Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][C:14]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][CH3:26])=[C:15]([CH3:17])[N:16]=1)(C)(C)C.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34](Cl)(=[O:36])=[O:35]>>[CH2:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([C:14]1[S:13][C:12]([NH:11][CH2:10][CH2:9][CH2:8][NH:7][S:34]([C:30]2[S:29][CH:33]=[CH:32][CH:31]=2)(=[O:36])=[O:35])=[N:16][C:15]=1[CH3:17])=[O:27])[CH3:26]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCc1ccccc1C(=O)c1sc(NCCCNC(=O)OC(C)(C)C)nc1C
Product: CCc1ccccc1C(=O)c1sc(NCCCNS(=O)(=O)c2cccs2)nc1C

Procedure:
The title compound was prepared from {3-[5-(2-Ethyl-benzoyl)-4-methyl-thiazol-2-ylamino]-propyl}-carbamic acid tert-butyl ester and thiophene-2-sulfonyl chloride according to example BF. Off-white oil, 55%. MS (m/e): 448.1 (M+H, 100%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([OH:21])=O)[CH:15]=2)[N:10]=1.C[N:23](C=O)C>ClCCl>[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([NH2:23])=[O:21])[CH:15]=2)[N:10]=1
Reactant: CN(C)C=O
Reactant: COc1ccc2cc(C(=O)O)ccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc2cc(C(N)=O)ccc2n1
Temperature: 25 °C

Procedure:
Oxalyl chloride (10.3 cm3) was added dropwise to a stirred solution of 2-methoxyquinoline-6-carboxylic acid (12.0 g) in dichloromethane (100 cm3) and DMF (0.1 g) at 0°. The mixture was warmed to room temperature and after 2 hours volatile material was removed in vacuo. The residue was taken into dichloromethane (100 cm3), cooled to 0° and treated cautiously with aqueous ammonia solution (30 cm3 of S.G. 0.880). After 2 hours the mixture was concentrated in vacuo and the solid residue was recrystallised from isopropanol to afford 2-methoxyquinoline-6-carboxylic acid amide, m.p. 212°-214°, (7.9 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.[I:28]I>CCO.CCOC(C)=O.S([O-])([O-])(=O)=O.[Ag+2]>[OH:1][C:2]1[C:7]([I:28])=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1
Reactant: II
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(I)c3O)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of the title compound from Example 1 Step B (2.00 g, 5.30 mmol) and silver sulfate (1.653 g, 5.30 mmol) in EtOH (53 mL) was added iodine (1.35 g, 5.30 mmol). The resulting suspension was stirred vigorously at ambient temperature. After 4 h, the reaction mixture was diluted with EtOAc, and the organic phase was washed successively with water, sat. aq. sodium bisulfate, and sat. aq. NaHCO3. The organic phase was then concentrated in vacuo. The title compound was separated from the para-iodo isomer upon purification by flash chromatography on silica gel (0 to 15% EtOAc in hexanes, then 15% EtOAc in hexanes, then 15 to 100% EtOAc in hexanes; the title compound is the later eluting isomer): LCMS m/z 504.5 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 13.08 (s, 1H), 8.17 (s, 1H), 8.10 (t, J=8.0 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.86 (dd, J=7.5, 1.5 Hz, 1H), 7.82 (dd, J=8.0, 1.5 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 6.75 (t, J=8.0 Hz, 1H), 4.33 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][O:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Br:14][C:15]1[N:19]2[N:20]=[C:21](Cl)[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1.[F-].[K+]>CS(C)=O>[Br:14][C:15]1[N:19]2[N:20]=[C:21]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: Fc1cccc(C2COCCN2)c1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1cccc(C2COCCN2c2ccc3ncc(Br)n3n2)c1
Temperature: 180 °C

Procedure:
In step 2-5, a suspension of 3-(3-fluorophenyl)morpholine (1.59 g, 6.9 mmol), 3-bromo-6-chloroimidazo[1,2-b]pyridazine (12-1) (1.5 g, 8.29 mmol) and potassium fluoride (1.6 g, 27.6 mmol) in DMSO (6 mL) was heated at 180° C. for 18 hours while stirring. The resulting solution was cooled to room temperature and purified with HPLC to yield 4-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-3-(3-fluorophenyl)morpholine (2-5) as a yellow foam.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH3:26])[C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:27]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH3:26])[C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:23])([CH3:24])[C:17]=3[CH:25]=2)=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(OCCCCSc2ccccc2)cc2c1NC(=O)OC2(C)C
Reactant: OO
Product: Cc1cc(OCCCCS(=O)c2ccccc2)cc2c1NC(=O)OC2(C)C

Procedure:
Prepared analogously to Example 2 from 6-(4-phenylmercapto-butoxy)-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][CH2:25]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:32]1([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][CH2:25][N:41]3[CH2:40][CH2:39][C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]3)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccccc1C(=O)N1CCC(CCCS(=O)(=O)[O-])(c2ccc(Cl)c(Cl)c2)C1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C(=O)N1CCC(CCN2CCC(C(N)=O)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Yield: 70.9 %

Procedure:
2-[3-(3,4-Dichloro-phenyl)-1-(2-methoxybenzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (323 mg, 0.68 mmol) was dissolved in THF (4 mL) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (165 mg, 0.69 mmol), water (1 mL), and sodium bicarbonate (105 mg, 1.25 mmol) were added and the solution was heated at reflux for 21 hours. The solution was concentrated in vacuo. The aqueous phase was extracted with dichloromethane (3×) and the organic phase was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (30 g) with a gradient from ethyl acetate to 6% methanol in dichloromethane to give 280 mg (73%) of the title compound.
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O.[OH:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[O:18][C:17](=[O:25])[CH:16]=1>CC(C)=O>[CH3:1][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[O:18][C:17](=[O:25])[CH:16]=1
Reactant: O=c1cc(O)cc(C(F)(F)F)o1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cc(C(F)(F)F)oc(=O)c1
Yield: 107.7 %

Procedure:
Sodium carbonate (1.35 g, 13 mmol) and dimethyl sulfate (2.17 g, 17 mmol) were added to a solution of 4-hydroxy-6-trifluoromethylpyran-2-one (3.0 g, 17 mmol) in acetone (50 mL). The mixture was heated under reflux for 3 hours and, after cooling, filtered. Concentration of the filtrate resulted in 2.9 g of crude product as a brown oil. It was possible to obtain 4-methoxy-6-trifluoromethylpyran-2-one (2.74 g, 14 mmol, 83%) as colorless needles with a melting point of 61° C. by crystallization from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]1=[O:22].[C:23](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:23])[C:12]1=[O:22]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-n1ccc2c(Cl)cccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1c(C(F)(F)F)cc(=O)n(-n2ccc3c(Cl)cccc32)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
A mixture of 169B (0.88 g, 2.7 mmol), dry acetonitril (10 mL), potassium carbonate (0.41 g, 2.9 mmol) and methyl iodide (0.88 g, 6.2 mmol) is stirred overnight at room temperature. The solids are removed by filtration. The motherliquor is concentrated under reduced pressure. The residue obtained is purified by flash chromatography (ethyl acetate/petrol ether 2/8) to yield the product as a brown oil (0.23 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([CH3:30])([C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[N:16][N:15]=2)[CH3:13])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C1C=CC2N(O)[N:38]=[N:37]C=2C=1.O.NN>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([CH3:13])([C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:27])[F:28])=[N:16][N:15]=2)[CH3:30])=[C:6]([CH:10]=1)[C:7]([NH:37][NH2:38])=[O:8]
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: NN
Solvent: CC#N
Solvent: O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl}ethoxy)benzoic acid (1.00 g) was suspended in acetonitrile (10 ml), and WSC•monohydrochloride (654 mg) and HOBt (461 mg) were added to thereto, followed by stirring at room temperature for 30 minutes. A mixture of hydrazine monohydrate (1.1 ml) and acetonitrile (10 ml) was ice-cooled and the above reaction solution was added thereto, followed by stirring for 2 hours. The reaction solution was concentrated under reduced pressure and water and saturated aqueous sodium bicarbonate solution were added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=100:1 to 99:5). The resulting solid was washed with diisopropylether to obtain, as a white solid, 5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzohydrazide (817 mg).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH-].[K+].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([CH3:24])=[CH:18]2>CS(C)=O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[C:19]([CH3:24])=[CH:18]2
Reactant: ClCCN1CCOCC1
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)cc(C)n2CCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-chloroethylmorpholine HCl (138 mg, 0.74 mmol) in 0.3 mL DMSO was added pulverized KOH (104 mg, 1.86 mmol), then after 5 min, a solution of 5-methoxy-2-methylindole (138 mg, 0.74 mmol) in 0.2 mL DMSO was added and the reaction stirred at room temperature overnight. The reaction mixture was partitioned between H2O and toluene, and the organic extract washed two times with H2O, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 5% MeOH in CH2Cl2 to give a final yield of 120 mg (0.44 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.47 (s, 3H), 2.49-2.62 (m, 4H), 2.66 (t, J=7.3 Hz, 2H), 3.76 (t, J=4.5 Hz, 4H), 3.89 (s, 3H), 4.18 (t, J=7.3 Hz, 2H), 6.22 (s, 1H), 6.86 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.89, 41.12, 54.15, 55.91, 58.01, 66.98, 99.87, 102.01, 109.45, 110.32, 128.53, 131.82, 137.06, 154.05. MS m/z 275.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[CH:16]=2)[NH:11][N:10]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([C:21]([N:46]4[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: CN1CCNCC1
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)O)c3)cc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)N4CCN(C)CC4)c3)cc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 5.6 %

Procedure:
To a solution of 3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid (25 mg, 72 μmol) in anhydrous DMF (1.5 mL) was added PS-DCC resin (Argonaut Technologies) (180 mg, 0.22 mmol, 1.21 mmol·g−1) and N-methylpiperazine (9.6 μL, 86 μmol). The resulting mixture was stirred at 60° C. for 16 h. The resin was filtered off, washing with dichloromethane and ether and the filtrate concentrated. The residue was dissolved in dichloromethane and treated with a PS-trisamine resin (Argonaut Technologies) (20 mg). The resin was again removed by filtration and washed with dichloromethane and ether. The filtrate was concentrated and the resulting crude product was purified by reverse phase mass-triggered HPLC using a gradient of acetonitrile in water containing 0.1% of formic acid to afford {3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone (1.7 mg, 4.0 μmol, 6% yield). 1H-NMR (500 MHz, d6-DMSO) δ8.87 (d, 1H), 8.37 (d, 1H), 8.24 (t, 1H), 8.02 (dt, 1H), 7.98 (dt, 1H), 7.68 (dd, 1H), 7.64 (t, 1H), 7.47 (ddd, 1H), 7.23 (d, 1H), 7.11 (dt, 1H), 3.86 (s, 3H). MS: m/z 346 [MH+].
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5].C(N(C(C)C)CC)(C)C.[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:29]([O:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:30])=[O:5]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@@H]1CCCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred suspension of (S)-piperidine-2-carboxylic acid methyl ester hydrochloride salt (5.0 g, 27.8 mmol) in dichloromethane (DCM) (35 mL ) at 0° C. was added diisopropylethylamine (DIPEA) (10.1 mL, 58.4 mmol) followed by N-(benzyloxycarbonyloxy)succinimide (7.63 g, 30.6 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The residue was diluted with DCM and washed with 1.0-M HCl. The organic layer was washed with brine, dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (20% ethyl acetate in hexane) to afford the title compound as a pale yellow oil (7.72, 100%): 1H NMR (400 MHz, CD3OD) δ 1.19–1.88 (5H, m), 2.15–2.28 (1H, m), 2.91–3.12 (1H, m), 3.70–3.73 (3H, 2s), 4.00–4.07 (1H, m), 4.82–4.87 (1H, m), 5.03–5.21 (2H, m), 7.24–7.39 (5H, m); 13C NMR (100 MHz, CD3OD) δ 22.0, 22.1 (CH2), 26.0, 26.1 (CH2), 28.1 (CH2), 43.4, 43.5 (CH2), 53.1 (CH3), 56.2, 56.5 (CH), 68.8, 68.9 (CH2), 129.2 (CH), 129.5 (CH), 129.9 (CH), 138.4 (C), 167.0 (CO), 173.7 (CO).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:17][C@@H:18]([CH2:20][OH:21])[CH3:19]>C(#N)C>[Br:1][C:2]1[C:3]([NH:17][C@H:18]([CH3:19])[CH2:20][OH:21])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: C[C@@H](N)CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H](CO)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 22.8 g (100 mmol) of 5-bromo-2,4-dichloropyrimidine in 100 ml of acetonitrile is mixed at 0° C. first with 17.0 ml (125 mmol) of triethylamine and then with 9.4 g (125 mmol) of D-alaninol. The batch is stirred overnight at room temperature. The precipitate that is formed is suctioned off, washed with water, and completely dried. 21.5 g (81 mmol, corresponding to 81% of theory) of the product is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=1.[Li]CCCC.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][C:23]=1[O:30][CH3:31]>C(OCC)C>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]([C:2]2[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=2)[OH:27])=[CH:24][C:23]=1[O:30][CH3:31]
Reactant: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Reactant: COc1cc(C=O)ccc1F
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C(O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: -72 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene, prepared as described in Procedure 3, (1.00 g, 3.44 mmol) in diethyl ether in (10 mL) at −72° C. was added 2.5 M n-BuLi (1.37 mL, 3.44 mmol) dropwise. Upon completion of addition, the reaction mixture was stirred for 15 minutes at −72° C., then 4-fluoro-3-methoxybenzaldehyde (0.53 g, 3.44 mmol) was added while the reaction mixture temperature was maintained below −52° C. The reaction mixture was stirred for 3 h at −72° C. The reaction mixture was quenched by the addition of 1N HCl and the aqueous portion was extracted with EtOAc (2×). The combined organic layers were washed with sat. NaCl, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by ISCO using a gradient of 0-50% EtOAc/hexane as eluent to yield (4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol (0.83 g, 66% yield). HPLC: RT=3.85 min (Phenomenex Luna C18 5μ column, eluting with 10-90% aqueous methanol containing 0.1% phosphoric acid over a 4 minute gradient, flow rate 4 mL/min, monitoring at 220 nm); 1H NMR (CDCl3): 7.05-6.8 (m, 6H), 5.87 (tt, J=2.8, 52.9 Hz), 5.75 (s, 1H), 3.85 (s, 3H).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12]([CH:14]=[CH2:15])=[O:13].[N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>ClCCl>[OH:17][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12](=[O:13])[CH:14]=[CH2:15]
Reactant: O=Nc1ccccc1
Reactant: C=CC=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=CC(=O)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of acrolein (56 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([OH:17])=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:18][C@H:19]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20]1>>[C:26]1([CH2:25][CH2:24][N:21]2[CH2:22][CH2:23][C@H:19]([NH:18][C:15]([CH:13]3[C:14]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[O:6][C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)=[O:17])[CH2:20]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C1c2ccccc2Oc2ccccc21

Procedure:
9-Xanthenylcarboxylic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-9-xanthenylcarboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[O:16][C:15]([CH3:17])=[N:14][CH:13]=1)[C:6](O)=[O:7].O.[NH2:19][NH2:20]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[O:16][C:15]([CH3:17])=[N:14][CH:13]=1)[C:6]([NH:19][NH2:20])=[O:7]
Reactant: NN
Reactant: COc1cc(C(=O)O)ccc1-c1cnc(C)o1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)NN)ccc1-c1cnc(C)o1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (115 g) was added to a suspension of 3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzoic acid (83.0 g) in THF (1 L) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was cooled to −10° C., hydrazine monohydrate (173 mL) was added, and the mixture was stirred at room temperature for 16 hr. The solvent in the reaction mixture was evaporated under reduced pressure, and water was added to the residue. The resultant solid was collected by filtration, washed with water, dried under reduced pressure, and washed with IPE to give the title compound (85.8 g). 1H NMR (300 MHz, DMSO-d6) δ 2.48 (3H, s), 3.97 (3H, s), 4.53 (2H, brs), 7.44-7.58 (3H, m), 7.68 (1H, d, J=8.0 Hz), 9.85 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([N:22]3[CH2:27][CH2:26][CH:25]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:24][CH2:23]3)=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1.[Sn].[O:37]1[CH2:42][CH2:41]O[CH2:39][CH2:38]1>Cl[Pd](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>[Si:29]([O:28][CH:25]1[CH2:26][CH2:27][N:22]([C:16]2[CH:17]=[N:18][C:19]3[C:14]([CH:15]=2)=[CH:13][C:12]([S:11][C:8]2[N:6]4[CH:7]=[C:2]([C:38]([O:37][CH2:42][CH3:41])=[CH2:39])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=2)=[CH:21][CH:20]=3)[CH2:23][CH2:24]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2cnc3ccc(Sc4nnc5ccc(Br)cn45)cc3c2)CC1
Reactant: C1COCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Sn]
Product: C=C(OCC)c1ccc2nnc(Sc3ccc4ncc(N5CCC(O[Si](C)(C)C(C)(C)C)CC5)cc4c3)n2c1
Temperature: 120 °C
Yield: 90 %

Procedure:
The solution of (76.1) (100 mg, 0.175 mmol) and PdCl2(PPh3)2 (12.30 mg, 0.018 mmol) in 1,4-Dioxane (2 ml) was bubbled with Argon for 5 mins, Tin reagent (95 mg, 0.263 mmol) was added by injection and the mixture was bubbled with Argon for another 5 mins, and the tube was sealed and heated to 120° C. for 3 hr. Monitored the reaction by TLC. The solvent was evaporated and the residue was purified by flash chromatography and eluented with DCM/MeOH (40:1˜20:1) to give pure desired product (76.2) as orange oil (90 mg, yield 90%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.73 (s, 1H), 8.41 (s, 1H), 7.97 (d, 1H), 7.78 (d, 1H), 7.57 (s, 2H), 7.42-7.49 (m, 2H), 7.21 (s, 1H), 4.68 (s, 1H), 4.36 (s, 1H), 3.88-3.98 (m, 3H), 3.48-3.53 (m, 2H), 3.18-3.23 (m, 2H), 1.88-1.91 (m, 2H), 1.66-1.74 (m, 2H), 1.38 (t, 3H), 0.91 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:13]([O:15]CC)=[O:14])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[CH:1]1([C:4]2[N:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:13]([OH:15])=[O:14])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1nc2ccccn2c1C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1nc2ccccn2c1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of compound 12-B (1.04 g, 4.52 mmol) in MeOH (6 mL) and H2O (3 mL) was added sodium hydroxide (0.241 g, 6.04 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was acidified with 2N HCl to pH 4-5 and concentrated in vacuo. The resulting residue was taken up in EtOAc, and the organic layer was washed with H2O and then dried over Na2SO4. The mixture was filtered and the filtrate concentrated in vacuo to give Compound 12-C (0.841 g, 92%), which was used as such in the next reaction; MS m/z (M+H+) 203.