Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1.[C:13]1([C@H:19]2[O:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CS(C)=O.O>[OH:21][C@H:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:20][N:1]([CH2:20][C@H:19]([OH:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1
Reactant: NCCCc1ccc(C(N)=O)s1
Reactant: c1ccc([C@@H]2CO2)cc1
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(CCCN(C[C@H](O)c2ccccc2)C[C@H](O)c2ccccc2)s1

Procedure:
30 g of 5-(3-aminopropyl)-2-thiophenecarboxamide and 20.2 ml of (R)-phenylethylene oxide were stirred at 95° for 24 hours in 400 ml of dimethyl sulphoxide. After cooling, the mixture was diluted with 1.3 l of water and extracted three times with about 600 ml of methylene chloride. The methylene chloride solutions were washed twice with water, dried over sodium sulphate and evaporated in vacuo. Chromatography of the residue on silica gel with ether/methanol gave 21 g of 5-[3-[bis[(R)-β-hydroxyphenethyl]amino]propyl]-2-thiophenecarboxamide; UV: ε276 =9900; [α]D =-69° (c=0.1% in dioxan).
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH:13]=[N:14][OH:15].[C:20]([C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[C:20]([C:22]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:15][N:14]=[C:13]([C:12]2[CH:11]=[C:10]([F:9])[CH:18]=[C:17]([F:19])[CH:16]=2)[CH2:28]1)#[N:21]
Reactant: ON=Cc1cc(F)cc(F)c1
Reactant: C=C(C#N)C(=O)OCC
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C#N)CC(c2cc(F)cc(F)c2)=NO1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
NCS (850 mg, 6.37 mmol) was added to a solution of 3,5-difluorobenzaldehyde oxime (1.00 g, 6.37 mmol) in DMF (60 ml), and the mixture was stirred at 40° C. for 1 h. Heating was then switched off, and ethyl 2-cyanoacrylate (1.20 g, 9.55 mmol) and NaHCO3 (561 mg, 6.68 mmol) were added. The mixture was stirred at RT for 2 h, and water (400 ml) was then added. The mixture was extracted with MTBE (3×50 ml), and the combined organic phases were washed with dilute sulfuric acid (0.5 M, ml), dried over Na2SO4 and concentrated. Chromatography of the residue on silica gel using the mobile phase heptane/EtOAc gave 810 mg of slightly contaminated ethyl 5-cyano-3-(3,5-difluorophenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.Cl.[CH2:15]([NH2:18])[CH2:16][CH3:17].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([NH:18][CH2:15][CH2:16][CH3:17])=[O:13])=[CH:7][CH:8]=1
Reactant: CCCN
Reactant: COc1ccc(CCC(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-methoxyphenyl)propionic acid (8.0 g, 44.4 mmol), propylamine hydrochloride (4.24 g, 44.4 mmol), 4-dimethylaminopyridine (0.65 g, 5.33 mmol) and triethylamine (6.9 mL, 48.96 mmol) in methylene chloride (70 mL) was added 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (10.21 g, 53.28 mmol). The reaction mixture was stirred overnight at ambient temperature followed by dilution with methylene chloride. The mixture was washed with 1N hydrochloric acid, 2N sodium hydroxide, water, brine and dried. Evaporation of the solvent yielded the pure product (10.36 g; 95.4%): 1HNMR (400 MHz, CDCl3) δ 7.76 (brs, 1H), 7.10 (d, 2H, J=8.8 Hz), 6.79 (d, 2H, J=8.0 Hz), 3.68 (s, 3H), 2.95 (q, 2H, J=5.6 Hz). 2.71 (t, 2H, J=7.6 Hz), 2.28 (t, 2H, J=7.2 Hz), 1.34 (m, 2H), 0.77 (t, 3H, J=7.2 Hz); ESMS m/z (relative intensity) 222.2 (M+H+, 100).
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)C.O.[NH2:23][NH2:24]>O>[C:2]1([C:1]2[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:24][N:23]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Temperature: 85 °C

Procedure:
22.4 Grams (0.10 moles) of dibenzoylmethane in 200 ml. of isopropyl alcohol are heated to reflux (approximately 85° C.), and to this is added hydrazine hydrate at a rate sufficient to maintain reflux. Thirty minutes after addition, the reaction is complete. The reaction mixture is permitted to cool and is then poured into water. The desired product as a fine white solid precipitates and is filtered, washed with cold water and dried, yielding 22.1 grams of product, melting point 198.5° C. to 200.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:9][CH:6]([CH2:7][O:8]1)[N:5](C(OC(C)(C)C)=O)[CH2:4]2.[CH3:17][C:18](OCl)=[O:19]>C(Cl)Cl>[CH:6]12[CH2:9][C:3]([CH2:2][NH:1][C:18](=[O:19])[CH3:17])([O:8][CH2:7]1)[CH2:4][NH:5]2
Reactant: CC(=O)OCl
Reactant: CC(C)(C)OC(=O)N1CC2(CN)CC1CO2
Solvent: ClCCl
Product: CC(=O)NCC12CNC(CO1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 4-(aminomethyl)-5-oxa-2-azabicyclo[2.2.1]heptane-2-carboxylate (Wuxi AppTec, CAS 1357351-98-4) (50 mg, 0.22 mmol), TEA (44.4 mg, 0.44 mmol) in DCM (2 mL) was added CH3CO2Cl (26 mg, 0.33 mmol) at 0° C. After 2 hours, the solvent was removed under reduced pressure. The residue was treated with TFA in DCM. After stirring for 2 hours at room temperature, the residue was used in next step without purification. MS: calc'd (MH+) 271, measured (MH+) 271.
Reaction SMILES: C1(C)C=CC(S([NH:10][C:11]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:12]=2/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])(=O)=O)=CC=1.ClC1C=C2C(C(CC(O)=O)=[C:35]([C:39]([C:41]3[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=3)=[O:40])N2)=CC=1>>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[C:12]2[C:11](=[CH:22][CH:21]=[C:20]([O:23][C:24]([F:25])([F:26])[F:27])[CH:19]=2)[NH:10][C:35]=1[C:39]([C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=1)=[O:40]
Reactant: COC(=O)/C=C/c1cc(OC(F)(F)F)ccc1NS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Product: COC(=O)Cc1c(C(=O)c2cc(C)ccn2)[nH]c2ccc(OC(F)(F)F)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-2-p-toluenesulfonylamino-5-(trifluoromethoxy)cinnamate (step 2) and 2-bromoacetyl-4-methylpyridine hydrobromide (Preparation is described in step 2 of Example 31).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[CH2:4].[CH:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([CH3:13])[CH:7]=1.S(=O)(=O)(O)O.[OH-].[Na+]>COC(C)(C)C>[CH3:4][C:3]1([CH3:5])[C:10]2[CH:9]=[C:8]([CH3:13])[CH:7]=[CH:6][C:11]=2[O:12][CH2:2]1
Reactant: Cc1ccc(O)cc1
Reactant: C=C(C)CCl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: Cc1ccc2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Chloro-2-methylpropene (9.7 mL) was added dropwise to a mixed solution of p-cresol (CAS #106-44-5, 10.8 g) and concentrated sulfuric acid (2.5 g), and the mixture was stirred at room temperature for one hour and 20 minutes. The reaction solution was ice-cooled and a 5 N sodium hydroxide aqueous solution (20 mL) was added, followed by stirring at 90° C. for 45 minutes. A 5 N sodium hydroxide aqueous solution (10 mL) was added to the reaction solution, and the mixture was stirred at 90° C. for two hours and 45 minutes. The reaction solution was left to cool to room temperature. tert-Butyl methyl ether was added to the reaction solution, and the organic layer was separated. The resulting organic layer was sequentially washed with water (three times) and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Merck silica gel 60 (230-400 mesh); elution solvent:heptane:ethyl acetate=1:0→49:1). The target fraction was concentrated and the resulting residue was purified again by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane). The target fraction was concentrated and the resulting residue was distilled under reduced pressure to obtain 1.87 g of the target compound (bp. 102° C./20 mmHg). The property values of the compound are as follows.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])[C:14]=2[CH:30]=1.CN1CCOCC1>ClCCl>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])[C:14]=2[CH:30]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)c1cccc(CN2CCOc3ccc(N)cc32)c1
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCCC(=O)Nc1ccc2c(c1)N(Cc1cccc(C(=O)OC)c1)CCO2
Reaction time: 0.5 h

Procedure:
Hexanoyl chloride (0.135 g.) was added dropwise to a stirred solution of methyl 3-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)benzoate (X) (0.3 g.), and N-methylmorpholine (0.101 g.) in dichloromethane (30 ml.). After 0.5 hours, the mixture was diluted with dichloromethane, washed with water, dried (MgSO4) and evaporated to give an oil which was filtered through a short column of silica gel using 35:65 v/v ethyl acetate:hexane to give the title compound as a syrup; partial NMR (80 MHz, CDCl3): 0.8-1.9[complex m,9H, CH3 (CH2)3 ]; 2.2(m,2H, CH2CONH); 3.3(m,2H, N.CH2.CH2.O); 3.9(s,3H, OMe); 4.2(m,2H, N.CH2.CH2O); 4.5(s,2H, N.CH2Ar).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[C:17]([CH3:19])[N:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15](=[O:26])[CH:14]=2)[C@H:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:9]1)C1C=CC=CC=1.CC(O)=O>CCO.[Pd]>[C:27]1([C@H:10]2[C@@H:11]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15](=[O:26])[CH:14]=3)[CH2:12][NH:8][CH2:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)Cn1c(C)cc([C@H]2CN(Cc3ccccc3)C[C@H]2c2ccccc2)cc1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Cn1c(C)cc([C@H]2CNC[C@H]2c2ccccc2)cc1=O
Reaction time: 24 h

Procedure:
A mixture of 4-(1-benzyl-cis-3-phenylpyrrolidin-4-yl)-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 5 above (0.30 g, 0.66 mmol), 10% Pd on carbon (100 mg), and HOAc (1 mL) in EtOH (10 mL) was stirred under an atmosphere of hydrogen at ambient pressure and temperature for 24 h. The catalyst was removed by filtration and the filtrate solvent was removed in vacuo. The residue was partitioned between CH2Cl2 and aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and the solvent was removed in vacuo to give the title compound as an oil (0.2 g, HPLC RT=4.98 min, method A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1.[F:22][C@@H:23]1[CH2:27][NH:26][C@H:25]([CH2:28][O:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[CH2:24]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:26]3[CH2:27][C@@H:23]([F:22])[CH2:24][C@H:25]3[CH2:28][O:29][C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=3)=[O:21])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: O=C(O)Cc1ccc2nc(Nc3ccccc3Cl)oc2c1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](F)CN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](F)CN2C(=O)Cc2ccc3nc(Nc4ccccc4Cl)oc3c2)cc1
Temperature: 0 °C
Yield: 66.9 %

Procedure:
In DMF (5 ml), 2-(2-chlorophenylamino)-6-benzoxazolylacetic acid (303 mg, 1.0 mmol), methyl 4-((2S,4S)-4-fluoro-2-pyrrolidinylmethoxy)benzoate (253 mg, 1.0 mmol), EDC•HCl (288 mg, 1.5 mmol), HOBt (203 mg, 1.5 mmol) and triethylamine (0.70 ml, 5.0 mmol) were stirred at room temperature for 14 hours. The reaction mixture was poured in ice water (30 ml), followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby from chloroform/acetone (10/1) eluate fractions, the title compound (360 mg, 67%) was obtained as a colorless amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7](Cl)=[N:6][N:5]2[CH:11]=1.O1C[CH2:15][CH2:14][CH2:13]1.C([Mg]Br)CC.Cl>Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:13][CH2:14][CH3:15])=[N:6][N:5]2[CH:11]=1
Reactant: C1CCOC1
Reactant: Clc1cn2nc(Cl)ccc2n1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC[Mg]Br
Agent: Cl
Solvent: O
Product: CCCc1ccc2nc(Cl)cn2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,6-Dichloroimidazo[1,2-b]pyridazine (0.50 g, 2.66 mmol) and bis(triphenylphosphine)nickel(II) dichloride (0.17 g, 0.27 mmol) were added to tetrahydrofuran (5.0 ml) under a nitrogen stream, and a solution of n-propylmagnesium bromide in tetrahydrofuran (2 M, 1.99 ml, 3.99 mmol) was added dropwise over 10 minutes to the mixture under ice-cooling. The mixture was stirred for 10 minutes under ice-cooling, and the reaction mixture was warmed to room temperature and stirred for 4 hours at room temperature. Cold water (50 ml) was added to the reaction mixture which was then acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid, a saturated saline, an aqueous saturated sodium bicarbonate solution and a saturated saline in this order. The resulting organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated. The concentrated residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7) to give the title compound as white crystals. The yield was 0.21 g (40.4%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[N:6]2[N:5]=[CH:4][N:3]=1.[Br:15]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:15])[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ncnn2c(CCCO)ccc12
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CCCO)cc(Br)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 173.5 %

Procedure:
To a solution of 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-propan-1-ol (5.40 g, 28.09 mmol) in anhydrous DMF (56 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (3.96 g, 13.9 mmol, 0.50 eq) proportionwise at −50° C. The reaction mixture was warmed to 0° C. and stirred at 0° C. for 2 h. The reaction mixture was quenched with water and poured into EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated at reduced pressure. Crystallization from DCM afforded 6.54 g (85.9%) of the desired product as a beige solid. 1H-NMR (DMSO-d6) 7.83 (s, 1H), 6.61 (s, 1H), 4.52 (broad s, 1H), 3.41 (t, 2H), 2.83 (t, 2H), 1.75 to 1.77 (m, 2H); MS LC-MS [M+H]+=271/273, RT=1.40 min.
Reaction SMILES: [CH3:1][S:2]([N:5]([S:7]([NH:10][C:11](=[O:15])OCC)(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3].[NH2:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([CH3:25])[N:18]=1>ClC1C=CC=CC=1>[CH3:1][S:2]([N:5]([S:7]([NH:10][C:11]([NH:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([CH3:25])[N:18]=1)=[O:15])(=[O:8])=[O:9])[CH3:6])(=[O:3])=[O:4]
Reactant: CCOC(=O)NS(=O)(=O)N(C)S(C)(=O)=O
Reactant: COc1cc(C)nc(N)n1
Solvent: Clc1ccccc1
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)n1
Temperature: 50 °C
Yield: 96.4 %

Procedure:
52.0 g of ethyl (N-methylsulfonyl-N-methylamino)sulfonylcarbamate are dissolved in 500 ml of chlorobenzene, 27.8 g of 2-amino-4-methoxy-6-methylpyrimidine are added at room temperature, and the mixture is heated at 50° C. for 5 hours. After cooling to 0° C., the precipitate is filtered off. After washing with 100 ml of chlorobenzene, 68.8 g of the desired product of a purity of 98.9% are obtained; this corresponds to a yield of 96.4% of theory. The melting point of the product is 118°-120° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2([C:16]([NH:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH:20]3[OH:25])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][CH:4]=1.Br[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[C:36]([F:39])([F:38])[F:37]>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2([C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=4[C:36]([F:37])([F:39])[F:38])[CH2:21][C:20]3=[O:25])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:8])=[CH:26][CH:27]=1
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1ccc(F)cc1
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Agent: Cl
Product: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3C(F)(F)F)CC2=O)CCCCC1)c1ccc(F)cc1

Procedure:
In accordance with the same procedure as in Example 85, except that 4-[N-[1-[N-(4-fluorobenzoyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride and 1-bromo-4-fluoro-2-trifluoromethylbenzene was used instead of 1-bromo-4-fluoro-2-thiomethoxybenzene in Step 1 thereof, 137 mg of the titled compound was prepared.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH2:2][CH:3]=[CH2:4].C(=O)([O-])[O-].[K+].[K+].Br[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][OH:18].CN(C)C=O>C1COCC1>[CH3:7][O:6][C:1](=[O:5])[CH2:2][CH2:3][CH2:4][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][OH:18]
Reactant: OCc1ccccc1Br
Reactant: C=CCC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)CCCc1ccccc1CO
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To an ice cooled solution of methyl 3-butenoate (2.0 g, 20 mmol) in THF (20 ml) 9-borabicyclo(3,3,1)nonane (49 ml, 0.5M in tetrahydrofurane) was added within 1 hour. After additional stirring for 4.5 hours potassium carbonate (7.5 g, 54 mmol), 2-bromobenzyl alcohol (3.4 g, 18.2 mmol), dimethylformamide (60 ml) and palladium (dppf)-dichloride (0.665 g, 0.91 mmol) were added and the mixture was stirred at 60° C. overnight. After cooling the mixture was filtered over Celite and evaporated. The residue was purified by column chromatography (eluent hexane/ethyl acetate: 4:1 gradually to 1:1) to yield 2.46 g (65%) of product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](I)[CH3:19]>CC#N>[CH2:18]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:19]
Reactant: CCI
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a solution of 3-bromophenylacetic acid (10.0 g, 46.5 mmol) in CH3CN (150 mL) was added K2CO3 (7.39 g, 53.5 mmol) followed by ethyl iodide (5.6 mL, 70.0 mmol). The mixture was heated at reflux for 2.5 h and was cooled to room temperature. The volatiles were removed in vacuo and water was added. The aqueous solution was extracted with EtOAc (3×) and the combined organic extracts were washed with brine. The organic solution was dried (MgSO4), filtered, and concentrated to provide (3-bromo-phenyl)-acetic acid ethyl ester (9.30 g) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 1H), 7.38 (m, 1H), 7.21-7.16 (m, 2H), 4.14 (q, 2H), 3.56 (s, 2H), 1.24 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([OH:27])=O)[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[NH:36]1[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:36]5[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]5)=[O:27])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: N#CC1CNC1
Agent: Cl
Product: CC1Cc2ccc(-c3ccnc(C(=O)N4CC(C#N)C4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61A starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61A, Step 2) and azetidine-3-carbonitrile hydrochloride (Astatech, Cat. No. 52028). (M+H)+: m/z=524.3.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:4]=[N:3]1.[CH3:21][O:22][CH:23]([O:32][CH3:33])[CH2:24][NH:25][C@@H:26]([CH2:28][CH2:29][CH2:30][CH3:31])[CH3:27].C(OCC)(=O)C>CCCC(C)C>[CH3:21][O:22][CH:23]([O:32][CH3:33])[CH2:24][N:25]([C@@H:26]([CH2:28][CH2:29][CH2:30][CH3:31])[CH3:27])[C:15](=[O:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:9]1[CH:18]=[CH:19][CH:20]=[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:8]=1
Reactant: CCCC[C@@H](C)NCC(OC)OC
Reactant: Cn1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Product: CCCC[C@@H](C)N(CC(OC)OC)C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1
Reaction time: 2 h

Procedure:
The subtitled compound (234 mg) was prepared using a similar method to that described in Preparation 3 Step iii) from 3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 2a, Step i)] and (R)—N-(2,2-dimethoxyethyl)hexan-2-amine [Preparation 13] and the reaction mixture was stirred for 2 h. The elution gradient used was 30-50% ethyl acetate in isohexane. 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.62 (s, 1H), 7.36-7.24 (m, 3H), 7.11-7.05 (m, 1H), 4.69-4.63 and 4.41-4.37 (m, 1H), 4.38-4.31 and 3.85-3.76 (m, 1H), 3.94 (s, 3H), 3.85-3.76 (m, 2H), 3.74-3.65 (m, 2H), 3.43-3.37 (m, 6H), 3.33-3.25 (m, 1H), 3.22-3.14 (m, 1H), 2.94-2.85 (m, 2H), 2.80-2.57 (m, 2H), 1.59-1.12 (m, 9H), 0.93-0.85 (m, 3H); a ˜1:1 mixture of rotamers is observed.