Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]Cl)[CH:2]=1.[C:11]([O-:14])(=[O:13])[CH3:12].[K+]>CC(C)=O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:11]([O:14][CH2:9][C:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:14][C:11](=[O:13])[CH3:12])[CH:2]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)[O-]
Reactant: ClCc1cccc(CCl)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OCc1cccc(COC(C)=O)c1
Yield: 164.7 %

Procedure:
m-Xylylene dichloride (25.0 g, 143 mmol) and potassium acetate (34.0 g, 171 mmol) were suspended in acetone (125 ml). To the suspension was added benzyltriethylammonium chloride (4.8 g) and the mixture was refluxed for 2.5 hr. The reaction mixture was cooled and filtered. The solvent was evaporated and toluene (50 ml) was added. The toluene layer was washed with water (50 ml) and saturated brine (50 ml) and the solvent was evaporated to give m-xylylene glycol diacetate (31.3 g, 98.7%) as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.[O:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]=[O:22]>C1COCC1>[O:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)[OH:22]
Reactant: O=Cc1ncco1
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Solvent: C1CCOC1
Product: OC(c1ccc(OC2CCCCO2)cc1)c1ncco1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4-(2-Tetrahydro-3-H-pyranoxy)phenylmagnesium bromide (6.7 mmol) in THF (0.5 M) was added dropwise to a solution of oxazole-2-carbaldehyde (5.15 mmol) in THF (8 mL). After it was stirred at room temperature for 2.5 hours, the reaction was quenched with water and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was column chromatographed (silica gel, 1:2 EtOAc/hexane). Compound M11.1 was obtained. MS ESI (pos.) m/e: 276 (M+H). 1H NMR (400 MHz) (DMSO-d6) δ 8.02 (s, 1H); 7.31 (d, J=8.7 Hz, 2H); 7.14 (s, 1H); 6.97-7.01 (m, 2H); 6.27 (d, J=5 Hz, 1H); 5.74 (d, J=5 Hz, 1H); 5.44 (s, 1H); 3.74 (m, 1H); 3.52 (M, 1H); 1.72-1.81 (m, 3H); 1.52-1.60 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=O)=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:17]([C:7]1[N:8]([CH2:12][C:13]2[N:16]=[C:30]([C:29]3[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:35])[F:36])=[CH:34][CH:33]=3)[O:15][N:14]=2)[C:9]2[C:5]([CH:6]=1)=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH2:18][CH3:19]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 150 °C
Yield: 64.1 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.200 g, 0.616 mmol) in anhydrous acetonitrile (6.0 mL) under N2, was added 4-(trifluoromethyl)benzoyl chloride (0.513 g, 2.46 mmol) and N,N-diisopropylethylamine (1.0 mL, 10.4 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.189 g (64% yield) of pure product: MS (ES) m/z 478 (M+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH:6]([O:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24]([CH3:27])(=[O:26])=[O:25])[NH:13][C:12]=2[CH:11]=1)([CH3:8])[CH3:7]>>[CH:6]([O:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24]([CH3:27])(=[O:25])=[O:26])[N:13]([CH2:2][CH2:3][CH2:4][Cl:5])[C:12]=2[CH:11]=1)([CH3:8])[CH3:7]
Reactant: ClCCCBr
Reactant: CC(C)Oc1ccc2c(c1)Nc1cccc(S(C)(=O)=O)c1S2
Product: CC(C)Oc1ccc2c(c1)N(CCCCl)c1cccc(S(C)(=O)=O)c1S2
Yield: 104.2 %

Procedure:
Crude 2-isopropoxy-6-methylsulphonyl-10-(3-chloropropyl)phenothiazine (128 g.) is prepared by reacting 1-bromo-3-chloropropane (100 g.) with 2-isopropoxy-6-methylsulphonylphenothiazine (m.p. 179°-180°C.; 100 g.).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:5]=1[Cl:14].[OH-].[K+]>CO>[Cl:14][C:5]1[C:6]([O:12][CH3:13])=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[C:3]([OH:15])=[O:2]
Reactant: COC(=O)c1cc(OC)cc(OC)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)c(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
Into a solution of 12 g (52.0 mmol) of 2-chloro-3,5-dimethoxy-benzoic acid methyl ester (prepared according to the method of T. R. Kasturi and E. M. Abraham, Indian Journal of Chemistry, 1973; 11:1099-1104) in 40 mL of methanol was added 60 mL (60 mmol) of 1N potassium hydroxide solution. After stirring overnight at room temperature, the methanol was removed in vacuo, and the residue was suspended in 800 mL of water. The aqueous layer was extracted three times with diethyl ether and the acidified with concentrated hydrochloric acid to a pH of 3. The resulting white solid was filtered, washed well with water, and air-dried to give 9.82 g (87%) of the title compound.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC)=[CH:6][CH:5]=1.[Cl-].[CH3:21][O:22][C:23](=[O:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=O)=[CH:26][CH:25]=1.O>N1C=CC=CC=1.O1CCCC1>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]2[N:19]=[C:28]([C:27]3[CH:31]=[CH:32][C:24]([C:23]([O:22][CH3:21])=[O:33])=[CH:25][CH:26]=3)[O:1][N:2]=2)=[CH:9][CH:8]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCCCCCCCOc1ccc(C(=N)NO)cc1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOc1ccc(-c2noc(-c3ccc(C(=O)OC)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
To a solution of N-Hydroxy-4-octyloxybenzamidine (1.89 g) in pyridine (10 ml) was added terephthalic acid monomethyl ester chloride (1.67 g) in tetrahydrofuran (15 ml) dropwise at 0° C. The mixture was stirred at room temperature for 15 minutes, and poured into water. The precipitate was collected by filtration, dried and dissolved in pyridine (10 ml). The solution was refluxed for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with 1N HCl, water and brine. The separated organic layer was dried over magnesium sulfate and the solvents were removed under reduced pressure. The residue was triturated with acetonitrile and collected by filtration. The solid was dried to give Methyl 4-[3-(4-n-hexyloxyphenyl)-1,2,4-oxadiazol-5-yl]benzoate (2.27 g).
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]([OH:15])[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH2:2][CH3:3].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][CH:26]([CH2:29][N:4]([CH:5]2[CH2:6][CH2:7][C:8]3[C:13](=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=3)[CH2:14]2)[CH2:1][CH2:2][CH3:3])[CH2:27][CH2:28]1)=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CCCNC1CCc2ccc(O)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
To a solution of 7-propylamino-5,6,7,8-tetrahydro-naphthalen-2-ol (937 mg, 4.6 mmol) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.46 g, 6.9 mmol) in dichloroethane (40 mL) was added sodium triacetoxyborohydride (2.1 g, 10.12 mmol) in a single portion. The reaction was allowed to stir at room temperature for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc (75 mL) and 5% aq. KOH (75 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford 4-{[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (1.37 g).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[O:6][CH2:5]2.N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].[C:34]([Cu])#[N:35].[C-]#N.[Na+]>O.OS(O)(=O)=O.C1(C)C=CC=CC=1>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][CH2:18][C:7]1([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]2[C:4](=[CH:3][C:2]([C:34]#[N:35])=[CH:10][CH:9]=2)[CH2:5][O:6]1
Reactant: N#C[Cu]
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(N)ccc21
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
5-Amino-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (18 g, 0.06 mole) is dissolved in water (100 ml) and H2SO4(8 ml). NaNO2(4.1 g, 0.06 mole) is dissolved in water (20 ml) and added dropwise below 5° C. The diazotised solution is stirred for 0.5 hour at 0-5° C. pH is brought to 6.5 by adding a saturated solution of Na2CO3. This solution is added to a mixture of water (100 ml) and toluene (120 ml) containing CuCN(6 g, 0.067 mole) and NaCN (10 g, 0.2 mole) at 50-60C°. Stirring is continued for 0.5 hour. The phases are separated and the aqueous phase is further extracted with toluene (100 ml). The combined organic phase is washed with NaCN(10% aq., 2×50 ml). The solvent is removed in vacuo and the residue is chromatograhed on silica gel (ethyl acetate: n-heptane: triethylamine; 85:10:5 ) to give the title compound (6 g, 32%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:14])([CH3:13])[NH:9][CH2:10]2)=[CH:5][C:4]=1[OH:15].N1C=CN=C1.[CH:21]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22].O>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:13])([CH3:14])[NH:9][CH2:10]2)=[CH:5][C:4]=1[O:15][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:21]([CH3:23])[CH3:22]
Reactant: COc1cc2c(cc1O)CC(C)(C)NC2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)NC2
Temperature: 25 °C
Reaction time: 22 h
Yield: 81.6 %

Procedure:
To a solution of 224 (1.25 g, 6 mmol) in DCM (50 ml) was added imidazole (1.73 g, 25.4 mmol) and triisopropylsilyl chloride (2.71 ml, 12.7 mmol). The reaction mixture was stirred at rt for 22 h. Water (30 ml) and Chloroform (30 ml) were added. The layers separated and the aqueous layer extracted with chloroform (3×30 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo. Purification by column chromatography eluting with EtOAc:MeOH:TEA; 10:1:01 afforded the title compound (1.78 g, 81%) as colourless oil. 1H NMR (270 MHz; CDCl3) 1.06 (18H, d, J=6.7 Hz, 6×CH3CH), 1.14 (6H, s, 2×CH3), 1.14-1.28 (3H, m, 3×CH), 2.51 (2H, s, CH2), 3.74 (3H, s, OCH3), 3.89 (2H, s, CH2), 6.46 (1H, s, CH), 6.51 (1H, s, CH). 13C NMR (67.5 MHz; CDCl3) 12.95 (CH3), 18.03 (CH3), 27.76 (CH), 41.17 (CH2), 43.97 (CH2), 48.78 (C(CH3)2), 55.56 (OCH3), 112.96 (CH), 117.39 (CH), 126.24 (C), 126.92 (C), 143.58 (C), 149.34 (C). LC/MS (ES+) tr=2.65 min, m/z 364.36 (M++H).
Reaction SMILES: Cl.[C:2]1([CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:15][C:16]1([CH3:29])[C:20]2([CH2:24][S:25](Cl)(=[O:27])=[O:26])[C:21]([CH2:23][CH:17]1[CH2:18][CH2:19]2)=[O:22]>C(Cl)(Cl)Cl>[CH3:15][C:16]1([CH3:29])[CH:17]2[CH2:18][CH2:19][C:20]1([CH2:24][S:25]([N:11]1[CH2:10][CH2:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:14])[CH2:13][CH2:12]1)(=[O:27])=[O:26])[C:21](=[O:22])[CH2:23]2
Reactant: CC1(C)C2CCC1(CS(=O)(=O)Cl)C(=O)C2
Reactant: Cc1ccccc1N1CCNCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1N1CCN(S(=O)(=O)CC23CCC(CC2=O)C3(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, 0° C. solution of 1-(o-tolyl) piperazine hydrochloride (50.0 g; 235 mmol) and TEA (83 mL; 590 mmol) in chloroform (1000 mL) was added (+)-10-camphorsulfonyl chloride (65.5 g; 260 mmol). The solution was stirred at 0° C. for 1 h and then at ambient temperature for 3 h. The solution was extracted with 5% aqueous HCl (2×500 mL), water (500 mL), and saturated aqueous NaHCO3 (2×500 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The resulting solid was recrystallized from methanol to give the title compound, mp 112°-114° C. (69 g; 75%).
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH2:8][C:9]([OH:11])=O)[C:6](=[O:12])[C:5]([NH:13][CH2:14][C:15]([F:23])([F:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:4][CH:3]=1.C(O)(=O)C(O)=O.[C:30]([N:49]1[CH:53]=[C:52]([C:54]2[CH:61]=[CH:60][CH:59]=[CH:58][C:55]=2[CH2:56][NH2:57])[N:51]=[CH:50]1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[Cl:1][C:2]1[N:7]([CH2:8][C:9]([NH:57][CH2:56][C:55]2[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=2[C:52]2[N:51]=[CH:50][N:49]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:53]=2)=[O:11])[C:6](=[O:12])[C:5]([NH:13][CH2:14][C:15]([F:23])([F:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:4][CH:3]=1
Reactant: O=C(O)Cn1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1=O
Reactant: NCc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1=O)NCc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
A solution of [6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]-acetic acid (25 mg, 0.058 mmol, preparation described in example 17), 2-(1-trityl-1H-imidazol-4-yl)-benzylamine oxalate salt (35 mg, 0.070 mmol, preparation described in example 2), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17 mg, 0.087 mmol), 1-hydroxy-7-azabenzotriazole (12 mg, 0.087 mmol) and diisopropylethylamine (40 ul, 0.23 mmol) in N,N-dimethylformamide (1 ml) was stirred at room temperature overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine. Drying and solvent evaporation gave 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]-N-[2-(1-trityl-1H-imidazol-4-yl)-benzyl]-acetamide; 1H NMR (CDCl3, 300 MHz) δ 9.11 (m, 1H), 8.65 (d, 1H, J=4.6 Hz), 8.02 (s, 1H), 7.80 (m, 1H), 7.61 (m, 1H), 7.47 (m, 1H), 7.38–7.15 (m, 18H), 6.99 (d, 1H, J=1.2 Hz), 6.78 (s, 1H), 6.36 (m, 1H), 4.78 (s, 2H), 4.43 (d, 2H, J=6.4 Hz), 4.14 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH3:10])[CH2:3][NH:4][C:5]([NH:7][CH2:8][CH3:9])=O.S(Cl)(Cl)=O>C(Cl)Cl>[CH2:8]([NH:7][C:5]1[O:11][C:2]([CH3:1])([CH3:10])[CH2:3][N:4]=1)[CH3:9]
Reactant: CCNC(=O)NCC(C)(C)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCNC1=NCC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of N-(2-methyl-2-hydroxypropyl)-N′-ethylurea (7.2 g, 45 mmol) in CH2Cl2 (100 mL) at 0° C. was added a solution of thionyl chloride (5.4 g, 45 mmol) in CH2Cl2 (20 mL). The mixture was warmed to ambient temperature. After 2 hours, the mixture was concentrated in vacuo, and the resulting solid triturated with boiling water. The mixture was cooled to ambient temperature and made basic by addition of saturated aqueous K2CO3. The mixture was extracted with methylene chloride, dried over K2CO3, and concentrated in vacuo to afford 3.2 g (50% yield) of 2-ethylamino-5,5-dimethyloxazoline; NMR (DMSO-d6/TFA) 3.2 (s, 2), 3.0 (q, 2), 1.3 (s, 6), 1.0 (t, 3) ppm.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[O:18][CH:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]([OH:23])[CH2:21][N:22]=2)[CH:14]=[CH:15][CH:16]=1>ClCCCl>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[O:18][CH:19]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:20]([O:23][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:21][N:22]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=C=Nc1ccccc1
Reactant: OC1CN=C(c2cccc(Cl)c2)OC1c1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1CN=C(c2cccc(Cl)c2)OC1c1ccccc1
Yield: 49.1 %

Procedure:
Phenyl isocyanate (1.43 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-(3-chlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (3.55 g) in 1,2-dichloroethane (45 cc). The solution is heated to reflux for 4 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 100 g) contained in a column 2.5 cm in diameter [eluent: cyclohexane/ethyl acetate (7:3 by volume)], collecting 20-cc fractions. Fractions 6 to 11 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-2-(3-chlorophenyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (2.4 g), m.p. 126° C., is obtained.
Reaction SMILES: O1C2=CN=CC=C2C(=O)C1.C(OC([C:16]1[O:25][C:19]2=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=[C:18]2[C:17]=1[OH:26])=O)C>>[Cl:24][C:21]1[N:20]=[C:19]2[O:25][CH2:16][C:17](=[O:26])[C:18]2=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1oc2nc(Cl)ccc2c1O
Agent: O=C1COc2cnccc21
Product: O=C1COc2nc(Cl)ccc21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridin-3(2H)-one (A.2.4.3), 3-hydroxy-6-chlorofuro[2,3-b]pyridine-2-carboxylic acid ethyl ester replacing 3-hydroxyfuro[2,3-c]pyridine-2-carboxylic acid ethyl ester;
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[S:6]([Cl:12])([N:9]=[C:10]=[O:11])(=[O:8])=[O:7]>C1C=CC=CC=1>[Cl:12][S:6]([NH:9][C:10](=[O:11])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7]
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butanol (3.2 g, 36.9 mmol) in benzene (13 mL) was added sulfurisocyanatidoyl chloride (3.5 mL, 36.6 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with hexane. The mixture was cooled in an ice-bath, resulted in white solid precipitation. The solid was filtered, washed with hexane, dried and used in the next step immediately (3.2 g, 41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=O.C(Cl)(=O)C([Cl:17])=O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([Cl:17])=[O:13]
Reactant: O=C(O)CCc1ccc(F)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 3-(2,4-difluorophenyl) propanoic acid (28.7 g, 0.15 mol) and dimethylformamide (5 drops) at ambient temperature was added dropwise oxalyl chloride (50 mL, Aldrich). The mixture was stirred at ambient temperature for 18 h. The excess oxalyl chloride was removed by distillation in vacuo to give 3-(2,4-difluorophenyl)propionyl chloride. A solution of the 3-(2,4-difluorophenyl)propionyl chloride in dichloromethane (300 mL) was added dropwise to a mixture of aluminum chloride (23.4 g, 0.18 mol, Aldrich) in dichloromethane (300 mL) at ice bath temperature. After the addition was completed, the mixture was refluxed for 3.5 h and allowed to come to ambient temperature overnight. The reaction mixture was poured into ice water (1500 mL), the two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed successively with 0.1N aqueous sodium hydroxide and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to give 21.7 g of crude 4.6-difluoro-1-indanone. Chromatography on silica gel with hexanes: dichloromethane (3:1) as eluent gave 10.1 g of a light yellow solid. Recrystallization of 0.5 g from acetone: water mixture gave 0.2 g of 4,6-difluoro-1-indanone as a white solid: mp 97-99° C.; NMR (CDCl3): d 7.02-7.27 (m, 2H), 3.12 (t, 2H), 2.76 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Reactant: CC(C)(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(O)c1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
To a mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol) and 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propan-2-ol (114 mg, 0.44 mmol) in toluene (1.5 mL) and EtOH (1.5 mL) was added 2N aqueous potassium carbonate solution (0.7 mL, 1.4 mmol). The reaction mixture was degassed with N2 for 10 minutes, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.0 mg, 0.018 mmol), and heated to reflux for 16 hours. After cooling to room temperature, the reaction was quenched with 1N NaOH (1 mL). The mixture was stirred for 30 minutes, acidified with 1N HCl to pH 5 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase chromatography (Biotage C18 column, 0-40% MeCN/water) to give the title compound (42 mg, 35% yield) as a solid. MS (ES−) 329.1 (M−H)+. 1H NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 7.74 (s, 1H), 7.55 (d, J=8.20 Hz, 2H), 7.37 (d, J=8.20 Hz, 2H), 1.57 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CCCCCC.[C:27]1([C:33](=[O:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[NH4+].[Cl-]>C1COCC1.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:33]([OH:35])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:34])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccccc1
Reactant: Cc1ccnc(NC(=O)OC(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(CC(C)(O)c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
The solution of (4-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (100 mg, 0.48 mmol) in dry THF (5 mL) is cooled down to −78° C. The 1.6 M n-BuLi in hexane solution (1.5 mL, 2.4 mmol) is added dropwise at −78° C. Then the cooling bath is removed and the mixture is stirred at room temperature for 15 min. The reaction mixture is cooled down to −78° C. again and 1-phenyl-ethanone (0.28 mL, 2.4 mmol) is added. The mixture is stirred for another 30 min at −78° C. and saturated NH4Cl aquaous solution (25 mL) is added. The reaction mixture is then warmed up to room temperature and EtOAc (50 mL) is added along with water (30 mL). The resulting mixture is stirred for 10 min and the aqueous layer is separated and extracted with EtOAc (2×35 ml). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) afforded 140 mg of desired product.