Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)C=CC=CC=1.CO.Cl.[H][H]>[Pd].O>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: c1ccc(CN2CCC(Nc3cccnc3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: c1cncc(NC2CCNCC2)c1

Procedure:
A mixture of 20 parts of N-[1-(phenylmethyl)-4-piperidinyl]-3-pyridinamine, 160 parts of methanol, 30 parts of water and 12 parts of a concentrated hydrochloric acid solution is hydrogenated at normal pressure and at a temperature between 22°-39° C., in the presence of 7 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The oily residue is dissolved in water. This solution is rendered alkaline with ammonium hydroxide, saturated with solid potassium carbonate and then extracted with methylbenzene. The extract is dried over potassium carbonate and evaporated. The solid residue is recrystallized from a mixture of 40 parts of benzene and 32 parts of 1,1'-oxybisethane, yielding 3 parts of N-(4-piperidinyl)-3-pyridinamine; mp. 127°-129° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:34][C:33]3[C:28](=[N:29][CH:30]=[CH:31][C:32]=3[O:35][C:36]3[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][C:37]=3[F:43])[CH:27]=2)=[N:24][CH:25]=1>C1(C)C=CC=CC=1.C(O)C>[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:34][C:33]3[C:28](=[N:29][CH:30]=[CH:31][C:32]=3[O:35][C:36]3[CH:42]=[CH:41][C:39]([NH:40][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:13])=[CH:38][C:37]=3[F:43])[CH:27]=2)=[N:24][CH:25]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of 2 (2.69 g, 13.80 mmol) in toluene (16.5 mL) and ethanol (16.5 mL) was added a suspension of 31 (4.87 g, 11.50 mmol) in toluene (41 mL) and ethanol (41 mL). The mixture was stirred for 1 h at room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent EtOAc/MeOH, 98/2) to afford intermediate 32 (5.31 g, 8.58 mmol, 74% yield) as a beige solid. MS (m/z): 619.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.47 (s, 1H), 11.83 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.54 (d, J=5.2 Hz, 1H), 8.38 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.02 (dd, J=12.4, 1.6 Hz, 1H), 7.92 (dd, J=8.2, 1.8 Hz, 1H), 7.54-7.52 (m, 2H), 7.37 (dd, J=8.6, 5.8 Hz, 2H), 7.17 (t, J=9.0 Hz, 2H), 6.68 (d, J=5.2 Hz, 1H), 5.66 (s, 1H), 4.18 (dd, J=10.6, 5.0 Hz, 2H), 3.97-3.94 (m, 2H), 3.82 (s, 2H), 2.10-1.98 (m, 1H), 1.47 (dd, J=14.0, 1.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]1([CH3:19])[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[O:13]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:18][C:14]1[O:13][C:12]([CH3:19])([CH3:11])[C:16](=[O:17])[CH:15]=1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccc(Cl)cc2Cl)=CC1=O
Temperature: 60 °C
Yield: 69.9 %

Procedure:
To a solution of 2,4-dichlorobenzaldehyde (2.3 g, 13.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was heated at 60° C. for 4 hours. After the reaction solution was cooled, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow solid. The crude product was triturated with 10% diethyl ether/pet. ether to afford a light yellow powder (2.6 g, 70% yield), m.p. 154°-156° C.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:6]=1[C:7]([OH:9])=[O:8]>C(Cl)(Cl)Cl.O1CCOCC1>[Br:1][C:13]1[C:5]([O:4][CH3:3])=[C:6]([C:10]([O:14][CH3:15])=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: BrBr
Reactant: COc1cccc(OC)c1C(=O)O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)c(OC)c1C(=O)O
Reaction time: 8 h

Procedure:
A solution of 15 ml of bromine (0.3 mol) in 50 ml of chloroform is added dropwise while stirring and cooling in ice to 54.9 g (0.3 mol) of 2,6-dimethoxybenzoic acid in 150 ml of dioxan. The solution is left at room temperature overnight. The solvent is evaporated and the residue recrystallized from aqueous ethanol. Yield: 59.3 g, m.p. 144°-45° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:20][CH3:21])=[C:7]([NH2:19])[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C(Cl)Cl>[C:1]([C:5]1[C:6]([O:20][CH3:21])=[C:7]([NH:19][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:33][CH:32]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ncccc1-c1cc(N)c(OC)c(C(C)(C)C)c1
Solvent: ClCCl
Product: COc1ncccc1-c1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(OC)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
step 3—To a solution of 100 (0.24 g, 0.85 mmol) and TEA (0.18mL, 1.3 mmol) in DCM (10 mL) at 0° C. was added 4-nitrobenzoyl chloride (0.19 g, 1.0 mmol). The resulting mixture was stirred at 0° C. for 3 h, and then warmed to RT. The mixture was then diluted with additional DCM, washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated. The crude residue so obtained was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.36 g (97%) of N-[3-tert-butyl-2-methoxy-5-(2-methoxypyridin-3-yl)phenyl]-4-nitrobenzamide (102) as a light yellow solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[C:9]([CH3:21])=[C:8]([F:22])[CH:7]=2)[CH2:3][CH2:2]1.Br[C:25]1[C:26](=[O:43])[N:27]([CH3:42])[C:28]2[N:33]([C:34]3[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=3[F:41])[N:32]=[CH:31][C:29]=2[N:30]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:7]=[C:8]([F:22])[C:9]([CH3:21])=[C:10]([C:25]3[C:26](=[O:43])[N:27]([CH3:42])[C:28]4[N:33]([C:34]5[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=5[F:41])[N:32]=[CH:31][C:29]=4[N:30]=3)[CH:11]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1c(=O)c(Br)nc2cnn(-c3c(F)cccc3F)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1nc2cnn(-c3c(F)cccc3F)c2n(C)c1=O
Temperature: 125 °C

Procedure:
A mixture of N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (520 mg, 1.63 mmol), 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (505 mg, 1.48 mmol) in 3.5 mL of dioxane and 1.5 mL of 2 N Na2CO3 was heated in a microwave at 125° C. for 25 min. It was diluted with EtOAc and washed with 1 N NaOH. The EtOAc layer was separated, dried and concentrated. Purification of the crude material on an ISCO 40 g column (with 30-75% EtOAc in Hexanes) provided N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylb enzamide as an off white amorphous solid. MS (ES+): 454.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=1)[CH3:4].C1OCCOCCOCCOCCOCCOC1.Br[CH2:35][CH2:36][CH2:37][CH2:38]Br>CN(C=O)C.O>[CH2:3]([O:5][C:6]([C:7]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:15])[CH3:4]
Reactant: BrCCCCBr
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cccc(Br)c2)CCCC1
Reaction time: 0.42 h
Yield: 91.2 %

Procedure:
Sodium hydride (60% in oil, 1.07 g, 26.8 mmol) is added to a solution of (3-bromo-phenyl)-acetic acid ethyl ester [2.59 g, 10.7 mmol] and 18-crown-6 (catalytic amount) in N,N′-dimethylformamide (50 mL). The mixture is stirred for 25 minutes and 1,4-dibromobutane (1.41 mL, 11.8 mmol) is added dropwise via syringe. The mixture is stirred for 18 hours at ambient temperature, diluted with water (100 mL) and extracted thrice with EtOAc (60 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 1-(3-bromo-phenyl)-cyclopentanecarboxylic acid ethyl ester [2.9 g, 91%] as an oil, which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([O:10][CH3:11])[CH:4]=1.B(Br)(Br)Br.C([O-])([O-])=O.[K+].[K+].C(Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([O:10][CH2:11][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:4]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: BrCc1ccccc1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Brc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
1,3-Dimethoxy-5-bromobenzene (14.5 g, 66.7 mmol) was dissolved in 40 mL CH2Cl2 and cooled to 0° C. BBr3 (100 mL, 1.0 M in CH2Cl2, 100 mmol) was added and the solution was stirred for 12 h at room temperature. The reaction was carefully quenched with MeOH and then concentrated to dryness. The resulting syrup was redissolved in EtOAc and was washed with H2O (3×25 mL). The organic phase was then dried over Na2SO4, filtered and concentrated to dryness. The residue was then dissolved in DMF (50 mL) and K2CO3 (20.2 g, 146.7 mmol) was added, followed by benzyl bromide (BnBr, 17.4 mL, 146.7 mmol). The reaction mixture was stirred for 3 h after which TLC analysis (60% EtOAc/hexanes) indicated that the reaction was complete. The reaction mixture was then diluted in EtOAc and washed with water (3×50 mL). The organic phase was dried over Na2SO4, filtered and concentrated to yield the crude product. The product was crystallized from isopropanol to yield 1,3-bis-Benzyloxy-5-bromobenzene 22 (21 g, 57 mmol, 85° A) yield) as a white powder. 1H NMR (CD2Cl2) δ 7.3-7.5 (m, 10H), 6.71 (s, 2H), 6.60 (s, 1H), 5.05 (s, 4H); 13C NMR (CD2Cl2) δ 161.2, 137.2, 128.9, 128.4, 127.8, 123.1, 111.0, 101.5, 70.0.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:44]1([CH2:50][C:51]([N:53]=[C:54]=[S:55])=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:54]([NH:53][C:51](=[O:52])[CH2:50][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[S:55])=[CH:28][CH:27]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Reaction time: 3 h
Yield: 45 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyridine (137 mg) and (+)-10-camphorsulfonic acid (151 mg) in ethanol (3.5 ml) was added a solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 2.73 ml) at room temperature, followed by stirring for 3 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2) to provide the titled compound (86.5 mg, 45%) as white powder.
Reaction SMILES: [CH:1]1([CH:6]([NH:8][C:9]2[CH:22]=[CH:21][C:12]([C:13]([CH2:15][C:16]([O:18]CC)=[O:17])=[O:14])=[CH:11][CH:10]=2)[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].S(=O)(=O)(O)O>O.C(O)C>[CH:1]1([CH:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([CH2:15][C:16]([OH:18])=[O:17])=[O:14])=[CH:21][CH:22]=2)[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)c1ccc(NC(C)C2CCCC2)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Nc1ccc(C(=O)CC(=O)O)cc1)C1CCCC1

Procedure:
Two grams of ethyl 4-(1-cyclopentylethylamino)-benzoylacetate is added to a solution of potassium hydroxide in 50 ml. of 1:9 water-ethanol. The reaction of neutralization with sulfuric acid gave a precipitate which is filtered, washed with water, and dried to yield 4-(1-cyclopentylethylamino)benzoylacetic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([NH:20]C(N2CCC(N3C4C(=NC=CC=4)N(COCC[Si](C)(C)C)C3=O)CC2)=O)[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C@H:10]1[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:20][C@H:17]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C@@H:10]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@H](NC(=O)N2CCC(n3c(=O)n(COCC[Si](C)(C)C)c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@H](N)CC[C@H]1c1cccc(F)c1F

Procedure:
A Methylene chloride (1 mL) solution of tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(4-(2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamido)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ylcarbamate (12 mg, 0.016 mmol) in TFA (0.5 ml, 6.5 mmol) was stirred at room temperature overnight. The solvent was removed via vacuum and the crude residue was partitioned between ethyl acetate and Sodium bicarbonate (sat). The ethyl acetate layer was separated, dried (sodium sulfate) and concentrated. The desired product was obtained by prep TLC eluting with 10% methanol in methylene chloride:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:23])[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+].[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[C:27]([O:23][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)[CH:12]([CH3:22])[CH2:13][N:14]1[CH2:15][CH:16]([CH3:21])[O:17][CH:18]([CH3:20])[CH2:19]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CN(CC(C)C(O)c2ccc(C(C)(C)C)cc2)CC(C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)OC(c1ccc(C(C)(C)C)cc1)C(C)CN1CC(C)OC(C)C1
Yield: 73 %

Procedure:
7.2 g (0.02 mole) of 1-(p-tert.-butyl-phenyl)-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-1-propanol (obtained according to Example 2) were stirred in 50 ml of acetic anhydride to room temperature for 3 hours. The reaction mixture was then introduced into 100 ml of water and the mixture was adjusted to a pH value of 7 with dilute sodium hydroxide solution and extracted with chloroform. The organic phase was dried over sodium sulphate and concentrated. The oily residue was taken up in ethyl acetate, the ethyl acetate mixture was shaken with active charcoal and filtered and the filtrate was concentrated. The resulting oil was digested with petroleium ether, a brown precipitate was separated off and the mixture was concentrated. 5.3 g (73% of theory) of 1-acetoxy-1-(p-tert.-butyl-phenyl)-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-propane were obtained as a viscous oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)[N:9]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)CCC>>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH2:20]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)cc3)n2)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(-c3ccc(-c4ccccn4)cc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Step D of Example 172, starting from [4-(4-bromophenyl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-tributylstannanyl-pyridine. Yield: 85 mg (44%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([O:33][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:7][N:6]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Oc1cccc(Cl)c1
Product: Clc1ccc(-c2cnc(Oc3cccc(Cl)c3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine from Reference Example 3 was reacted with 3-chlorophenol according to the procedure described in Example 74 to afford 2-(3-chlorophenyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine: HPLC/MS: m/e=461 (M++1); Rt=4.72 min; 1H-NMR 400 MHz (CDCl3): δ 7.00-7.12. (m, 2H), 7.11-7.18 (m, 2H), 7.20-7.30 (m, 7H), 8.60 (s, 1H).
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:16]([CH:21]=2)[C:17]([O:19]C)=[O:18])(=O)=O)=CC=1.[OH-].[K+]>C(O)C.O>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([CH:21]=1)[C:17]([OH:19])=[O:18]
Reactant: COC(=O)c1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(O)ccc1OCc1ccccc1

Procedure:
Methyl 5-{[(4-methylphenyl)sulfonyl]oxy}-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 37; 2.5 g, 6.06 mmol) was boiled with potassium hydroxide (2.38 g, 42.4 mmol) in a mixture of ethanol (60 ml) and water (15 ml) for 4 h. After the ethanol had been evaporated, the aqueous solution was washed with ethyl acetate (20 ml) and acidified with concentrated HCl. The mixture was extracted with ethyl acetate (3×30 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulphate and evaporated in vacuo to yield the title compound as a yellow oil. 1.35 g.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([C:40](=[O:43])[CH2:41][CH3:42])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:45].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:45].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([C:40](=[O:43])[CH2:41][CH3:42])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCC(=O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC(=O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C

Procedure:
To 1 mL of an ethyl acetate solution containing 30 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-2-oxo-5-propionylquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and stirred at room temperature. The resulting solid was filtered to give 18 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-5-propionyl-1,2-dihydro-2-oxoquinoline hydrochloride as a white solid.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][CH:6]=1)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][CH:9]=1)=[O:17]
Reactant: CCOC(OCC)c1ccc(C(=O)CC(C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)CC(=O)c1ccc(C=O)cc1
Yield: 65.1 %

Procedure:
Dissolve 1-[4-(diethoxymethyl)-phenyl]-3,3-dimethylbutan-1-one (3.49 g, 12.55 mmol) in acetone (50 mL). Add p-toluenesulfonic acid monohydrate (238 mg, 1.256 mmol). Heat the mixture under reflux for 3 h. Concentrate in vacuo and partition the residue between water and EtOAc. Extract the aqueous phase three times with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (1.67 g, 65%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1>>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([C@H:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@H](C2CCNCC2)C3)CC1
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC([C@@H]3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 37, the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 1. LC (method 5): tR=0.87 min; Mass spectrum (ESI+): m/z=470 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:14][OH:15]>C(O)C>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:14][OH:15]
Reactant: NO
Reactant: COc1ccc(C=O)c(Cl)c1O
Agent: Cl
Solvent: CCO
Product: COc1ccc(C=NO)c(Cl)c1O

Procedure:
A mixture of 30 g of 2-chloro-3-hydroxy-p-anisaldehyde and 230 ml of ethanol is stirred at 70° for 4 hours in the presence of 12.3 g of hydroxylamine hydrochloride, the reaction mixture is subsequently evaporated, the residue is dried in a high vacuum and recrystallized from methanol/water. There is obtained 2-chloro-3-hydroxy-p-anisaldehyde oxime of m.p. 174°-176°.