Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:22][C@H:23]1[CH2:25][O:24]1.B(F)(F)F.CCOCC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[CH2:22][C@@H:23]([OH:24])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(OCc2ccccc2)c(Br)c1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(OCc2ccccc2)c(C[C@H](C)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(benzyloxy)-2-bromo-4-methylbenzene (3a) (1.0 g, 3.6 mmol) in THF (20 mL) at −78° C. under N2 atmosphere was added n-BuLi (2.5 M, 1.6 mL, 3.9 mmol), the resulting mixture was stirred for 30 min and (S)-2-methyloxirane (0.38 mL, 5.4 mmol) and BF3.Et2O (0.67 mL, 5.4 mmol) were added to the mixture. It was stirred at −78° C. for 1.5 h and warmed up to ambient temperature, quenched with water (10 mL), extracted with EtOAc (30 mL), washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (10:1) to give the title compound (3b).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:13]([NH:15][S:16]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)(=[O:18])=[O:17])=[O:14])[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[O:7])#[N:2].C(N[C:32]1[CH:37]=CC=[CH:34][CH:33]=1)C>>[C:1]([CH2:3][CH2:4][CH:5]([C:13]([NH:15][S:16]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)(=[O:17])=[O:18])=[O:14])[C:6]([N:8]([CH2:9][CH3:10])[C:11]1[CH:34]=[CH:33][CH:32]=[CH:37][CH:12]=1)=[O:7])#[N:2]
Reactant: CCNc1ccccc1
Reactant: CCN(CC)C(=O)C(CCC#N)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Product: CCN(C(=O)C(CCC#N)C(=O)NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (1.00 g) obtained in Example 153 (3) and N-ethylaniline (379 μL). This was purified by silica gel column chromatography to give the title compound (687 mg) as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:13]2[CH2:14][CH2:15][CH2:16][C:12]=2[N:11]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:10]=1.[OH-].[Na+]>CO>[F:23][C:20]1[CH:19]=[CH:18][C:17]([N:11]2[C:12]3[CH2:16][CH2:15][CH2:14][C:13]=3[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:24])=[O:2])=[N:10]2)=[CH:22][CH:21]=1
Reactant: COC(=O)CCCCCc1nn(-c2ccc(F)cc2)c2c1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCc1nn(-c2ccc(F)cc2)c2c1CCC2
Yield: 81.4 %

Procedure:
A solution of the compound of Example 30 (1.3 g, 4 mmol) in methanol (120 ml) was treated with 1N sodium hydroxide (40 ml) and reacted at ambient temperature for 7 hours. The solution was concentrated, cooled, and acidified. The precipitate was extracted into ethyl acetate, dried and evaporated. The residue was crystallized from ethanol to yield pure title compound (1.03 g), m.p. 64°-67° C.
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=O.[C:23]([CH2:25][C:26]([NH2:28])=[O:27])#[N:24].Cl>CN(C=O)C.CO>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[NH:28][C:26](=[O:27])[C:25]([C:23]#[N:24])=[CH:5][C:6]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][CH:13]=1
Reactant: N#CCC(N)=O
Reactant: Cc1ccc(C(=O)C(=CN(C)C)c2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(-c2[nH]c(=O)c(C#N)cc2-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a slurry of NaH (1.38 g, 60% in mineral oil, 34.41 mmol) in DMF (20 mL) at 0° C. was added a solution of 3-(dimethylamino)-1-(4-methylphenyl)-2-phenylprop-2-en-1-one (2-2; 4.15 g, 15.64 mmol) and 2-cyanoacetamide (1.45 g, 17.2 mmol) in MeOH (1.5 mL) and DMF (40 mL) dropwise over 40 min. The resulting mixture was stirred at 90° C. for 4 h and cooled to rt. The mixture was poured into dilute HCl aqueous solution (240 mL, 0.25 M) and filtered, washed with water (40 mL) and dried in vacuo to afford 6-(4-methylphenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (2-3). 1H-NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 7.15-7.28 (m, 7H), 7.05-7.07 (m, 2H), 2.36 (s, 3H). LRMS m/z (M+H) Calcd: 287.3, found: 287.1.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH2:15][CH2:16][CH3:17])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26].Cl>CN(C=O)C>[CH2:26]([O:14][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][C:10]=1[CH2:15][CH2:16][CH3:17])[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: CCCc1cc(Oc2ccccc2)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccccc2)cc1CCC
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 4-phenoxy-2-propylphenol (PCT Application WO97/28115) in DMF was added potassium carbonate and allyl bromide. The reaction was stirred for 5 h at 50° C., and after cooling was neutralized with 1N HCl and extracted with ethyl acetate. The organic extract was washed with brine, dried over magnessium sulphate, filtered and concentrated to afford an oil which was chromatographed on silica gel (15% ethyl acetate:hexanes) to afford 2-propyl-4-phenoxyphenyl allyl ether.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[NH:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([CH2:15][NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)=[O:29])[CH2:9]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a Parr shaker flask containing compound of step B (14.0 g, 34.5 mmol) dissolved in MeOH (50 mL) was added Palladium hydroxide (2.8 g, 20 wt %). The suspension was shaken at rt under hydrogen (55 psi) overnight. The mixture was filtered through celite and concentrated to give the title compound as a white solid; yield 10.5 g, 97%; 1H NMR (CDCl3) δ 9.06 (t, 1H), 8.20 (m, 3H), 7.94 (d, 1H), 7.75 (t, 1H), 4.23 (m, 1H), 3.89 (d, 2H), 3.00-3.22 (m, 4H), 2.82 (m, 1H), 2.05 (m, 1H), 1.73 (m, 1H); MS m/z=316.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:70][CH2:71][CH2:72][OH:73]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:25](=[O:26])[NH:70][CH2:71][CH2:72][OH:73])([CH3:28])[CH3:27])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NCCO)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)phenyl]-2′-[5-fluoro-2-methylphenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg, 0.06 mmol), EDCl (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (1 mL) was added 2-amino-ethanol (11 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (9 mg).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10]C)=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH:12]=[O:13].Br>>[OH:1][C:2]1[C:9]([OH:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH:12]=[O:13]
Reactant: COc1cc(C=O)cc(C=O)c1O
Agent: Br
Product: O=Cc1cc(O)c(O)c(C=O)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
5.0 g of 4-hydroxy-5-methoxy-isophthalaldehyde are treated with 50 ml of constant-boiling hydrobromic acid and heated to boiling under reflux and while stirring under an argon atmosphere for 3 hours. After cooling 50 ml of ice-water are added thereto, and the separated precipitate is filtered under suction and washed with water. The crude product is taken up in ethyl acetate and filtered over 50 g of aluminum oxide (activity grade II). The crystalline material obtained is recrystallized from ethyl acetate/n-hexane. There is obtained 4,5-dihydroxyisophthalaldehyde in the form of slightly orange crystals of m.p. 201°-202°.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=2[C:26](O)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C>C(#N)C>[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][C:25]=2[C:26]([N:5]2[CH2:4][CH2:3][N:2]([C:8]3[CH:17]=[N:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH2:7][CH2:6]2)=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3cnc4ccccc4n3)CC2)c1

Procedure:
Prepared in analogy to example 1.1 (b) from 2-piperazin-1-yl-quinoxaline hydrochloride and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (example 2.3) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a yellowish foam.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][CH:13]([O:29][CH3:30])[C:14]1[N:15]=[CH:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.[Cl:31]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:31][C:16]1[O:17][C:18]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)=[C:14]([CH:13]([O:12][CH3:11])[O:29][CH3:30])[N:15]=1
Reactant: COC(OC)c1ncoc1-c1ccc(C(F)(F)F)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1nc(Cl)oc1-c1ccc(C(F)(F)F)cc1
Temperature: 5 °C
Reaction time: 5.5 h

Procedure:
LiHMDS (1.0 M in THF, 5.4 mL, 5.4 mmol) was added slowly to a solution of Example 52C (1.42 g, 4.94 mmol) in THF (20 mL) at −78° C. After 30 min solid hexachloroethane (1.29 g, 5.44 mmol) was added in one portion, and the reaction mixture was allowed to proceed for 5.5 hr with gradual warming to 5° C. The reaction was quenched with saturated aq NH4Cl solution (10 mL), and the mixture was partitioned between H2O and Et2O. The aqueous phase was extracted once with Et2O, and the combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The result was 1.83 g (115%) of the title compound as a dark yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, J=8.5, 2H), 7.88 (d, J=8.8, 2H), 5.53 (s, 1H), 3.33 (s, 6H). MS (DCI+) m/z 339 (M+NH4).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[CH2:34](OC(OCC)OCC)C.C1CCN2C(=NCCC2)CC1>ClCCCl>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][C:25]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[N:1]=[CH:34]2)[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(NC(=O)c2ccc(Oc3ccccc3)cc2N)ccc1OCCN1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCCl
Product: COc1cc(-n2cnc3cc(Oc4ccccc4)ccc3c2=O)ccc1OCCN1CCCC1

Procedure:
2-Amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide [Example C1] (50 mg, 0.11 mmol) was dissolved in 1,2-dichloroethane (5 ml) and treated with triethylorthoformate [Aldrich] (2 ml) then heated to reflux for 12 h. The mixture was cooled and DBU (0.1 ml) introduced. The solvent was evaporated then the residue purified by flash chromatography on silica gel (eluting with ammonia-methanol-dichloromethane) to obtain the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13]C1C=CC(C(F)(F)F)=CC=1N.CN1C(=O)CCC1.S(Cl)(Cl)(=O)=O>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[C:5]([Cl:13])[C:3]=1[NH2:4]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Solvent: Clc1ccccc1
Solvent: CN1CCCC1=O
Solvent: O=S(=O)(Cl)Cl
Product: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 94 %

Procedure:
A mixture (276 g) of 2-chloro-4-trifluoromethylaniline, 2-chloro-5-trifluoromethylaniline and NMP (0.73 m/m) was mixed with 500 ml chlorobenzene. Sulfuryl chloride (135 g) was added to the mixture at 55-60° C. liquid temperature over a period of 4 hours and the reaction temperature was maintained for further 2 hours. Additional 20.2. g of sulfuryl chloride was added for completion of reaction. Reaction medium on treatment and fractionation gave 2,6-dichloro-4-trifluoromethylaniline, in 94% yield on 2-chloro-4-trifluoromethylaniline.
Reaction SMILES: Cl.Cl.[CH:3]([S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[N:17]=[C:18]([NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]2)[NH:19][C:20](=[O:25])[C:21]=1[C:22]([NH2:24])=[O:23])(=[O:8])=[O:7])([CH3:5])[CH3:4].N1C=CC=CC=1.[S:39](Cl)([CH3:42])(=[O:41])=[O:40]>C(O)C>[CH:3]([S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[N:17]=[C:18]([NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:28]2)[NH:19][C:20](=[O:25])[C:21]=1[C:22]([NH2:24])=[O:23])(=[O:8])=[O:7])([CH3:5])[CH3:4]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(NC2CCCNC2)[nH]c(=O)c1C(N)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(NC2CCCN(S(C)(=O)=O)C2)[nH]c(=O)c1C(N)=O
Reaction time: 1 h

Procedure:
To a mixture of 4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-2-(piperidin-3-ylamino)-1,6-dihydropyrimidine-5-carboxamide dihydrochloride (Example 29) (67 mg) and pyridine (1.3 mL), mesyl chloride (0.10 mL) was added under ice cooling and stirred for 1 hour. After ethanol was added to the reaction system, the reaction system was concentrated. The resulting residue was partitioned using chloroform and saturated aqueous sodium hydrogen carbonate, and the organic layer was dried. The organic layer was concentrated, followed by an azeotropic process with toluene. The resulting residue was solidified with ethyl acetate-hexane. The resulting solid was recrystallized from ethanol to give 4-{[2-(isopropylsulfonyl)phenyl]amino}-2-{[1-(methylsulfonyl)piperidin-3-yl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide (43 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=O.[O:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[O:44][NH2:45]>>[C@@H:25]1([N:7]([CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[C:3]([CH:1]=[N:45][O:44][CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][O:38]3)[CH:4]=2)[C:8]([C:10]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=2[C:22]([OH:24])=[O:23])=[O:9])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Reactant: NOC1CCCCO1
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(C=NOC3CCCCO3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 76E and O-tetrahydro-2H-pyran-2-ylhydroxylamine were processed as described in Example 76F to provide the title compound.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:8]=1)C.[Li+].[OH-].O.[CH2:31]1COCC1>CO>[Br:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][CH:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[C:13]([CH:18]=1)[CH2:12][N:9]1[C:10]([CH3:31])=[CH:11][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:27])=[N:8]1
Reactant: C1CCOC1
Reactant: CCOC(=O)COc1ccn(Cc2cc(Br)ccc2OCC(CC)CC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(CC)COc1ccc(Br)cc1Cn1nc(OCC(=O)O)cc1C
Temperature: 100 °C

Procedure:
To a solution of {1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazol-3-yloxy}-acetic acid ethyl ester, 4, (0.017 g, 0.038 mmol) in a mixture of THF (1 mL) and methanol (0.5 ml) was added a solution of LiOH (0.05 g in 1 ml H2O). The resulting mixture was heated at 100° C. in an Emrys microwave reactor for 15 minutes. The mixture was poured into water (20 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine (30 mL), dried (MgSO4) and the volatiles were removed in vacuo. The crude product was purified on silica to yield 0.016 g of {1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yloxy}-acetic acid, 5 as a white solid.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][C:12]([N:20]([CH3:22])[CH3:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>CO>[CH2:1]([CH:8]1[C:9]2([C:28]3[NH:29][C:30]4[C:35]([C:27]=3[CH2:26][CH2:25][NH:24]2)=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([N:20]([CH3:22])[CH3:21])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(=O)C(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC2(NCCc3c2[nH]c2ccccc32)C(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(±)-2-benzyl-4-dimethylamino-4-phenylcyclohexanone (307 mg, 1 mmol) together with tryptamine (160 mg, 1 mmol) was dissolved in methanol and stirred at RT for 24 h. The solvent was then removed in a vacuum and the residue dissolved in 1,2-dichloroethane (20 ml). The mixture was mixed with trifluoroacetic acid (1.7 ml, 22.8 mmol) and stirred for 24 h at RT. For work up the reaction mixture was mixed with 2N NaOH (20 ml) and stirred for 20 min. The organic phase was separated and the aqueous phase extracted with dichloromethane (4×20 ml). The combined organic phases were dried with MgSO4. The solvent was then concentrated by evaporation in a vacuum. One of the possible diastereoisomers was isolated from the residue obtained (260 mg) by means of chromatographic purification [silica gel 60 G (10 g); ethyl acetate/ethanol 1:1 (80 ml), methanol (60 ml)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[CH2:26]([O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1)[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH2:26]([O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH:38][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:16])([F:14])[F:15])=[C:2]([Cl:1])[CH:3]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: CCOC(=O)Cc1ccc(CN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCOC(=O)Cc1ccc(CNC(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid, Example 26, step 3, was reacted with 4-(aminomethyl)phenylacetic acid ethylester (CAS 17841-69-9) and HBTU at 80° C. 4 h to give the title compound as a white foam. MS (m/e)=569.0 [M+H+].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:19](=[N:32][C:33]1[S:34][C:35](Br)=[C:36]([CH3:38])[N:37]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.O1CCOCC1>[C:19](=[N:32][C:33]1[S:34][C:35]([C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)=[C:36]([CH3:38])[N:37]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1nc(N=C(c2ccccc2)c2ccccc2)sc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(-c2sc(N=C(c3ccccc3)c3ccccc3)nc2C)cc1

Procedure:
4-Acetylphenyl boronic acid (1.8 g, 0.011 mol, 1.1 eq), tetrakistriphenylphosphine palladium(0) (0.7 g, 0.6 mmol), caesium carbonate (9.8 g, 0.03 mol) in water (10 ml), are added to a solution of benzhydrylidene-(5-bromo-4-methyl-thiazol-2-yl)-amine (3.5 g, 0.01 mol) in dioxane (80 ml) and heated at reflux for 6 h. The solvent is removed in vacuo, to yield an oily suspension which is partitioned between DCM (75 ml) and sat. sodium bicarbonate (75 ml). The layers are separated and the organics washed with water (75 ml) and brine (75 ml), dried (MgSO4 and charcoal), filtered and evaporated to a brown solid.
Reaction SMILES: [SnH3][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[O:13]1[C:17]2([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:20]1([OH:23])[CH2:21][CH2:22][C:17]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:18][CH2:19]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: [SnH3]c1ncccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ncccn2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-stannyl pyrimidine (200 mmol, 80 g), prepared as previously described in the literature (Tetrahedron, 1994, 50, 275-284), in THF (1 L) was added n-butyllithium (240 mmol, 150 mL) at −78° C. The reaction was stirred for 30 min at −78° C. and 1,4-dioxa-spiro[4.5]decan-8-one (200 mmol, 30 g) was added. The reaction was allowed to stir overnight while warming to ambient temperature. The reaction was then quenched using NH4Cl and extracted using EtOAc (3×400 mL). The organic layers were combined and dried over MgSO4 and concentrated in vacuo. The crude was taken to the next step.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:12](=O)[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].CC(C)([O-])C.[K+].Cl>C(O)(C)(C)C>[OH:15][C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[CH2:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[OH:11]
Reactant: O=C1CCCc2ccccc21
Reactant: O=Cc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Oc1ccccc1Cc1ccc2ccccc2c1O
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A solution of 1-tetralone (5.85 g, 0.040 mole) and salicylaldehyde (4.88 g, 0.040 mole) in t-butanol (400 mL) was treated with potassium t-butoxide (17.6 g, 0.160 mole) and heated at reflux for 16 hours. After cooling to room temperature, the solution was poured into stirred 1.0N hydrochloric acid. After isolation by extraction with ethyl acetate, the crude product was chromatographed with 4:1 petroleum ether/ether, to provide a tan solid. This was recrystallized (cyclohexane/chloroform) to give the title compound as white needles (5.24 g, 52%), mp 124°-125°.