Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)[NH:8][C:9](=[O:23])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[C:11]=2[CH3:12])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:39][C:40]1[O:44][C:43]([C:45]([O:47][CH3:48])=[O:46])=[CH:42][CH:41]=1>CN(C)C=O.CO>[C:28]([C:27]1[CH:26]=[CH:25][C:24]([CH:7]2[N:8]([CH2:39][C:40]3[O:44][C:43]([C:45]([O:47][CH3:48])=[O:46])=[CH:42][CH:41]=3)[C:9](=[O:23])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)[C:11]([CH3:12])=[C:6]2[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:31][CH:30]=1)#[N:29]
Reactant: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)C3CC3)C2c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 4-{5-(cyclopropylcarbonyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzonitrile (Example 22) (150 mg, 0.35 mmol) and potassium carbonate (98 mg, 0.71 mmol) in dimethylformamide (3 ml) is added methyl 5-(chloromethyl)-2-furoate (92 mg, 0.53 mmol). The suspension is stirred at room temperature overnight (16 h), then additional methyl 5-(chloromethyl)-2-furoate (6.1 mg, 0.35 mmol) and potassium carbonate (49 mg, 0.35 mmol) are added, and the suspension is stirred an additional 72 hours. The reaction mixture is diluted with methanol (5 ml) and purified directly by preparative HPLC (RP 18 column; eluent: acetonitrile/water 10:90→90:10). The title compound is isolated as a brownish amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][C:19]#[N:20]>C(#N)C>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([NH:1][CH2:16][CH2:17][CH2:18][C:19]#[N:20])=[CH:3][CH:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(NCCCC#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
p-Toluidine (10.407 g, 97.116 mmol) was dissolved in anhydrous acetonitrile and, after adding potassium carbonate (49.9 g, 361.272 mmol), stirred at room temperature for 10 minutes. After slowly adding 4-bromobutyronitrile (10.1 mL, 101.972 mmol) to the resultant reaction mixture, reaction was carried out at 100° C. for 2 days. The mixture was cooled to room temperature and the produced solid was removed by filtering. The filtrate was concentrated under reduced pressure. A target compound (13.23 g, 78.2%) was yielded. A target compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:8]([NH2:21])[N:7]=1.C1C(=O)N([Br:30])C(=O)C1.C(Cl)Cl>C(Cl)(Cl)Cl>[Br:30][C:11]1[N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:13]2[C:9]([N:10]=1)=[C:8]([NH2:21])[N:7]=[C:6]([O:5][CH2:4][CH2:3][CH:2]([CH3:22])[CH3:1])[N:14]=2
Reactant: CC(C)CCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)CCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.8 %

Procedure:
To a solution of 2-[(3-methylbutyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (266 mg) in dry chloroform (3.15 mL) at 0° C. was added NBS (163 mg). The reaction was warmed to room temperature and was stirred for 5 h. The reaction was taken up into DCM (20 mL) and extracted with water (20 mL). The organics were separated, dried using a hydrophobic frit and concentrated in vacuo to give the title compound as a green/brown solid (314 mg).
Reaction SMILES: [OH-].[NH4+:2].[O:3]1[CH2:8][CH2:7][N:6]([CH:9]([CH3:15])[C:10](OCC)=[O:11])[CH2:5][CH2:4]1>CO>[O:3]1[CH2:8][CH2:7][N:6]([CH:9]([CH3:15])[C:10]([NH2:2])=[O:11])[CH2:5][CH2:4]1
Reactant: [NH4+]
Reactant: CCOC(=O)C(C)N1CCOCC1
Agent: [OH-]
Solvent: CO
Product: CC(C(N)=O)N1CCOCC1

Procedure:
3.5 g (40 mmole) of morpholine were added to a mixture of 3.6 g (20 mmole) of ethyl 2-bromopropionate and 50 ml of dry benzene, and then the mixture was heated under reflux for 7 hours. At the end of this time, the reaction mixture was filtered, the filtrate was concentrated by evaporation under reduced pressure, and the residue was dissolved in chloroform. The resulting solution was washed with water, dried, and concentrated by evaporation under reduced pressure, to give 3.19 g of ethyl 2-morpholinopropionate. 10 ml of methanol and 10 ml of a concentrated aqueous solution of ammonium hydroxide were then added to 3.1 g (16.6 mmole) of this ethyl 2-morpholinopropionate, and the resulting mixture was heated under reflux for 28 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was dried by heating it under reduced pressure, to give 2-morpholinopropionamide as a precipitate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][NH2:19]>ClCCl>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][NH:19][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1CC(=O)O
Reactant: NCc1cccs1
Solvent: ClCCl
Product: COc1ccccc1CC(=O)NCc1cccs1
Reaction time: 1 h

Procedure:
N,N'-Carbonyldiimidazole (8.1 g) is added to a stirred solution of 2-(2-methoxyphenyl)acetic acid (8.3 g) in anhydrous dichloromethane (80 cc), cooled to +5° C.; stirring of the reaction mixture is continued for 1 hour and a half and (2-thienyl)methylamine (5.1 cc) is then added. Stirring of the reaction mixture is continued for 1 hour at +5° C. and then for 2 hours at ambient temperature. The reaction mixture is then washed with distilled water (2×40 cc); the organic solution is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid residue obtained is washed with isopropyl ether (30 cc), drained and dried. N-(2-Thienyl)methyl-2-(2-methoxyphenyl)acetamide (10.5 g) melting at 84° C. is obtained.
Reaction SMILES: O[C:2]([CH3:15])([CH3:14])[CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5]1.S(Cl)([Cl:18])=O>>[Cl:18][C:2]([CH3:15])([CH3:14])[CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5]1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(O)CC1NC(=O)c2ccccc21
Product: CC(C)(Cl)CC1NC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
1,3-Dihydro-3-(2-hydroxy-2-methylpropyl)-2H-isoindol-1-one (12 g, described in Example 2) is added portionwise to thionyl chloride (72 ml) while stirring at room temperature. After 2 hr the reaction is evaporated and the residue is chromatographed on silica gel using acetone-toluene (3:7). The eluates are evaporated and crystallized from ethyl acetate-diethyl ether to give the title compound (2.2 g); mp 153°-155° C. and Anal. Calcd for C12H14ClNO: C, 64.43% H, 6.31% N, 6.27% and Found: 64.25% H, 6.26% N, 6.17%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][C:13]1=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][C:13]1=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O=C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C1COCCN1c1ccc([N+](=O)[O-])cc1F
Temperature: 120 °C
Reaction time: 6 h
Yield: 53.4 %

Procedure:
3,4-Difluoro-1-nitrobenzene (0.50 mL, 4.52 mmol) was dissolved in 8 mL NMP. To it was added morpholin-3-one (0.91 g, 9.04 mmol) and cesium carbonate (2.95 g, 9.04 mmol). The mixture was stirred at 120° C. for 6 h. It was cooled to RT, diluted with 200 mL EtOAc, washed with brine three times, dried, concentrated in vacuo and subjected to silica flash column (0-30% EtOAc in DCM) to isolate 4-(2-fluoro-4-nitrophenyl)morpholin-3-one (580 mg, 53%). It was dissolved in 200 mL EtOAc and 100 mL MeOH. To it was added 500 mg 10% Pd/C. The mixture was stirred under a hydrogen balloon for overnight. The mixture was filtered through celite, and the solid cake was thoroughly washed with MeOH. The filtrate was concentrated in vacuo to afford 4-(4-amino-2-fluorophenyl)morpholin-3-one in quantitative yield.
Reaction SMILES: S(O)(=O)([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=O.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].N([O-])=O.[Na+].Cl.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.C([O-])(O)=O.[Na+]>[CH3:8][C:7]1[C:6]([NH2:9])=[CH:5][CH:4]=[CH:3][C:12]=1[OH:15]
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: Cc1c(N)cccc1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 500 mL erlenmeyer flask was added sulfanilic acid (14.38 g, 83 mmol), sodium carbonate (4.29 g, 40.5 mmol) and distilled H2O (83 mL), when all of the sulfanilic acid dissolved, the solution was cooled in an ice bath to 0° C. and a solution of sodium nitrite (6.16 g, 89.3 mmol) in H2O (15 mL) was added in one portion. The ice bath was allowed to warm to +15° C. and the mixture was stirred at this temperature 1 h. The reaction mixture was poured onto a mixture of ice (100 g) and 12N HCl (17.4 mL). The ice was allowed to melt and the solid diazonium salt was collected by suction filtration on a scintered glass frit. O-cresol (9.10 g, 84.1 mmol) was dissolved in a solution of NaOH (1.21 g, 30.25 mmol) in H2O (100 mL). This solution was cooled to 0° C. and the solid diazonium salt was added in one portion. This well stirred mixture was maintained at +15° C. for 4 h. The temperature of the mixture was raised to +60° C. and sodium dithionite (35 g, 1.03 mol) was added portionwise. The reaction was allowed to proceed at +60° C. for 15 min. The mixture was cooled to room temperature, diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The EtOAc extract was dried (MgSO4), filtered, concentrated in vacuo and chromatographed on 100 g of silica gel using 1:3 EtOAc-hexane as eluant. There was obtained 2-methyl-3-amino-phenol as a tan solid.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:10]([Cl:20])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[I-:21].[Na+]>CC(C)=O>[I:21][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:10]([Cl:20])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Br)c1ccc(C2CCCCC2)c(Cl)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(I)c1ccc(C2CCCCC2)c(Cl)c1

Procedure:
A mixture of 40.5 g. (0.1 moles) of ethyl α-bromo-3-chloro-4-cyclohexylphenylacetate and 150 g. of sodium iodide in 1 liter of anhydrous acetone is refluxed for 4 hours. The reaction mixture is then evaporated to dryness and extracted with ether. The ether is then washed with water, dried and evaporated to dryness to obtain ethyl α-iodo-3-chloro-4-cyclohexylphenylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:22]=[N:23][C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:25][CH:26]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(Cl)nc1
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(N2CCOCC2)nc1
Temperature: 25 °C

Procedure:
A solution of 5-chloro-2-(6-chloropyridin-3-ylcarbonyl-amino)-N-(5-chloropyridin-2-yl)benzamide (0.2 g) and morpholine (2 mL) in DMSO (2 mL) was heated at 80° C. in a sealed tube overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water, sodium bicarbonate, and dried over sodium sulfate. After evaporation of the solvent, the product was purified by RPHPLC [ethyl acetate/hexane (3:7)]. Yield=0.054 g.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][NH:29][CH3:30]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][N:29]([CH3:30])[CH3:28])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CN(C)CC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N-methylmethanamine (0.5 ml, 2.0 M in MeOH), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 289 (M+, 1), 84 (2), 69 (2), 59 (3), 58 (bp).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[OH:4][CH2:3][CH:2]([NH:1][C:13]([NH:12][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[S:14])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: Cc1ccc(C(N)CO)cc1
Product: Cc1ccc(C(CO)NC(=S)Nc2ccc(-c3ncn(-c4ccc(C(F)(F)F)cc4)n3)cc2)cc1

Procedure:
The title compound was prepared with 2-amino-2-(p-tolyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.39 g, 99%): 1H NMR (300 MHz, CDCl3) δ 8.06 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.7 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 6.76 (t, J=8.5 Hz, 2H), 6.63-6.49 (m, 7H), 5.12-5.00 (m, 1H), 3.56-3.08 (m, 2H), 1.73 (s, 3H); ESIMS m/z 498 ([M+H]+).
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[C:12](=O)([O-:14])[O-:13].[K+].[K+].[C]=O.C(OCC)C>O.CN(C)C=O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl.CCCCCC>[N+:8]([C:7]1[CH:6]=[CH:5][C:4]([C:12]([OH:14])=[O:13])=[C:3]([CH3:11])[CH:2]=1)([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc([N+](=O)[O-])c1I
Agent: Cl[Pd]Cl
Agent: [C]=O
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Yield: 31.2 %

Procedure:
A mixture of 1.0 g (3.8 mmol) of 2-iodo-nitrotoluene, 2.1 g (15.2 mmol) potassium carbonate and 27 mg (0.038 mmol) of palladium(II) dichloride bis(triphenylphosphine) in a mixture of 5 mL of water and 10 mL of N,N-dimethylformamide. This was placed in a Fisher/Porter bottle under 15 psig of carbon monoxide and heated at 70 C for 16 hours. The solution became homogeneous when heated. The reaction was cooled, diethyl ether and water was added, the organic layer separated and discarded. The aqueous layer was acidified with 1N hydrochloric acid, extracted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered and concentrated to yield 0.5 g of crude material. This dissolved in ethyl acetate, hexane added and the resulting brown solid discarded. The filtrate was concentrated, and then recrystallized form diethyl ether/hexane to afford 215 mg of 4-nitro-2-methylbenzoic acid, m/e=182 (M+H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](OC)=[CH:7][C:8](=[O:13])[C:9]([Cl:12])([Cl:11])[Cl:10])(=[O:3])[CH3:2].[Cl:16][C:17]1[C:18]([NH:23][NH2:24])=[N:19][CH:20]=[CH:21][CH:22]=1>C(O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][C:8]([OH:13])([C:9]([Cl:10])([Cl:11])[Cl:12])[N:23]([C:18]2[C:17]([Cl:16])=[CH:22][CH:21]=[CH:20][N:19]=2)[N:24]=1)(=[O:3])[CH3:2]
Reactant: COC(=CC(=O)C(Cl)(Cl)Cl)COC(C)=O
Reactant: NNc1ncccc1Cl
Solvent: CCO
Product: CC(=O)OCC1=NN(c2ncccc2Cl)C(O)(C(Cl)(Cl)Cl)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
27.5 g (0.1 mol) of 5,5,5-trichloro-2-methoxy-4-oxopent-2-en-1-yl acetate and 14.4 g (0.1 mol) of 3-chloro-2-hydrazinopyridine were initially charged in 200 ml of ethanol, and the mixture was stirred at 25° C. for 3 h. The precipitate was filtered off and washed with cyclohexane.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][CH2:11][C@H:12]([CH3:17])[C:13]([O:15]C)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[CH2:1]([O:8][CH2:9][O:10][CH2:11][C@H:12]([CH3:17])[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C)COCOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H](COCOCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (S)-3-benzyloxymethyloxy-2-methylpropionate (1.20 g; 5 mmole) was dissolved in methanol (12 ml), and a lN sodium hydroxide solution (5.5 ml) was added thereto with ice-cooling, followed by stirring at room temperature for overnight. The reaction mixture was diluted with water (30 ml) and washed with ether (20 ml) two times. The aqueous layer was acidified with 6N hydrochloric acid with ice-cooling and extracted with ethyl acetate (30 ml) three times. The extracts were combined together, washed with water and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (S)-3-benzyloxymethyloxy-2-methylpropionic acid.
Reaction SMILES: Br[C:2]1[C:3]([C:23]2[N:27]([CH2:28][CH3:29])[C:26]([CH3:30])=[N:25][CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:22])(=[O:21])[NH:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:31][N:32](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:31]([C:2]1[C:3]([C:23]2[N:27]([CH2:28][CH3:29])[C:26]([CH3:30])=[N:25][CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15](=[O:22])(=[O:21])[NH:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:13][CH:14]=2)=[N:6][CH:7]=1)#[N:32]
Reactant: CN(C)C=O
Reactant: CCn1c(-c2nc(Nc3ccc(S(=O)(=O)NCCOC)cc3)ncc2Br)cnc1C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCn1c(-c2nc(Nc3ccc(S(=O)(=O)NCCOC)cc3)ncc2C#N)cnc1C
Temperature: 120 °C
Yield: 26 %

Procedure:
A suspension of 5-bromo-4-(1-ethyl-2-methylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine (Method 80; 0.35 g, 0.70 mmol), zinc cyanide (0.05 g, 0.42 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.02 g, 0.02 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (0.03 g, 0.05 mmol) in DMF (7 ml, 0.1M) was degassed (N2 purge), then heated at 120° C. for 48 h. The mixture was cooled and filtered through diatomaceous earth, then concentrated in vacuo and the residue was purified by flash silica chromatography DCM:MeOH (97:3) to give the title compound as a yellow oil (80 mg, 26%). NMR 1.22 (t, 3H), 2.52 (s, 3H), 3.15 (q, 2H), 3.27 (s, 3H), 3.42 (t, 2H), 4.41 (q, 2H), 5.08 (t, 1H), 7.75 (d, 1H), 7.83 (d, 1H), 7.90 (s, 1H), 8.18 (s, 1H), 8.68 (s, 1H); m/z 442.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[C:14]2[N:15]=[CH:16][O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].[Pd].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:2]1([C:9]2[C:14]3[N:15]=[CH:16][O:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: Clc1cccc2ocnc12
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: c1ccc(-c2cccc3ocnc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
a 500 mL 2-neck round-bottomed flask was equipped with a reflux condenser and replaced by nitrogen. 70 mL of THF that was dried with 0.11 mol of Mg metal was added to the above flask and then, 0.10 mol of 1-bromobenzene was added in a dropwise fashion. The reaction was significantly exodermic and thus a cooling bath was equipped to reduce the temperature inside the reactor less than 50° C. It was agitated for 2 hours at room temperature, 0.11 mol of zinc chloride was added with 100 mL of THF, and further agitated for 2 hours to obtain a slurry-phase reaction mixture. Another flask was replaced by nitrogen and then 0.10 mol of 4-chlorobenzo[d]oxazole derivative, 0.10 mol of Pd, and 3 mol % of Pd(PPh3)4 were dissolved in 100 mL of THF. The prepared solution was added to the reaction mixture and then agitated 60° C. for 24 hours. After the reaction is complete, the resulting product was placed on a silica gel column to remove an inorganic slurry, and then a THF solution was concentrated under vacuum to obtain 4-phenylbenzo[d]oxazole using column chromatography at a yield of 89%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:11]([N:13]([CH2:18][CH2:19]OS(C)(=O)=O)[S:14]([CH3:17])(=[O:16])=[O:15])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl>CN(C=O)C>[CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:11]([CH3:12])[N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:18][CH2:19][N:25]1[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]([C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)N(CCOS(C)(=O)=O)S(C)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H](COCc2ccccc2)N(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Reaction time: 0.75 h
Yield: 100.2 %

Procedure:
A solution of (2R,3R)-O-benzyl-2-tert-butoxycarbonylamino-3-[N-(2-methanesulfonyloxyethyl)-N-methanesulfonylamino]butanol (2.6 g) in dry DMF (15 ml) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 189 mg) in dry DMF (10 ml) at 4° C. over 20 minutes. The mixture was stirred at same temperature for 45 minutes and then poured into a mixture of ice and 1N HCl (8 ml). The mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl solution, dried over MgSO4 and concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: AcOEt in n-hexane 40% and 50%) to give 2.1 g of (2R,3R)-2-benzyloxymethyl-1-tert-butoxycarbonyl-4-methanesulfonyl-3-methylpiperazine as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:14]3[O:19][CH2:18][CH2:17][N:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:15]3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=O.O[Li].O.[CH3:27][CH:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:29]>>[CH2:20]([N:16]1[CH2:17][CH2:18][O:19][CH:14]([C:9]2[C:8]3[C:12](=[CH:13][C:5]([C:3]([N:33]4[CH2:34][CH2:35][N:30]([CH:28]([CH3:29])[CH3:27])[CH2:31][CH2:32]4)=[O:2])=[CH:6][CH:7]=3)[NH:11][CH:10]=2)[CH2:15]1)[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)N1CCNCC1
Reactant: COC(=O)c1ccc2c(C3CN(CC(C)C)CCO3)c[nH]c2c1
Agent: [Li]O
Solvent: O
Product: CC(C)CN1CCOC(c2c[nH]c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)C1

Procedure:
According to the procedure described for the conversion of an ester functionality to a piperazine amide functionality like in example 72, step 2 the title compound was prepared from 3-(4-isobutyl-morpholin-2-yl)-1H-indole-6-carboxylic acid methyl ester and (after ester cleavage with LiOH.H2O), 1-(2-propyl)-piperazine (commercially available). The title compound was obtained as light brown foam. MS (m/e): 413.4 (MH+).