Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:13])[CH2:11][NH2:12].[C:14](/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=O)[CH3:28])=[CH:22][CH:21]=1)([O:16][CH3:17])=[O:15]>O>[C:14](/[CH:18]=[CH:19]/[C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([NH:12][CH2:11][CH:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[OH:13])[CH3:28])=[CH:24][CH:25]=1)([O:16][CH3:17])=[O:15]
Reactant: NCC(O)c1cc2ccccc2o1
Reactant: COC(=O)/C=C/c1ccc(CC(C)=O)cc1
Solvent: O
Product: COC(=O)/C=C/c1ccc(CC(C)NCC(O)c2cc3ccccc3o2)cc1

Procedure:
A mixture of 2-(2-benzofuranyl)-2-hydroxyethanamine (1.0 g) and 4-[(E)-2-carbomethoxyethenyl]phenyl propan-2-one (1.13 g) was heated under reflux using a Dean and Stark head until the theoretical amount of water had been removed. The solvent was evaporated, the residue dissolved in methanol (50 ml) and sodium borohydride (0.5 g) added. The solvent was evaporated, the residue partitioned between water and ethyl acetate and the organic layer dried (magnesium sulphate). Removal of the solvent gave an oil which was chromatographed on Kieselgel 60. Elution with 2% methanol-chloroform gave N-[2-(4-[(E)-2-carbomethoxyethenyl]phenyl)-1-methylethyl]-2-(2-benzofuranyl)-2-hydroxyethanamine, as a 54:46 mixture of diastereoisomers, m.p. 85-89 (cyclohexane).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1C)([O-:3])=[O:2].BrN1[C:17](=[O:18])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:10][C:6]1[CH:7]=[C:8]([CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH:17]=[O:18]
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C=O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of nitroxylene (150 g), N-bromo succinimide (160 g) and benzoylperoxide (4.8 g) in carbontetrachloride (1200 ml) was heated to reflux for 4 hours with a mechanical stirrer. The precipitated succinimide was filtered and the filtrate evaporated. The oily residue was dissolved in chloroform (800 ml) and bistetrabutyl ammonium chromate (420 g) was added. The solution was refluxed for 3 hours, cooled to room temperature and diluted with benzene (500 ml) and filtered. The salts were washed with ethyl acetate until no desired material appeared on thin layer chromatography. The combined organic layer was evaporated and the residue, after chromatography, afforded the desired aldehyde in 50% yield. m.p. 81°-82° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:8](=[O:9])[C:7](=[O:10])[C:6]=2[NH:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]([C:33]([O:35]C)=[O:34])[NH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:20][CH:19]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:3][CH2:2]1.[OH-].[Li+]>C1COCC1.CO.O>[CH:1]1([NH:4][C:5]2[C:8](=[O:9])[C:7](=[O:10])[C:6]=2[NH:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][C@@H:26]([C:33]([OH:35])=[O:34])[NH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:23]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)N[C@@H](COc1ccc(-c2cccc(Nc3c(NC4CC4)c(=O)c3=O)c2)cc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)N[C@@H](COc1ccc(-c2cccc(Nc3c(NC4CC4)c(=O)c3=O)c2)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The compound of Example 17 (22.0 mg, 0.04 mmol, 1 equiv) was dissolved in THF/MeOH/H2O 3:1:1 (1 mL) and cooled to 0° C. Solid lithium hydroxide (5.3 mg, 0.22 mol, 5 equiv) was added and the reaction mixture was stirred for two hours at 0° C. The solvents were removed under reduced pressure and the residue was taken up with H2O (2 mL). The resulting solution was acidified with 0.1 N HCl to pH 3 and stirred for 30 min., while a white precipitate was formed. The precipitated title compound was isolated by filtration and dried under vacuum. Yield 15.0 mg, 70.2%. 1H NMR (DMSO, 200 MHz) δ 10.45 (brs, 1H); 9.65 (s, 1H); 8.61 (s, 1H); 7.90-7.71 (m, 1H); 7.65-7.55 (m, 1H); 7.59-7.43 (m, 1H); 7.39-7.17 (m, 3H); 7.02 (d, 1H); 6.84 (d, 1H); 4.49-4.38 (m, 1H); 4.30-4.19 (m, 1H); 4.0 (q, 2H); 3.19-3.02 (m, 1H); 1.17 (t, 3H); 0.85-0.65 (m, 4H). MS (EI) 502 (M+Na), 480 (M+H), 321.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([F:11])[C:5]=1[F:12].[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:14][O:13][CH:3]([O:2][CH3:1])[C:4]1[C:5]([F:12])=[C:6]([F:11])[C:7]([F:10])=[C:8]([C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=1
Reactant: COC(OC)c1ccc(F)c(F)c1F
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)c1cc(C(OC)OC)c(F)c(F)c1F

Procedure:
Starting materials: 1-(dimethoxymethyl)-2,3,4-trifluorobenzene (Intermediate 39) and diethyl oxalate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=2[O:10][N:9]=1.C([Li])CCC.[I:24]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.CCOCC.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[C:16]([I:24])[C:11]=2[O:10][N:9]=1
Reactant: II
Reactant: COc1ccc2c(-c3ccccc3F)noc2c1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(-c3ccccc3F)noc2c1I
Reaction time: 1 h

Procedure:
10 g of 3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole are dissolved in 400 ml of dry THF at -40° C. and treated with 21 ml of 2.2M n-butyllithium. After stirring for one hour, I2 (11.7 g) in 90 ml of ether is added. The reaction mixture is poured into Na2S2O3, then H2O. Drying and concentration gives 3-(2-fluorophenyl)-7-iodo-6-methoxy-1,2-benzisoxazole, mp 135°-138° C.
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:20]3[C:21]([CH3:24])=[N:22][O:23][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[O:6])([CH3:4])[NH2:3].C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:4][C:2]1([CH3:1])[NH:3][C:33](=[O:35])[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[C:20]4[C:21]([CH3:24])=[N:22][O:23][C:19]=4[CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[C:5]1=[O:6]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1noc2cccc(Oc3ccc(NC(=O)C(C)(C)N)cc3)c12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1noc2cccc(Oc3ccc(N4C(=O)NC(C)(C)C4=O)cc3)c12
Reaction time: 0.08 h

Procedure:
2-methyl-N1-{4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}alaninamide (Intermediate 25, 18 mg) was dissolved in 4 ml of ethyl acetate. Triethylamine (0.017 ml, 0.12 mmol) was then added followed by a solution of triphosgene (8.21 mg, 0.028 mmol) in 1.0 ml of ethyl acetate. After stirring for 5 minutes, DMAP (3.4 mg, 0.028 mmol) was added and the reaction mixture was stirred at room temperature for 10 minutes. After quenching with a saturated aqueous solution of NaHCO3, the mixture was extracted two times with ethyl acetate and the collected organic layers were dried over sodium sulphate, filtered and evaporated. The crude obtained was charged on a silica gel column and eluted with c-Hex/EtOAc as eluents (from all 100:0 to 0:100). This afforded 10 mg of the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:16][N:15](C(OCC2C=CC=CC=2)=O)[CH2:14]1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1.C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: O=C(OCc1ccccc1)N1CCC(Oc2ccccc2)C(OCc2ccc3ccccc3c2)C1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: c1ccc(OC2CCNCC2OCc2ccc3ccccc3c2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 47 %

Procedure:
30 mg, 0.065 mmol) of benzyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-phenoxy-piperidine-1-carboxylate were dissolved in 1.6 ml of tetrahydrofuran, cooled to 0° C. and treated in succession within 25 minutes with a solution of 95 ml (0.32 mmol, approximately 5 eq.) of a 70% sodium dihydrido-bis-(2-methoxyethoxy)-aluminate solution (SDMA) in toluene and 1.6 ml of tetrahydrofuran. This reaction solution was stirred at 0° C. for 2.5 hours. Subsequently, it was poured into a mixture of saturated potassium sodium tartrate solution and ice and extracted four times with 50 ml of methylene chloride each time. The organic phases were washed twice with water, evaporated under reduced pressure and dried in a high vacuum. The orange coloured resin was separated on silica gel using a 95:5 mixture of methylene chloride and methanol as the eluent. There were obtained 10 mg (47% of theory) of (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-phenoxy-piperidine as a colourless, amorphous solid; Rf : 0.38 (SiO2, methylene chloride:methanol=9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([CH:13]([CH3:15])[CH3:14])[C:11](=[O:16])[O:10]C2=O)=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.O(C1N=C(CO)C=CC=1)C1C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@H:12]([C:11]([OH:16])=[O:10])[CH:13]([CH3:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)C1C(=O)OC(=O)N1c1ccc(Cl)cc1
Agent: CN(C)c1ccccn1
Agent: OCc1cccc(Oc2ccccc2)n1
Solvent: C1CCOC1
Product: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Reaction time: 20 h

Procedure:
To a solution of 3-(4-chlorophenyl)-4-isopropyl-oxazolidine-2,5-dione (336 mg, 1.32 mmol) and dimethylaminopyridine in 5 ml of dry tetrahydrofuran is added a solution of (6-phenoxy-2-pyridyl)methanol (254 mg, 1.26 mmol) in 3 ml of dry tetrahydrofuran. The reaction mixture is stirred for about 20 hours, under dry air, and then diluted with ether followed by washing with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. After drying over calcium sulfate, solvent is evaporated. The crude product, yellow liquid, is chromatographed on a rotary chromatograph eluting with 15% ether/hexane to give the (6-phenoxy-2-pyridyl)methyl ester of N-(4-chlorophenyl)valine, a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[OH-].[K+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH:29]([OH:32])[CH2:30]Cl)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>C(O)(C)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH2:28][CH:29]([OH:32])[CH2:30][O:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH2:4][CH2:5][CH2:6][C:7]4=[O:12])[CH2:26][CH2:27]2)=[CH:20][CH:21]=1
Reactant: OC(CCl)CN1CCN(c2ccc(Cl)cc2)CC1
Reactant: O=C1CCCc2c(O)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C1CCCc2c(OCC(O)CN3CCN(c4ccc(Cl)cc4)CC3)cccc21
Yield: 79 %

Procedure:
A solution of 4.05 g (0.025 mol) 5-hydroxy-1-oxotetraline in 50 ml isopropanol was mixed with 25 ml 1N isopropanolic potassium hydroxide solution and heated under reflux for ten minutes. Thereafter, the crude 1-(4-chlorophenyl)-4-(3-chloro-2-hydroxypropyl)-piperazine prepared above was added thereto after the whole of the reaction mixture had been dissolved by the addition of 20 ml hot isopropanol and the reaction mixture then stirred under reflux for six hours. During this time, a weak current of nitrogen was passed through the apparatus. After cooling and filtering off with suction the precipitated potassium chloride, the filtrate was acidified by stirring with approximately 7N methanolic hydrochloric acid. Upon cooling, colorless crystals separated out which were filtered off and recrystallized from approximately 85% aqueous ethanol. There were obtained 8.92 g (79% of theory) 5-{3-[4-(4-chlorophenyl)-1-piperazinyl]-2-hydroxypropoxy}-3,4-dihydro-2H-naphthalene-1-one; m.p. 204°-205°C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]1([F:30])[CH2:27][NH:26][C@H:25]([CH2:28][OH:29])[CH2:24]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C:23]([F:30])([F:22])[CH2:24][C@H:25]3[CH2:28][OH:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CC(F)(F)CN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC(F)(F)C[C@H]1CO

Procedure:
The title compound was synthesized in analogy to Example 47b), using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 1 b) and (S)-(4,4-difluoropyrrolidin-2-yl)methanol hydrochloride (CAS 623583-10-8) as starting materials and isolated as colorless oil. MS (EI): m/e=404.5 [MH+].
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[CH:14][N:13]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH2:33]([C:36]1[CH:37]=[N:38]C(Br)=[N:40][CH:41]=1)[CH2:34][CH3:35]>>[CH2:33]([C:36]1[CH:37]=[N:38][C:24]([N:21]2[CH2:22][CH2:23][CH:18]([C:15]3[CH:16]=[CH:17][C:12]([CH2:11][O:10][C:9]4[CH:31]=[CH:32][C:6]([N:1]5[CH:5]=[N:4][N:3]=[N:2]5)=[CH:7][CH:8]=4)=[N:13][CH:14]=3)[CH2:19][CH2:20]2)=[N:40][CH:41]=1)[CH2:34][CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(-n4cnnn4)cc3)nc2)CC1
Reactant: CCCc1cnc(Br)nc1
Product: CCCc1cnc(N2CCC(c3ccc(COc4ccc(-n5cnnn5)cc4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tert-butyl 4-[2-[4-(tetrazol-1-yl)phenoxymethyl]pyridin-5-yl]piperidine-1-carboxylate (Example 17) (56 mg, 0.13 mmol) and 5-propyl-2-bromopyrimidine (36 μL, 0.26 mmol) following a procedure analogous to that in Example 48 as a white crystal (6 mg, yield 10%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[NH:14][C:15](=O)[CH3:16].C([O-])(=O)C.[NH4+:23].C(O)(=O)C>O>[CH3:11][O:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][C:7]=1[O:12][CH3:13])[N:14]=[C:15]([CH3:16])[N:23]=[C:3]2[OH:2]
Reactant: [NH4+]
Reactant: COC(=O)c1cc(OC)c(OC)cc1NC(C)=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2nc(C)nc(O)c2cc1OC
Temperature: 25 °C

Procedure:
To the crude 2-acetylamino-4,5-dimethoxy-benzoic acid methyl ester obtained above was added ammonium acetate (7.98 g, 0.104 mol) and acetic acid (10 mL). The mixture was heated at reflux in a pressure tube until the formation of the desired cyclization product, as indicated by LC/MS: m/z 221 (M+H). After cooling to RT, the reaction mixture was diluted with water, and extracted with EtOAc 3 times. The combined organic phase was basified with aq. NaOH solution, and washed 3 times with EtOAc. The aqueous layer was then acidified with aq. HCl and extracted three times with EtOAc. The combined organic extract was dried over Na2SO4 and concentrated in vacuo, affording 6,7-dimethoxy-2-methyl-quinazolin-4-ol (0.15 g), which was used without further purification. LC/MS: m/z 221 (M+H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH3:37])=[CH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[H][H]>C(#N)C>[Si:1]([O:8][CH2:9][CH:10]([C@@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[CH3:37])[CH3:11])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Reactant: [H][H]
Solvent: O
Solvent: CC#N
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@@H]2C(C)CO[Si](C)(C)C(C)(C)C)cc1

Procedure:
To a solution of (3S,4S)-4-(1-t-butyldimethylsilyloxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (20 g) in acetonitrile (200 ml), there were added 5% platinium on activated carbon (4.0 g) and water (4 ml) under nitrogen atmosphere. The mixture was stirred at 10° C. in a hydrogen gas flow until 2.2 equivalents of hydrogen had been taken up. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate and the washings were combined together and concentrated in vacuo to give (3S,4S)-4-(1-t-butyldimethylsilyloxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di-(p-anisyl)methyl-2-azetidinone as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.Cl.[CH3:11][N:12]1[CH2:19][CH2:18][CH2:17][C@@H:13]1[C:14](O)=[O:15].C1C=CC2N(O)N=NC=2C=1.O.C(Cl)CCl>C(Cl)Cl.C([O-])(O)=O.[Na+].[Na+].[Cl-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:14]([C@H:13]2[CH2:17][CH2:18][CH2:19][N:12]2[CH3:11])=[O:15])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CN1CCC[C@@H]1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CN1CCC[C@@H]1C(=O)NNc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 65.4 %

Procedure:
A mixture of (5-fluoro-pyridin-2-yl)-hydrazine (889 mg, 7.00 mmol), N-methyl-D-proline hydrochloride (1.274 g, 7.7 mmol) and HOBt.H2O (95 mg, 0.70 mmol) in DCM (20 mL) was treated with EDC (1.494 g, 7.8 mmol), and the mixture stirred at RT for 6.5 h. The mixture was then diluted with sat. aq. NaHCO3 solution, NaCl added, and the mixture extracted with DCM (8×20 mL). The combined organics were dried and concentrated in vacuo to give (R)-1-methyl-pyrrolidine-2-carboxylic acid N′-(5-fluoro-pyridin-2-yl)-hydrazide as a pale orange solid (1.09 g). This was dissolved in THF (20 mL) then Ph3P (2.40 g, 9.16 mmol), Et3N (2.6 mL, 18.3 mmol), and hexachloroethane (2.17 g, 9.16 mmol) added sequentially. The mixture was stirred at RT for 4 h, then was filtered, the filter-cake washed with diethyl ether, and the combined organics concentrated in vacuo. The residue was purified on a SCX-2 cartridge (50 g), washing with methanol then eluting basic components with 0.2-2 M ammonia in methanol. Product containing fractions were combined and concentrated in vacuo. The residue was further purified by FCC, using 0-100% EtOAc in cyclohexane, then 8-10% MeOH in EtOAc, to give the title compound as a pale red oil (876 mg, 57%). LCMS (Method 3): Rt 0.55 min, m/z 221 [MH+].
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=[O:31])OC4C=CC=CC=4)[CH:17]=3)=[CH:13][CH:12]=2)=[O:9])[C:4](=[O:34])[N:3]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH3:41][NH:42][CH2:43][CH2:44][OH:45]>CN1C(=O)CCC1>[OH:45][CH2:44][CH2:43][N:42]([CH3:41])[C:23](=[O:31])[NH:22][C:18]1[CH:17]=[C:16]([O:15][C:14]2[CH:32]=[CH:33][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:34])[N:3]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[CH:12][CH:13]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cc2)c(=O)n(-c2ccccc2)n1C
Reactant: CNCCO
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)N(C)CCO)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Yield: 52 %

Procedure:
A mixture of phenyl (4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy)pyridin-2-yl)carbamate (50 mg, 0.093 mmol), NMP (3 mL) and 2-(methylamino)ethanol (8.4 mg, 0.112 mmol) was heated at 40° C. for 2 hours. The solvent was evaporated under reduced pressure at 40° C., and then diluted with EtOAc (10 mL). The resulted mixture was washed with water (7 mL×3), followed by washing with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was washed with EtOAc (2 mL) to give the title compound as a white solid (25 mg, 52%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:19])[CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH2:25]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH:25][C:2]1[C:11]2[C:6](=[C:7]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:19])[CH:3]=1
Reactant: Cc1cc(Cl)c2cccc(Oc3ccccn3)c2n1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(Oc3ccccn3)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methyl-8-(pyridin-2-yloxy)-quinoline and 3,4-dichlorobenzylamine.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:14]([N:16]([C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:15]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CCNCCCCCCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCCCCN(CC)c1ccc(C(F)(F)F)cc1C=O
Temperature: 25 °C
Yield: 66.4 %

Procedure:
2-Fluoro-5-trifluoromethyl-benzaldehyde (1 g) is dissolved in toluene (5 ml) and thereto are added ethyl 7-ethylamino-heptanoate (3.98 g) and potassium carbonate (2.88 g) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=97:3→83:17) to give ethyl 7-[ethyl-(2-formyl-4-trifluoromethyl-phenyl)-amino]-heptanoate (1.29 g). MS (m/z): 374 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][CH2:11][CH:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>ClCCl>[CH2:1]([O:8][C:9](=[O:18])[NH:10][CH2:11][CH:12]([S:14](=[O:16])(=[O:15])[NH:28][CH:25]1[CH2:26][CH2:27][N:22]([CH:19]([CH3:21])[CH3:20])[CH2:23][CH2:24]1)[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N1CCC(N)CC1
Reactant: CC(CNC(=O)OCc1ccccc1)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(NS(=O)(=O)C(C)CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
245 mg (0.84 mmol) of crude (2-chlorosulfonyl-propyl)-carbamic acid benzyl ester in 3 ml dichloromethane were added dropwise to a solution of 143 mg (1.2 equiv.) 1-isopropyl-piperidin-4-ylamine and 214 μl DIPEA in 3 ml dichloromethane. After 2 h stirring at room temperature the reaction mixture was washed with 5 ml of a saturated NaHCO3-solution. The organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure to give crude [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-propyl]-carbamic acid benzyl ester as yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[C:13]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:21][CH3:22])=[O:8])([OH:15])=[O:14]
Reactant: CCO
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1C(=O)O

Procedure:
A mixture of 3-nitrophthalic acid (35 g) in ethanol (300 ml) containing conc. sulfuric acid (20 ml) was heated under reflux for 24 hours. The solvent was evaporated in vacuo and the residue was poured into cold water (700 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with water and shaken with an aqueous solution of potassium carbonate. The aqueous layer was made acidic with hydrochloric acid and the mixture was extracted with methylene chloride. The organic layer was washed with water, then dried, followed by evaporation of the solvent. The resultant solid (29 g, 74%) was used for the subsequent reaction without purification.