Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[C:4](=[O:13])[CH:3]=1.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>CN(C)C=O>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[C:4](=[O:13])[CH:3]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1ccn(-c2ccsc2)c(=O)c1
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccn(-c2ccsc2)c(=O)c1
Temperature: 100 °C

Procedure:
A mixture of 4-methyl-1-(3-thienyl)pyridin-2(1H)-one (0.73 g, 3.8 mmol), tert-butoxybis(dimethylamino)methane (3 mL, 15 mmol), and N,N-dimethylformamide (4 mL) is heated in a 100° C. oil bath for 3 hours and then concentrated to dryness under reduced pressure. A quantitative yield of 4-(2-dimethylamino-vinyl)-1-thiophen-3-yl-1H-pyridin-2-one is carried on without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(Cl)c1Cl

Procedure:
A mixture of 2,3-dichlorobenzoic acid (39.4 g 0.2M) and thionyl chloride (100 mls) was heated to reflux for 21/2 hours. The cooled solution was evaporated down in vacuo and distilled under nitrogen. Yield 35.5 g (85%), b.p. 146°-148° C. at 31 mm of mercury pressure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]=1O)([O-:3])=O.[OH-].[Na+].C1C2C(=[O:42])C3C(=CC=CC=3)C=2C=CC=1.N(C1C=CC=CC=1)=NC1C=CC=CC=1>O.C(O)CCCCCCC>[OH:42][C:13]1[C:14]([C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N+:1]([O-:3])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:10]1
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(N=Nc2ccccc2)cc1
Solvent: O
Solvent: CCCCCCCCO
Product: CC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Temperature: 50 °C

Procedure:
2-nitro-2'-hydroxy-3',5'-di-t-butylazobenzene 23.7 g was added to a mixture of n-octanol 50 g, water 14 g and 97% sodium hydroxide 8.2 g, and the resultant mixture was heated to 65° C. The mixture was then cooled to 50° C., and 9-fluorenone 2.0 g was added thereto. The resultant mixture was stirred at 90°~97° C. for 2 hours, thus almost all of the azobenzene having disappeared to produce 2-(2-hydroxy-3,5-di-t-butylphenyl)benzotriazole-N-oxide. Thus, the reaction of Process (b) was completed.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([C@@H:13]3[CH2:17][NH:16][C@@H:15]([C:18]([OH:20])=O)[CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.[CH3:30][NH:31][CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:30][N:31]([CH3:32])[C:18]([C@H:15]1[CH2:14][C@H:13]([N:11]2[CH:12]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([C:21]4[S:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)[CH:4]=3)[CH:9]=[N:10]2)[CH2:17][NH:16]1)=[O:20]
Reactant: Nc1ncc(-c2cnn([C@@H]3CN[C@@H](C(=O)O)C3)c2)cc1-c1nc2ccccc2s1
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H]1C[C@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)CN1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (2R,4S)-4-[4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-pyrrolidine-2-carboxylic acid (10.00 mg, 0.019 mmol), dimethylamine (0.009 g, 0.2 mmol), TBTU (12.4 mg, 0.0388 mmol), and DMF (1 mL) was charged with DIPEA (0.03 mL, 0.2 mmol) and allowed to stir at rt for 10 min. The solution was used directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.40-2.51 (m, 1H), 2.87 (d, J=6.1 Hz, 1H), 3.04 (s, 3H), 3.09 (s, 3H), 3.72 (br. s., 1H), 3.85 (dd, J=12.5, 6.4 Hz, 1H), 5.02 (t, J=8.7 Hz, 1H), 5.29 (br. s., 1H), 7.42-7.48 (m, 1H), 7.54 (td, J=7.7, 1.3 Hz, 1H), 7.96 (s, 1H), 8.02 (dd, J=15.2, 7.6 Hz, 2H), 8.14 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 8.33 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH2:1]([CH:3]([CH:6]([OH:10])[CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].Cl[Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].C1(NC2CCCCC2)CCCCC1>C(O)C>[CH2:1]([CH:3]([CH:6]([OH:10])[CH2:7][CH2:8][CH3:9])[CH2:4][O:5][Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCO[Si](Cl)(OCC)OCC
Reactant: CCCC(O)C(CC)CO
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCO
Product: CCCC(O)C(CC)CO[Si](OCC)(OCC)OCC
Yield: 50 %

Procedure:
2-Ethyl-1,3-hexanediol was mixed with chlorotriethoxysilane and dicyclohexylamine in a 1:1:1 ratio at 0° C. in absolute ethanol. The resulting product, 2-ethyl-1-triethoxysiloxy-3-hexanol, was obtained in 50% yield and was dissolved to a 10% by weight solution in a 50/50 by volume mixture of ethanol/cyclomethicone.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[OH:13][CH2:14][C:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.[NH2:25][C@@H:26]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:37][CH:36]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[C:15]12([CH2:14][O:13][C:1]([NH:25][C@@H:26]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:39][CH:40]=3)[C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])=[O:2])[CH2:24][CH:19]3[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]3)[CH2:22]1)[CH2:16]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccc(C[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
892 mg (5.5 mmol) of carbonyldiimidazole (CDl) were added to a solution of 830 mg (5 mmol) of 1-hydroxymethyladamantane in 10 ml of tetrahydrofuran and the mixture was stirred overnight at RT. It was then treated with 1 g (2.57 mmol) of tertbutyl (2S)-2-amino-3-(4-(3-ethoxycarbonyl-propyloxy)phenyl)propionate and 442 μl (2.57 mmol) of diisopropylethylamine (DIPEA) and the mixture was stirred overnight at 50° C. After cooling, it was taken up in ethyl acetate and the organic phase was washed successively with 3% strength citric acid solution, sodium hydrogencarbonate solution, 3×H2O and saturated NaCl solution. The organic phase was dried using MgSO4, the drying agent was filtered off and the filtrate was concentrated. The residue was chromatographed on silica gel using CH2Cl2/CH3OH (99/1). 1.19 g (85%) of an oil were obtained, which was employed without further purification for the synthesis of (4.4).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:10](Cl)(=[O:13])[CH:11]=[CH2:12]>C1(C)C=CC=CC=1>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:10](=[O:13])[CH:11]=[CH2:12])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(=O)Cl
Reactant: CCCCNCCCC
Solvent: Cc1ccccc1
Product: C=CC(=O)N(CCCC)CCCC
Temperature: 25 °C

Procedure:
In a 2 liter 3-necked flask were combined 129 g (1 mol) di-(n-butyl)amine (Fisher Scientific) and 0.5 l dry toluene and cooled to 5° C. 46 g (0.5 mol) acryloyl chloride dissolved in 50 ml toluene were added slowly so the temperature remained below 10° C. After the addition the flask was warmed to 25° C. and the precipitate removed by filtration. 1 g DNPD was added, and after concentration on a rotary evaporator the product was distilled at 20 torr and 61°-63° C. Yield 77 g (84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH2:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.N1C=[CH:23][N:22]=[N:21]1.[K].CCOCC.[CH3:31][N:32](C=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH2:12])[CH2:10][N:22]2[CH:23]=[N:32][CH:31]=[N:21]2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: c1c[nH]nn1
Reactant: C=C(c1ccc(F)cc1)C1(c2ccc(F)cc2)CO1
Agent: [K]
Solvent: CCOCC
Product: C=C(c1ccc(F)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1

Procedure:
A mixture of 10.2 g (0.040 mol) of crude 2-(4-fluorophenyl)-2-[1-(4-fluorophenyl)ethenyl]oxirane and 7.0 g (0.065 mol) of potassium triazole in 60 mL of DMF was heated at 60° overnight, then cooled and poured into 100 mL of 1:1 Et2O/nexanes. After washing the organic layer three times with H2O and once with brine, a precipitate formed in the organic layer. Filtering gave 4.8 g of a brown solid which was recrystallized from 500 mL of cyclohexane to yield 2.5 g of a light-tan powder, mp 136°-137°: NMR (CDCl3) δ1.7 (br s, OH); 4.7 (q, 2H); 5.3 (s, 1H); 5.5 (s, 1H); 6.8-7.1 (m, 6H); 7.4 (m, 2H); 7.8 (s, 1H); 7.9 (s, 1H); IR (nujol) 3120 (br), 1900, 1600, 1505, 1220, 1139, 835 cm-1.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]([CH3:11])[O:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][C@@H:21]([CH3:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CN1C(=O)CCC1>O.CCOC(C)=O>[CH3:25][C@@H:21]1[N:22]([C:2]2[C:3]3[CH:10]([CH3:11])[O:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:18])[CH2:20]1
Reactant: CC1OCc2ncnc(Cl)c21
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1OCc2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Temperature: 90 °C
Yield: 88.7 %

Procedure:
A mixture of 4-chloro-5-methyl-5,7-dihydrofuro[3,4-d]pyrimidine (0.340 g, 1.99 mmol), (S)-tert-butyl-3-methylpiperazine-1-carboxylate (0.439, 2.19 mmol), TEA (0.56 mL, 4.0 mmol) and NMP (3 mL) was heat to 90° C. for 4 hours. The reaction was cooled to room temperature and diluted with H2O and EtOAc. The organic layer was separated and the aqueous layer extracted with EtOAc (3×20 mL). The combined organics were dried with MgSO4 and concentrated. The residue was purified by column chromatography (EtOAc) to give (3S)-tert-butyl 3-methyl-4-(5-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.590 g, 89%) as an off white solid. LCMS (APCI+) m/z 235 [M-C5H9O2+H+]; Rt=2.71 min. This material was dissolved in DCM (5 mL) to which was added excess 4 N HCl in dioxane (2 mL) and the reaction allowed to stir at room temperature overnight. The reaction was concentrated to give 5-methyl-4-((S)-2-methylpiperazin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine dihydrochloride (0.540 g, 93%) was an off white solid. 1H NMR (CD3OD, 400 MHz) δ 8.82 (s, 1H), 5.83-5.79 (m, 1H), 5.18-5.05 (m, 1H), 4.48-4.36 (m, 1H), 3.87-3.73 (m, 1H), 3.58-3.52 (m, 1H), 3.48-3.43 (m, 3H), 1.51-1.46 (m, 5H). LCMS (APCI+) m/z 235 [M+H+]; Rt=1.13 min.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([C:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH:28]=2)[CH:9]=1.[Br:50]N1C(=O)CCC1=O>C(#N)C>[Br:50][C:9]1[C:10]([C:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH:28]=2)=[N:11][C:12]2[N:13]([N:14]=[CH:15][C:16]=2[C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=1[NH2:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Solvent: CC#N
Product: Nc1c(Br)c(C2=CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.071 mmol, 50 mg) was charged to a 20 mL scintillation vial containing 1 mL acetonitrile. To this solution was added N-bromosuccinimide (0.078 mmol, 14 mg). The reaction mixture was allowed to stir at room temperature for 1 hour. After 1 hour, the reaction was concentrated in vacuo and the crude intermediate was dissolved in 1 mL TFA. The reaction mixture was stirred for 1 hour at room temperature and concentrated in vacuo to yield 6-bromo-3-(quinolin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][CH2:11][CH2:12][Cl:13])=[C:6]([CH:8]=1)[NH2:7].Cl.[N:15]([O-])=O.[Na+].O.O.Cl[Sn]Cl>C(O)(C(F)(F)F)=O>[ClH:13].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][CH2:11][CH2:12][Cl:13])=[C:6]([NH:7][NH2:15])[CH:8]=1
Reactant: Nc1cc(Br)ccc1SCCCCl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NNc1cc(Br)ccc1SCCCCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-Bromo-2-[(3-chloropropyl)sulfanyl]aniline (0.938 g, 3.3 mmol) was dissolved in TFA (4 mL). The reaction flask was cooled to 0° C. and HCl (15 mL) was added. To the resulting suspension, an aqueous solution of NaNO2 (0.25 g, 3.7 mmol, 3 mL H2O) was slowly added. The flask was warmed to rt and stirred for 2 hrs. The flask was re-cooled to 0° C. and was transferred via cannula to an aqueous solution of SnCl2.2H2O (1.49 g, 6.6 mmol, 3 mL of H2O). The solution was stirred for 3 hours. The precipitate was collected by filtration and the residue was air-dried overnight. 1-{5-bromo-2-[(3-chloropropyl)sulfanyl]phenyl}hydrazine hydrochloride was isolated (0.800 g, 73%) was a light-brown powder. 1H NMR (CD3OD, 300 Mhz) δ7.42 (d, 1H, 8.0 Hz), 7.14-7.21 (m, 2H), 3.66 (t, 2H, 6.2 Hz), 2.97 (t, 2H, 6.9 Hz), 1.90-1.99 (m, 2H) ppm. MS (CI, NH3): 297 (base, M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:21][OH:22])([CH2:19][OH:20])[C:7](=[O:18])[N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.O.[CH3:24][C:25]1C=CC(S(O)(=O)=O)=C[CH:26]=1.COC(OC)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:19][O:20][C:25]([CH3:26])([CH3:24])[O:22][CH2:21]3)[C:7](=[O:18])[N:8]2[C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(CO)(CO)c2ccc(Br)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)OC
Product: CC(C)(C)OC(=O)N1C(=O)C2(COC(C)(C)OC2)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution or tert-butyl 6-bromo-3,3-bis(hydroxymethyl)-2-oxoindoline-1-carboxylate (1.00 g, 2.69 mmol) and 4-methylbenzenesulfonic acid hydrate (0.026 g, 0.134 mmol) in DMF (27 mL) was added 2,2-dimethoxypropane (0.49 mL, 4.03 mmol). The solution was stirred at rt overnight followed by the addition of additional 2,2-dimethoxypropane (0.49 mL, 4.03 mmol) and 4-methylbenzenesulfonic acid hydrate (0.026 g, 0.134 mmol). After stirring at 60° C. for 5 h, the solution was poured into saturated aqueous NaHCO3 and extracted with DCM. The combined organic extracts were purified by column chromatography (eluting with a gradient of 0-30% EtOAc in hexanes) to give tert-butyl 6′-bromo-2,2-dimethyl-2′-oxospiro[[1,3]dioxane-5,3′-indoline]-1′-carboxylate as a white solid. Mass Spectrum (ESI) m/e=434.0 [(M+Na+) (79Br)] and 436.0 [(M+Na+) (81Br)].
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([F:18])[CH:10]=1)(=[O:7])[CH3:6].N1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCC(O)CC>CCOCC>[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH:22]([CH2:23][CH3:24])[CH2:21][CH3:20])=[O:14])=[C:11]([F:18])[CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Reactant: c1ccncc1
Solvent: CCC(O)CC
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCC(CC)OC(=O)c1ccc(OC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
Thionyl chloride in an amount of 60 ml was added to 11.9 g (0.06 mol) of 4-acetoxy-2-fluorobenzoic acid, and the mixture was allowed to react under reflux for 7 hours. Then, excessive thionyl chloride was distilled off, and then 10 ml of pyridine and 3.5 g (0.0420 mol) of 3-pentanol were dropwise added. After the dropwise addition, the mixture was stirred at room temperature over 1 day and night, and then diluted with 200 ml of ether. An organic layer was consecutively washed with diluted hydrochloric acid, with a 1N sodium hydroxide aqueous solution and with water, and dried over magnesium sulfate. The solvent was distilled off, and the resultant crude end product was purified by silica gel column chromatography using hexane/ethyl acetate as a solvent to give 10.7 g (yield 90%) of the end product.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[C:8](Cl)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN1CCCC1=O>[CH2:14]([NH:21][C:8]1[N:7]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:11]([F:12])=[CH:10][N:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)Nc1nc(Cl)ncc1F
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc(NCc2ccccc2)ncc1F
Temperature: 140 °C
Reaction time: 17 h
Yield: 78.4 %

Procedure:
To 5 ml of N-methylpyrrolidone were added 1.8 g of 4-(t-butylamino)-2-chloro-5-fluoropyrimidine and 4.0 g of benzylamine, and the mixture was stirred at 140° C. for 17 hours and separated by adding 300 ml of distilled water and 40 ml of chloroform. The chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated pale yellow crystals were dispersed in diisopropylether and collected by filtration to obtain 1.9 g of the title compound.
Reaction SMILES: C1(OC)C=CC=CC=1.C([O:13][C:14](=[O:36])[C@@H:15]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])(C)(C)C>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[Br:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[CH:25]=[CH:24][C:23]([S:20]([NH:19][C@@H:15]([CH:16]([CH3:18])[CH3:17])[C:14]([OH:36])=[O:13])(=[O:22])=[O:21])=[CH:28][CH:27]=2)=[CH:34][CH:33]=1
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1)C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
To a solution of anisole (4.9 g, 0.045 mol) in trifluoroacetic acid (200 mL) was added in small portions the tert-butyl ester (21.1 g) prepared in Step (c). The solution was stirred at room temperature for 16 hours, then poured over ice. The aqueous suspension was diluted with chloroform, the layers separated, and the organic portion was washed with saturated sodium chloride, dried (MgSO4) and concentrated to dryness. The resulting solid was suspended in hexanes/diethyl ether (9:1) and collected by filtration to give the title compound (17.7 g, 96%) as a white solid, mp 192°-193° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].[C:17](Cl)(=[O:19])[CH3:18]>C(OCC)(=O)C.O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[NH:1][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: NC1Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NC1Cc2ccccc2C1

Procedure:
To a cooled mixture of 2-aminoindan (1.2 mol, 160.00 g) in ethyl acetate (1019 mL) at about 5-7° C. was added a solution of Na2CO3 (2.4 mol, 254.65 g) in water (1528 mL) while stirring, followed by the addition of a solution of acetyl chloride (1.32 mol, 109.19 g) slowly over 2 hours. The reaction temperature was maintained below 10° C. by adjusting the addition rate. During the addition, a suspension was formed. After the addition of acetyl chloride, the mixture was stirred at the room temperature for 1 hour. The precipitated solid was collected by vacuum filtration and the filter cake was washed with water (200 mL), EtOAc (200 mL), and air-dried for 48 hours. The first crop of the product was obtained as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]1[C:18]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[C:28]([O:37][CH3:38])[CH:29]=[CH:30][C:31]=3[O:35][CH3:36])[CH:26]2[CH3:39])=[N:19][C:20]([Cl:24])=[N:21][C:22]=1[CH3:23]>CN(C)C=O>[ClH:24].[CH3:16][C:17]1[C:18]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[C:28]([O:37][CH3:38])[CH:29]=[CH:30][C:31]=3[O:35][CH3:36])[CH:26]2[CH3:39])=[N:19][C:20]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[N:21][C:22]=1[CH3:23]
Reactant: Nc1ccc(F)cc1
Reactant: COc1ccc(OC)c2c1CCN(c1nc(Cl)nc(C)c1C)C2C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(OC)c2c1CCN(c1nc(Nc3ccc(F)cc3)nc(C)c1C)C2C
Product: Cl
Yield: 50.9 %

Procedure:
After 4-fluoroaniline(0.40 ml, 4.13 mmol) and triethylamine(0.58 ml, 4.13 mmol) were added to a solution of 5,6-dimethyl-2-chloro-4-(5,8-dimethoxy-1-methyl-1,2,3,4tetrahydroisoquinolin-2-yl)pyrimidine (1.0 g, 2.87 mmol) in dimethylformamide(5 ml), 0.67 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 25. (Yield: 51.2%)
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:14][CH:15]([F:29])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:24]=[C:25]([NH2:28])[NH:26][N:27]=1>>[F:29][CH:15]([F:14])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:24]=[C:25]([NH:28][C:11]([C@@H:9]2[CH2:10][C@H:8]2[CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:13])[NH:26][N:27]=1
Reactant: Nc1cc(-c2ccccc2OC(F)F)n[nH]1
Reactant: O=C(O)[C@@H]1C[C@H]1CN1CCCCC1
Product: O=C(Nc1cc(-c2ccccc2OC(F)F)n[nH]1)[C@@H]1C[C@H]1CN1CCCCC1
Yield: 25.5 %

Procedure:
The product was prepared according to the general synthetic method for the synthesis of ω-amino-alkanoic acid (1H-pyrazol-3-yl-5-aryl)-amides via the amino acid route, starting from trans (±)-2-piperidin-1-ylmethyl-cyclopropanecarboxylic acid (99.1 mg, 0.6 mmol, 1.3 eq) and 5-(2-difluoromethoxy-phenyl)-2H-pyrazol-3-ylamine (125.7 mg, 0.4 mmol, 1.0 eq). The crude product was purified through SiO2 column with gradient elution from 100% DCM to DCM-NH3 in MeOH 2 N 80:20. The title product (39.9 mg, 23% yield) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[C:14]([OH:16])=O)[CH3:2].[N:17]1([C:23]2[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([C:23]2[N:28]=[CH:27][C:26]([NH:29][C:14]([C:4]3[N:5]=[C:6]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[O:7][C:3]=3[CH2:1][CH3:2])=[O:16])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CCc1oc(-c2ccccc2)nc1C(=O)O
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: CCc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 16 above, 5-ethyl-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 5-ethyl-2-phenyl-oxazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C21H22N4O3 (m/e) 378, obsd 379 (M+H).