Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][OH:23])=[CH:19][CH:18]=1.[OH-].[K+].C1C2C(CCCC2)CCC1>[Cu].C(Cl)(Cl)Cl>[OH:23][CH2:22][CH2:21][C:20]1[CH:24]=[CH:25][C:17]([N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[CH:18][CH:19]=1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: OCCc1ccc(I)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCC2CCCCC2C1
Product: OCCc1ccc(N2c3ccccc3C=Cc3ccccc32)cc1
Temperature: 200 °C
Reaction time: 40 h
Yield: 29.8 %

Procedure:
A mixture of 8.7 g (45 mmol) of 5H-dibenz[b,f]azepine, 12.4 g (50 mmol) of p-iodophenethyl alcohol, 2.8 g (50 mmol) of potassium hydroxide, 4.8 g (75 mmol) of copper powder, and 20 ml of decalin was heated at an external temperature of 200° C. while stirring in a nitrogen stream for 40 hours. The reaction mixture was cooled nearly to room temperature, chloroform was added thereto, followed by filtration using Celite to remove any insoluble matter. The filtrate was concentrated. To remove decalin, n-hexane was added to the residue, followed by filtration. The filter cake was reprecipitated in methanol, and the resulting crude product was purified by silica gel column chromatography to give 4.2 g (30%) of 5-(4-(2-hydroxyethyl)phenyl)-5H-dibenz[b,f]azepine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:13]=[N:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]3[N:13]=[N:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(NC2CCNCC2)nn1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1ccc(NC2CCN(Cc3ccc(C(F)(F)F)cc3)CC2)nn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
To a mixture of 6-(piperidin-4-ylamino)-pyridazine-3-carbonitrile (D3) (0.15 g, 0.7 mmol) and α,α,α-trifluoro-p-tolualdehyde (0.15 ml, 1.1 mmol) in dichloromethane (2 ml), was added sodium triacetoxyborohydride (0.232 g, 1.1 mmol) and acetic acid (0.041 ml). The reaction mixture was then stirred at room temperature for 18 h. A saturated solution of sodium hydrogen carbonate was then added and the organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by HPLC. The desired fractions were collected and the solvent was evaporated in vacuo to yield E7 (0.101 g, 38%) as a solid. C18H18F3N5 requires 361. Found 362 (MH+); mp: 243.1° C.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH2:28])=[O:27].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:22][C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([NH2:28])=[O:27])=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: NC(=O)c1cccc(N)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of the 4-adamantan-1-yl-phenoxy acetic acid (114.6 mg, 0.40 mmol) and 3-amino benzamide (81.7 mg, 0.60 mmol) ware dissolved in DMF (4.0 mL), and were added EDCHCl (115.1 mg, 0.60 mmol), HOBt (81.1 mg, 0.60 mmol) and DIPEA (0.15 mL, 0.60 mmol). The reaction mixture was stirred overnight and then partitioned between Ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:Ethyl acetate:MeOH=9:3:1) gave 3-[2-(4-Adamantan-1-yl-phenoxy)acetyl-amino]-benzamide as a white solid (145.0 mg, 89.6% yield).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([O:20][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=Cc1ccccc1F
Product: CC(C)(C)c1ccc(Oc2ccccc2C=O)cc1
Yield: 77 %

Procedure:
Preparation analogous to Example 12 a) from 2-fluoro-benzaldehyde and 4-tert-butylphenol. Yield: 77%, yellow oil after high vacuum distillation (93°-100° C., 0.9 mbar); TLC (silica gel; hexane/ethyl acetate=1:1; UV): Rf =0.65; 1H-NMR (CDCl3, 200 MHz): 1.35 (s, 9H); 6.75-7.55 (m, 7H); 7.92 (dd, 1H); 10.50 (s, 1H); MS: 254 (M+), 239.
Reaction SMILES: [C:1]1([C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2[O:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(OC)=C(C=CC=1OC)[CH:21]=[O:22]>>[CH3:16][O:15][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([O:13][CH3:14])[CH:11]=[CH:10][C:9]=1[CH:21]=[O:22]
Reactant: COc1cccc(OC)c1-c1ccccc1
Reactant: COc1ccc(C=O)c(OC)c1Cl
Product: COc1ccc(C=O)c(OC)c1-c1ccccc1
Yield: 95 %

Procedure:
Compound 2c was synthesized from 1c in 95% yield using the procedure described for 2a. 1H NMR(acetone-d6): δ 10.28 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.42–7.49 (m, 5H), 7.10 (d, J=8.8 Hz, 1H), 3.89 (s, 3H), 3.48 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([CH:19]=O)=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:26]([NH2:30])(=[O:29])[CH2:27][CH3:28].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:22]([F:24])([F:25])[F:23])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([CH2:19][NH:30][C:26](=[O:29])[CH2:27][CH3:28])=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C=O
Reactant: CCC(N)=O
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)NCc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Yield: 49.7 %

Procedure:
A mixture of 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carbaldehyde (120 mg), propionamide (66 mg), trifluoroacetic acid (68 μl) and triethylsilane (144 μl) in toluene (2 ml) is refluxed overnight. After 20 hours the reaction mixture is concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield N-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-ylmethyl}-propionamide (68 mg, compound 1.5 in Table 1) as a white foam. MS (HPLC/MS): 465 (MH+). Retention time: 1.98 min.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NCCCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1nc(C(=O)NCCCC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 90.3 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol) and 4-aminobutyric acid (97 mg, 0.94 mmol) (Aldrich) in 0.5 M NaOMe/MeOH (1.25 mL, 0.63 mmol) was microwaved at 120° C. for 1 h. Reaction mixture was diluted with water (60 mL), acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 109 mg (0.28 mmol) in 89% yield. LC-MS ESI−: 390.04 (M−1)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:16][NH:17][NH2:18]>CO>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:17]([CH3:16])[NH2:18])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CNN
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(N)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2g of 4,6-dichloropyrimidine were dissolved in 30 ml of methanol, mixed with 1.37 g of triethylamine and 0.63 g of methyl hydrazine and stirred for 2 days at room temperature. 0.1 ml of methyl hydrazine and 0.2 ml of triethylamine were then added and stirred for 4 days at room temperature. After rotating out the solvent, a residue of 2.4 g of crude 6-chloro-4-(1-methyl-hydrazino)-pyrimidine were obtained, which was immediately processed further.
Reaction SMILES: BrC1C=CC(O[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=C(C(C)(C)C)C=1.[C:19]12([C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][C:30]=3[OH:36])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1C=CCCC1>ClCCl>[C:19]12([C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][C:30]=3[O:36][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH2:20][CH:21]3[CH2:27][CH:25]([CH2:24][CH:23]([CH2:22]3)[CH2:28]1)[CH2:26]2
Reactant: Oc1cc(Br)ccc1C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)c1cc(Br)ccc1OC1CCCCO1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1ccc(C23CC4CC(CC(C4)C2)C3)c(OC2CCCCO2)c1

Procedure:
Using the same general procedure as for the preparation of of 4-bromo-2-t-butyl-1-(2-tetrahydropyranoxy) benzene (Compound H), but instead using 12.56 g (40.9 mmol) of 2-(1-adamantyl)-5-bromophenol (Compound G), 1.03 g (4.1 mmol) of pyridinium p-toluenesulfonate, 5.16 g (5.6 ml, 61.3 mmol) of 3,4-dihydro-2H-pyran and 50 ml of dichloromethane produced a clear, orange solution. During aqueous workup, the organic phase was washed with 3×150 ml-portions of sat. aqueous NaHCO3 solution to produce a light yellow solid. Purification by flash chromatography (silica, 3% ethyl acetate in hexane) yielded the title compound as a white solid. PMR (CDCl3):d 1.6-2.1 (21H, m), 3.65-3.72 (1H, m), 3.8-3.93 (1H, m), 5.45 (1H, t, J=2.8 Hz), 7.04-7.08 (2H, m), 7.32 (1H, br s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[Br:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>[C].[Rh].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[Br:23])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(Br)c(C=C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Rh]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c(CC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
A mixture of N-tert-butoxycarbonyl-4-(2-bromo-5-methoxybenzal)piperidine (87.7 g, 0.229 mol), 5% rhodium-carbon (25.6 g), ethyl acetate (150 mL) and ethyl alcohol (150 mL) was stirred at 40° C. for 16 hours under a hydrogen atmosphere. The precipitate was filtered and then washed with ethyl acetate, and the filtrate was concentrated to dryness. The residue was diluted with ethyl acetate (800 mL) and washed with a saturated aqueous sodium chloride solution (100 mL). The dilution was dried over anhydrous magnesium sulfate and then concentrated to dryness to obtain 78.7 g (0.205 mol, 89%) of N-tert-butoxycarbonyl-4-(2-bromo-5-methoxybenzyl)piperidine.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Cl:12])=[C:6]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH:5]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][C:6]=1[O:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23]
Reactant: COC(=O)c1cc(OC)c(Cl)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)cc(OCCc2ccc(Cl)cc2Cl)c1Cl
Temperature: 60 °C
Reaction time: 16 h

Procedure:
0.51 g (1.31 mmol) of 4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-methoxy-benzoic acid methyl ester was dissolved in 15 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1–2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[C@H:24]([C:25]([OH:27])=[O:26])[CH2:23][C:22]3([CH2:32][CH2:31][N:30]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:29][CH2:28]3)[CH2:21]2)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.O[CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=[O:43].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[C@H:24]([C:25]([O:27][CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=[O:43])=[O:26])[CH2:23][C:22]3([CH2:32][CH2:31][N:30]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:29][CH2:28]3)[CH2:21]2)=[CH:38][CH:39]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)CN1CCC2(CC1)C[C@@H](C(=O)O)N(Cc1ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc1)C2
Reactant: CN(C)C(=O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)COC(=O)[C@@H]1CC2(CCN(CC(C)(C)C)CC2)CN1Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
To an N,N-dimethylformamide (1 mL) solution of the compound (80 mg) obtained in Example 32(5), 2-hydroxy-N,N-dimethylacetoamide (CAS Registry Number: 14658-93-6; 77 mg), diisopropylethylamine (39 μL) and N,N,N′,N′-tetramethyl-O-(7-azobenzotriazol-1-yl)uronium hexafluorophosphate (86 mg) were added. The reaction solution was stirred at room temperature for 16 hours. To this solution, an aqueous saturated sodium hydrogen carbonate solution was added, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHROMATOREX NH (trade name), manufactured by Fuji Silysia Chemical Ltd.) (ethyl acetate:methanol=1:0→30:1→15:1) to obtain the title compound (68 mg) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:24][NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32](C)=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:9][C:10]([NH:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1.[OH-:36].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:24][NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([O:36][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:9][C:10]([NH:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1ccc(NC(=O)CC(CNS(=O)(=O)c2ccc(C)cc2)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CC(CNS(=O)(=O)c1ccc(Oc2ccccc2)cc1)c1ccc(Cl)cc1)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of ester 38 (0.065 g, 0.107 mmol) in methanol (1.5 ml) and THF (1.5 ml) was stirred in presence of NaOH 1M (1 ml) for 2 h at 80° C. After cooling to rt, the solution remaining was concentrated in vacuo. HCl 1M (1.5 ml) was added and the formed white solid was filtered, washed with water (10 ml) and dried. The pure acid 40 was obtained without further need for purification (0.050 g, 0.088 mmol, 83%), mp 119-121° C. 1H NMR (400 MHz, CD3OD) δ 2.61 (1H, dd, J 8.4, 14.8 Hz, H—CHCO), 2.82 (1H, dd, J 6.0, 14.8 Hz, H—CHCO), 3.09 (1H, dd, J 7.8, 13.4 Hz, H—CHNH), 3.16 (1H, dd, J 6.4, 13.2 Hz, H—CHNH), 6.99 (2H, d, J 9.2 Hz), 7.06-7.08 (2H, m), 7.17-7.24 (5H, m), 7.47.44 (2H, m), 7.54 (2H, d, J 9.2 Hz), 7.72 (2H, d, J 8.8 Hz), 7.91 (2H, d, J 9.2 Hz). 13C NMR (400 MHz, CD3OD) δ. νmax (pure sample)/(cm−1) 3359 (st) (OH), 1686 (st) (C═O), 1595 (st) (C═O), 1530 (st), 1487 (st), 1410 (md), 1318 (md), 1246 (st), 1150 (st) 1092 (md). MS (API-ES): m/z 563 [M+H]+ (100%), HRMS (API-ES) m/z found 563.10436 [M−H]−.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][S:19](O)(=[O:21])=[O:20]>ClC(Cl)C.C(Cl)Cl>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[CH:10][N:9]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][C:5]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:6][CH:7]=2)[N:13]=1
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)c1ccnc(Oc2ccccc2)n1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(Oc2nccc(C(F)(F)F)n2)cc1
Temperature: 50 °C
Reaction time: 7 h

Procedure:
To a solution of 2-phenoxy-4-trifluoromethylpyrimidine (3.0 g, 12.5 mmol, prepared under a) in dichloroethane (30 ml) was added a solution chlorosulfonic acid (10.2 g, 88 mmol) in DCM (20 ml). The reaction mixture was stirred 7 h at 50° C. Subsequently the reaction mixture was slowly quenched with water and extracted with MTBE. The organic layer was washed with water and dried and the solvent was removed in vacuo. The residue was suspended in n-pentane and stirred for 10 minutes. Filtration yielded 4-(4-trifluoromethylpyrimidin-2-oxy)benzenesulfonyl chloride as a brownish solid (1.5 g). 1H-NMR (CDCl3): δ=7.5 (m, 3H), 8.17 (m, 2H), 8.9 ppm (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[CH:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:23][N:24](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:23]([C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[CH:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(Cl)cc1)C(C)(C)C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(C#N)cc1)C(C)(C)C
Temperature: 130 °C
Yield: 43 %

Procedure:
tert-Butyl 1-(4-chlorophenyl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (Example 2a, 2.30 g, 7.06 mmol) and Zn(CN)2 (0.87 g, 7.4 mmol) were dissolved in DMF (20 mL) under N2 (g). Pd(PPh3)4 (0.86 g, 0.74 mmol) was added and the mixture was heated at 130° C. overnight. The mixture was cooled to rt, diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The product was purified on a silica column (EtOAc:hexane 1:10) to give tert-butyl 1-(4-cyanophenyl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (961 mg, 43%). tert-Butyl 1-(4-cyanophenyl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (961 mg, 3.04 mmol) was dissolved in 1.25 M HCl in MeOH at 0° C. and the mixture was stirred at rt for 8 h. The solvent was removed and the residue dried in vacuo to give 4-(2-amino-3,3-dimethyl-butanoyl)-benzonitrile hydrochloride (110 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C(N(CC)C(C)C)(C)C.Cl.[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH:24]([C:30]([Cl:32])=[O:31])[CH2:23]2>CN(C=O)C>[ClH:32].[N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:30]([CH:24]3[CH:25]4[CH2:28][CH2:29][N:22]([CH2:27][CH2:26]4)[CH2:23]3)=[O:31])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CN2CCC1CC2
Reactant: Nc1ccc2ncccc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2ncccc2c1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
172 mg (1.19 mmol) of 6-aminoquinoline are mixed with 461 mg (3.57 mmol) of N,N-diisopropylethylamine in 3 ml of DMF under argon at 0° C. 250 mg (2.57 mmol) of 3-quinuclidinecarbonyl chloride hydrochloride are dissolved in a little dry DMF and added dropwise to the reaction mixture at 0° C. It is then stirred at room temperature overnight. It is worked up by concentrating and taking up in dichloromethane. The crude product is chromatographed on silica gel 60 (mobile phase: dichloromethane/ethyl acetate 10:1, then dichloromethane/methanol 10:1, 3:1). The product fractions are combined and finally purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water, gradient 1:99→30:70).
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:3].[CH3:12][NH:13][CH2:14][C:15]#[CH:16].[ClH:17]>C(O)C>[ClH:17].[CH3:3][CH:2]([N:13]([CH2:14][C:15]#[CH:16])[CH3:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C#CCNC
Reactant: CCCCCCCCC(C)Br
Agent: Cl
Solvent: CCO
Product: C#CCN(C)C(C)CCCCCCCC
Yield: 100 %

Procedure:
2-Bromodecane (8.84 g, 40 mmoles) and N-methylpropargylamine (5.52 g, 80 mmoles) were heated in absolute ethanol (50 mL) for 72 h. to give, after treatment with 40 mmoles of ethanolic hydrochloric acid, the title compound in a yield of 100% (75% after recrystallization from methanol-ether), m.p.=130°-131° C.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[NH2:19][C:20]1[N:25]=[C:24]([CH3:26])[C:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([OH:37])=[O:36])=[CH:30][CH:29]=2)=[C:22]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[N:21]=1.[CH3:44][N:45]([CH3:49])[CH2:46][CH2:47]O>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:19][C:20]1[N:25]=[C:24]([CH3:26])[C:23]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH2:47][CH2:46][N:45]([CH3:49])[CH3:44])=[O:36])=[CH:32][CH:33]=2)=[C:22]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[N:21]=1
Reactant: CN(C)CCO
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of T3P (1.57M in THF, 0.42 ml) was added to a mixture of the product from example 34 step (viii) (0.15 g), N,N-dimethylethanolamine (0.08 ml), TEA (0.3 ml) and DMAP (0.02 g) in DMF (5 ml) and stirred at rt for 24 h. The mixture was partitioned between DCM/water, the organics separated, washed with aq NaHCO3 soln, brine, dried and evaporated under reduced pressure. The residue was purified by RPHPLC, then the product dissolved in MeCN (10 ml) and PS-TBD (0.1 g) added and left for 2 h. The mixture was filtered, the solvent evaporated under reduced pressure and the residue triturated with isohexane and filtered to afford the title compound, 0.034 g.
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2][CH2:3][C:4](O)=[O:5].C[CH2:18][N:19]=[C:20]=NCCCN(C)C.Cl.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.CNC>O1CCOCC1>[CH2:10]([O:9][C:7](=[O:8])[NH:1][CH2:2][CH2:3][C:4](=[O:5])[N:19]([CH3:20])[CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred, cooled (0° C.) solution of Z-Beta-Ala-OH (1.784 g, 8.0 mmol) in dioxane (20 ml) is added EDCI.HCl (2.145 g, 11.2 mmol), hydroxybenzotriazole (1.08 g, 8.0 mmol) and triethylamine (1.56 ml, 11.2 mmol). After stirring at 0° C. for 30 minutes, dimethylamine (0.397 g, 8.8 mmol) is added and stirring continued for a further hour. The reaction mixture was allowed to warm to room temperature and the solvent is removed in vacuo. Initial purification of the crude residue is carried out by flash chromatography of silica eluting with ethyl acetate. The combined organic factions are washed with water (3×20 ml), brine (1×50 ml) and dried over MgSO4. The solvent is removed in vacuo to yield the titled compound as a pale yellow solid.