cccc1Cl
Agent: Cl
Solvent: CCO
Product: Fc1cccc(Cl)c1Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.5 %

Procedure:
2-Chloro-6-fluoroaniline (0.48 g) and 2-chlorobenzimidazole (0.5 g) were mixed in a flask and then kept at 170° C. for 30 min. After cooling, the residue was dissolved out of the flask at boiling heat using 1 N HCl and 10% ethanol. The material dissolved out was then stirred at RT for 30 min, then the insoluble material was filtered off with suction and the filtrate was evaporated. The residue was purified by means of preparative HPLC on RP-18 using acetonitrile/water (0.05% TFA). The clean fractions were combined, the acetonitrile was stripped off, the residue was adjusted to pH 10 with potassium carbonate solution, extracted three times with EA, and then the combined phases were dried, filtered, and concentrated. The residue was taken up using HCl/water and freeze-dried. 27 mg of the title compound were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19].O>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5])[CH:18]=[CH2:17]
Reactant: O=Cc1cc(I)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(I)cc1C=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 2-hydroxy-5-iodo-benzaldehyde (16 g, 64.5 mmol) (Aldrich) in N,N-dimethylformamide (100 mL) was added K2CO3 (16 g, 115 mmo) and allyl bromide (20 g, 165 mmol) (Aldrich). The reaction mixture was stirred at 100° C. for 3 h, then cooled to room temperature and poured into water, extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, filtered and concentrated to give 2-allyloxy-5-iodo-benzaldehyde as a white solid (Yield: 18g, 97%).
Reaction SMILES: [Na].[CH:2]1C2C(=CC=CC=2)C=CC=1.C1(S([NH:21][C@@H:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)(=O)=O)C=CC=CC=1.Cl>COCCOC.O>[NH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:2])=[O:36])=[CH:32][CH:33]=1
Reactant: c1ccc2ccccc2c1
Reactant: COC(=O)Cc1ccc(C[C@@H]2CCC[C@H]2NS(=O)(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1ccc(C[C@@H]2CCC[C@H]2N)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
0.5 g (21 mmoles) of sodium is added to a mixture of 2.6 g (21 mmoles) of naphthalene and 20 ml of 1,2-dimethoxyethane, under a flow of nitrogen. After stirring 1 hour at 20° C., a solution of 2 g (5.2 mmoles) of methyl trans-4-[[2-[[(phenyl)sulfonyl]amino]cyclopentyl]methyl]benzeneacetate in 20 ml of 1,2-dimethoxyethane is added dropwise during 1 hour, at room temperature. After stirring 1 hour at 20° C., 40 ml of water are added dropwise, before washing with ethyl acetate. The aqueous phase acidified with diluted HCl is washed with ethyl acetate, before being concentrated to dryness under reduced pressure. The residue is captured by 50 ml of absolute ethanol and the white suspension obtained is saturated at 0° C. with gaseous HCl. After stirring 16 h at 20° C., the reaction mixture is concentrated under reduced pressure, captured with H2O, made basic with NH4OH and extracted with ethyl acetate. This organic phase after washing with H2O saturated with NaCl is dried over Na2SO4, concentrated, to give 0.5 g (yield=39.3%) of a partially crystallized brown oil, which is used without any other purification.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][C@@H:37]([CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])[C:38]([O:40][CH3:41])=[O:39])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[OH:36][C@@H:37]([CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)[C@H](CCS(C)(=O)=O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)[C@@H](O)CCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (2071 μl, 2.07 mmol) was added to (S)-methyl 2-(tert-butyldiphenylsilyloxy)-4-(methylsulfonyl)butanoate (Intermediate AA3) (450 mg, 1.04 mmol) in THF (3106 μl) under nitrogen. The resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with saturated NH4Cl (10 mL), extracted with Et2O (3×15 mL). The combined organic layers were back washed with water (10 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 100% ethyl acetate in isohexane to afford the product (120 mg, 59%). 1H NMR (400 MHz, CDCl3) δ 2.10-2.20 (1H, m), 2.38-2.46 (1H, m), 2.94 (4H, m), 3.10-3.24 (2H, m), 3.84 (3H, s), 4.34 (1H, q), 7.26 (3H, s).
Reaction SMILES: C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([CH3:41])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]2[CH2:51][O:52][CH2:53][C:54]([OH:56])=O)(=[O:44])=[O:43])=[C:37]([CH3:57])[CH:36]=1.[N:58]1([CH2:63][CH2:64][O:65][C:66]2([C:72]3[CH:77]=[CH:76][CH:75]=[C:74]([C:78]([F:81])([F:80])[F:79])[CH:73]=3)[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)[CH2:62][CH2:61][CH2:60][CH2:59]1>C(Cl)Cl>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH3:57])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]2[CH2:51][O:52][CH2:53][C:54]([N:69]2[CH2:70][CH2:71][C:66]([O:65][CH2:64][CH2:63][N:58]3[CH2:62][CH2:61][CH2:60][CH2:59]3)([C:72]3[CH:77]=[CH:76][CH:75]=[C:74]([C:78]([F:80])([F:79])[F:81])[CH:73]=3)[CH2:67][CH2:68]2)=[O:56])(=[O:43])=[O:44])=[C:39]([CH3:41])[CH:40]=1
Reactant: FC(F)(F)c1cccc(C2(OCCN3CCCC3)CCNCC2)c1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)N2CCC(OCCN3CCCC3)(c3cccc(C(F)(F)F)c3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Diisopropylethylamine (4 eq.), EDCl HCl (1.2 eq.) and HOBt (1 eq.) were added to a mixture of (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D] (0.65 mmol) in methylene chloride (10 ml). A mixture of 4-(2-(pyrrolidin-1-yl)ethoxy)-4-(3-(trifluoromethyl)phenyl)piperidine [amine H] and DIPEA (2 eq.) in methylene chloride (3 ml) was added dropwise, while cooling with ice, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and with sat. sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by means of column chromatography (silica gel, methanol/methylene chloride) to obtain the desired product. Yield: 78%. MS, Rt=3.9 min, m/z=696.4 [MH]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH2:37][O:38][CH3:39])=[N:22][C:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:24][C:25]=1[CH3:26]>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH2:37][O:38][CH3:39])=[N:22][C:23]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[N:24][C:25]=2[CH3:26])=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CCl
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C)nc(-c3ccc(C(F)(F)F)cc3)nc2COC)cc1C

Procedure:
In analogy to the procedure described in example 113A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-methoxymethyl-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 147E]) to give the title compound as light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:13]([O:17][C:18]([NH:20][C@H:21]([CH2:25][CH2:26][S:27][CH3:28])[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:13]([O:17][C:18](=[O:19])[NH:20][C@H:21]([CH2:25][CH2:26][S:27][CH3:28])[C:22]([NH:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:23])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc(CN)cc1OC
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C

Procedure:
To a 0° C. solution of (3,4-dimethoxyphenyl)methanamine (2 g, 12 mmol) in DCM (20 mL) was added sequentially (R)-2-((tert-butoxycarbonyl)amino)-4-(methylthio)butanoic acid (3.28 g, 13.2 mmol), PyBOP (6.85 g, 13.2 mmol) and DIPEA (4.18 mL, 23.92 mmol). The reaction mixture was stirred and allowed to warm up to ambient temperature over 2 h. The reaction was then quenched by the addition of water and the mixture was extracted twice with 100 mL DCM. The organic fraction was washed with 50 mL water, 50 mL brine, and the layers were separated. The organic fraction was dried over sodium sulfate, filtered, and evaporated. The residue was purified via silica gel chromatography, eluting with 30% ethyl acetate/petroleum ether. Yield 3.5 gms (R)-tert-butyl(1-((3,4-dimethoxybenzyl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate. LCMS (Method F) RT 2.3 min, m/z 399.2 (MH+); 1H NMR (400 MHz, chloroform-d) δ 1.41 (s, 9H), 1.91-1.98 (m, 1H), 2.07 (s, 3H), 2.10-2.14 (m, 1H), 2.47-2.61 (m, 2H), 3.65 (s, 6H), 4.25-4.27 (br s, 1H), 4.33-4.42 (m, 2H), 5.16 (br s, 1H), 6.47 (br s, 1H), 6.80 (s, 3H).