Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[C:12]([Cl:16])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.N#N.Cl[Sn](Cl)(Cl)Cl.ClC[CH:26]([O:29]C(CCl)CCl)CCl.Cl>O.C(Cl)Cl>[Cl:1][C:2]1[C:15]2[C:6](=[C:7]([CH:26]=[O:29])[C:8]3[C:13]([CH:14]=2)=[C:12]([Cl:16])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2cc3cccc(Cl)c3cc12
Reactant: ClCC(CCl)OC(CCl)CCl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N#N
Solvent: ClCCl
Solvent: O
Product: O=Cc1c2cccc(Cl)c2cc2c(Cl)cccc12
Yield: 21 %

Procedure:
1,8-Dichloroanthracene prepared by the method of H. O. House et. al. (J. Org. Chem. 38 1167 (1973)). A 3 L 3-neck flask fitted with overhead mechanical stirrer, thermometer, condenser, and N2 line was charged with 1,8-dichloroanthracene (17.3 g, 70 mmol) and CH2Cl2 (1500 mL). After further cooling with salt-ice bath to 5°, SnCl4 (Aldrich, 98%, 36.5 g, 0.14 mol, 16.4 mL), was added in one portion to the reaction. No temperature change occurred. The pot temperature was kept below 5°, and 1,1-dichloromethylmethylether (Aldrich, 16.09 g, 0.14 mol, 12.60 mL) was added dropwise over 1 h. The resulting suspension was warmed slowly to reflux (37°). Considerable HCl gas evolution occurred during the warming and the early part of the reaction at 37°. The reaction mixture was then cooled to 10° and hydrolysed by careful addition of 1 L of cold H2O. After 4 h the layers were separated and the organic layer filtered, dried with anhydrous Na2SO4 (Mallinckrodt, 100 g) and filtered again and the volume reduced to 100 mL. The clear yellow solution was passed through a 1000 g plug of SiO2 using PhCH3 as the eluting solvent with 500 mL fractions. This chromatography separated unreacted 1,8-dichloroanthracene (11 g, 63%) from the aldehyde and a more polar product. Fractions containing the aldehyde were combined and the PhCH3 removed, to give 5.83 g (21%) of 4,5-dichloro-9-anthracenecarbaldehyde mp 218°-220°, (PhCH3 /CH3OH), (C, H, Cl), (lit. 224°-226°, E. L. Stogryn, J. Med. Chem. 17 563 (1974)).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[OH:15][C:16]([CH3:21])([CH3:20])[C:17](O)=[O:18]>>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:17](=[O:18])[C:16]([OH:15])([CH3:21])[CH3:20])=[CH:10][CH:9]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: CC(C)(O)C(=O)O
Reactant: Nc1ccc(Nc2ccccc2)cc1
Product: CC(C)(O)C(=O)Nc1ccc(Nc2ccccc2)cc1
Temperature: 250 °C
Yield: 88.8 %

Procedure:
A 100 milliliter flask was charged with 18.4 grams (0.10 mole) p-aminodiphenylamine and 10.6 grams (0.102 mole) α-hydroxy isobutyric acid from Example 1. The mixture was heated to 190° C. where dehydration of the amine-acid salt begins. Water was distilled from the mixture as the temperature slowly increased to 250° C. 2.35 milliliters of distillate was collected and the color of the mixture turned from blue-black to clear amber. After cooling the mixture to 190° C., the amber liquid was poured into a crystallizing dish whereupon it immediately crystallized to give 24.0 gram of N-(4-anilinophenyl)-2-hydroxy-isobutyramide (89% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][C:13]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]1)[CH2:6][CH2:5]2.Cl[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]([F:46])([F:45])[F:44])=[CH:33][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:19][C:16]1([CH3:20])[O:17][CH2:18][C:13]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH2:12][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]([F:44])([F:45])[F:46])=[CH:35][CH:36]=4)[CH:3]=3)[CH2:8]2)[CH2:14][O:15]1
Reactant: FC(F)(F)c1ccccc1-c1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)NC1(CN2CCc3cc(O)ccc3C2)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(CN2CCc3cc(OCc4ccc(-c5ccccc5C(F)(F)F)cc4)ccc3C2)COC(C)(C)OC1

Procedure:
A mixture of the product of Step A (0.105 g; 0.27 mmol), the product of Step B (0.08 g; 0.03 mmol) and Cs2CO3 (0.09 g; 0.27 mmol) in anhydrous DMF (1 ml) was stirred overnight at room temperature and solvent was removed in vacuo. The residue was diluted to 15 ml EtOAc and washed with H2O, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by FCC (SiO2, hexane/EtOAc 9:1) to give the tilted compound (0.12 g; 71%), as colourless solid. 1H-NMR (CDCl3) 1.4 (s, 3H); 1.43 (s, 9H); 1.46 (s, 3H); 2.84 (s, 4H); 2.94 (s, 2H); 3.7 (s, 2H); 3.82 (d, 2H, J=11.5 Hz); 4.07 (d, 2H, J=11.5 Hz); 4.88 (broad s, 1H); 5.07 (s, 2H); 6.74 (d, 1H, J=2.4 Hz); 6.78 (dd, 1H, J=2.4, 8.4 Hz); 6.91 (d, 1H, J=8.4 Hz); 7.29-7.35 (m, 3H); 7.43-7.48 (m, 3H); 7.55 (tr, 1H, J=7.7 Hz); 7.73 (d, 1H, J=7.7 Hz).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[CH3:7])C.[OH-].[Na+]>>[CH3:7][N:6]1[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:4](=[O:3])[CH2:5]1
Reactant: CCOC(=O)CN(C)Cc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Product: CN1CC(=O)Nc2ccccc2C1
Temperature: 150 °C

Procedure:
2.0 g N-(o-aminobenzyl)sarcosine ethyl ester was dissolved in 40 g polyphosphoric acid and the mixture was heated to 150° C. for two hours, then cooled and charged with 300 ml icewater.pH was adjusted to 8 with 50% NaOH and the mixture was extracted with dichloromethane. The organic phase was dried over Na2SO4 and evaporated to give the title compound. M.p. 113°-114° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].N1C=CC=CC=1>CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[N:18][OH:19])=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(-c2ccc(O)cc2)ccc1C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1cc(-c2ccc(O)cc2)ccc1C=NO
Yield: 53.3 %

Procedure:
A mixture of 4′-hydroxy-3-methyl[1,1′-biphenyl]-4-carbaldehyde (310 mg, 1.46 mmol), hydroxylamine hydrochloride (203 mg, 2.92 mmol) and pyridine (236 ul, 2.92 mmol) in 15 mL absolute methanol was refluxed for 2.5 h. The solvent was removed under reduced pressure and the mixture was dissolved in ethyl acetate and water, extracted with ethyl acetate (×3), washed with brine, dried over sodium sulfate, and filtered. Evaporation of the solvent and purification by recrystallization (ethyl acetate, acetone and hexane) gave 177 mg (53%) of the title compound as a yellowish solid: mp 195-197° C.;
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Reactant: O=Cc1sccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Brc1ccsc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of 3-bromothiophene-2-carbaldehyde (500 mg, 2.62 mmol) and morpholine (0.68 mL, 7.85 mmol) and CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.11 g, 5.24 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc (100 mL) and the organic layer was washed with brine then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (silica, 0-5% MeOH in CH2Cl2) to afford the sub-title compound (580 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([NH:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:13][C:14]1[C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[C:17]([CH3:31])[O:16][N:15]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([N:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:18]3[C:14]([CH3:13])=[N:15][O:16][C:17]=3[CH3:31])=[CH:26][CH:25]=2)(=[O:28])=[O:29])=[CH:4][CH:3]=1
Reactant: CC(C)CNc1ccc(Cl)cc1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
N-(4-chlorophenyl)-4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutylbenzenesulfonamide was prepared in an array format. 4-chloro-N-isobutylaniline (1.493 mg, 0.099 mmol) was pre-weighed into a 2 mL vial, and 4-((3,5-dimethylisoxazol-4-yl)methoxy)benzene-1-sulfonyl chloride (30 mg, 0.099 mmol) then added, followed by 4-DMAP (approx 2 mg). Pyridine (0.3 mL) was added last. The reaction solution was capped and stood at RT for 3 days. After this time the reaction was not complete and the reaction were warmed to 80° C. for 2 hours. The pyridine was removed to almost dryness. DMSO (1 mL) was added to the residues which were then purified by mass directed autoPrep on a Sunfire C18 column using Acetonitrile Water with a Formic acid modifier. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the required products.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[CH2:7]([OH:12])[CH:8]([OH:11])[CH2:9][OH:10].[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15][OH:16].[CH2:19]([OH:24])[CH:20]([OH:23])[CH2:21][OH:22].[C:25]([OH:32])(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].ON1[C:38](=O)[CH2:37][CH2:36][C:35]1=O.CC(N=C=NC(C)C)C>C1COCC1>[CH2:27]([CH:26]([CH2:35][CH2:36][CH2:37][CH3:38])[C:25]([OH:32])=[O:31])[CH2:28][CH2:29][CH2:30][CH2:1][CH3:2].[OH:12][CH2:7][CH:8]([CH2:9][OH:10])[OH:11].[OH:18][CH2:13][CH:14]([CH2:15][OH:16])[OH:17].[OH:24][CH2:19][CH:20]([CH2:21][OH:22])[OH:23].[OH:6][CH2:1][CH:2]([CH2:3][OH:4])[OH:5]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Solvent: OCC(O)CO
Product: CCCCCCC(CCCC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 250 mL vessel, tetraglycerol (5.0 g, 15.91 mmol) was added and dissolved into anhydrous THF (50 mL). Hexanoic acid (11.96 mL, 95.44 mmol) was also dissolved into the reaction mixture which was stirred magnetically at room temperature for one hour to fully dissolve the reagents. N,N-dimethylaminopyridine (0.194 g, 1.59 mmol) and N-hydroxysuccinimide (0.183 g, 1.59 mmol) were both dissolved in the solution. When the catalysts were fully dissolved, N,N-diisopropylcarbodiimide (15.0 mL, 97.03 mmol) was pipetted into the vessel and was sealed to keep the reaction dry. The reaction proceeded overnight at 55° C. The solution was stripped of THF via rotoevaporation and redissolved into chloroform. The organic layer was washed 2× with sodium bicarbonate buffer and 2× with deionized water to remove unreacted starting materials. The chloroform was removed to yield a clear viscous liquid. NMR analysis supported full conversion of hydroxyl groups to the hexanoic esters.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[OH-].[Ca+2].[OH-].[CH2:20](O)[CH3:21]>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:20][CH3:21])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Product: CCOC(=O)c1ccc(C)cc1C
Yield: 95 %

Procedure:
To a solution of commercially available 2,4-dimethylbenzoic acid (67.8 g, 451 mmol) in 1000 mL of ethanol was added 10 mL of sulfuric acid. The mixture was refluxed over night, cooled down and was neutralized by adding calcium hydroxide in small portions (˜30 g). The suspension was filtered over celite and concentrated in vacuo. The crude product was purified by vacuum distillation yielding 76.4 g (95%) of 1 as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 1.38 (t, J=7.3 Hz, 3H), 2.34 (s, 3H), 2.57 (s, 3H), 4.33 (q, J=7.2 Hz, 2H), 7.01-7.06 (m, 2H), 7.82 (d, J=8.5 Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 14.3, 21.3, 21.7, 60.4, 126.3, 126.9, 130.7, 132.4, 140.1, 142.3, 167.6; MS (ESI) m/z=133.0 (100), 132.0 (57), 178.1 (M+, 51).
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:37]3[CH2:42][CH2:41][N:40]([CH:43]4[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]4)[CH2:39][CH2:38]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)OC(C)(C)C)=[C:23]([O:35][CH3:36])[CH:22]=3)[C:13]=12>ClCCl>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:13]3[C:14](=[N:15][CH:16]=[N:17][C:12]=3[NH2:11])[N:18]([CH:37]3[CH2:42][CH2:41][N:40]([CH:43]4[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]4)[CH2:39][CH2:38]3)[N:19]=2)=[CH:22][C:23]=1[O:35][CH3:36]
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.8 %

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 28 mL) was added to a solution of tert-butyl N-{4-[4-amino-1-[1-(1-methylpiperidin-4-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}carbamate (0.914 g, 1.70 mmol) in dichloromethane (5 mL) at 0° C. After 15 minutes, the ice-bath was removed and the reaction mixture was stirred at room temperature for 5 hours. Solvents were then evaporated and the residue was dissolved in dichloromethane. Saturated sodium bicarbonate was added to adjust the pH to about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated give 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.726 g, 97%). 1H NMR (CDCl3) δ 1.67 (m, 2H) 1.83 (m, 4H), 2.00 (m, 2H), 2.27 (s, 3H), 2.39 (m, 5H), 2.91 (m, 2H), 3.08 (m, 2H), 3.92 (s, 3H), 3.99 (m, 2h), 4.73 (m, 1H), 5.56 (bs, 2H), 6.82 (d, J=7.87, 1H), 7.08 (d, J=7.84, 1H), 7.13 (s, 1H), 8.34 (s, 1H).
Reaction SMILES: [C:1](#N)[CH3:2].Br[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1.C=C>Cl[Pd]Cl.O>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH:1]=[CH2:2])[CH:14]=[CH:13]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CC#N
Agent: Cl[Pd]Cl
Agent: C=C
Solvent: O
Product: C=Cc1ccc2cc(OC)ccc2c1
Temperature: 60 °C

Procedure:
A 20-gallon jacketed stainless steel reactor equipped with a mechanical agitator is charged with 12.8 kg of ACN, 12.45 kg of DEK and 12.4 kg of 2-bromo-6-methoxynaphthalene (BMN), 4.6 g of PdCl2, and 50.9 g of NMDP. The reactor is pressured and vented three times with 50 psig nitrogen. The reactor is then charged with 6.27 kg of TEA. The agitator is set at 158 rpm and the reactor is pressured and vented with 50 psig nitrogen. The agitator is set to 416 rpm, the reactor is pressured to 100 psig with ethylene and heated with tempered water on the jacket. The reaction temperature ranges from 87 to 98° C., while the pressure varies from 394 to 458 psig. The total reaction time is 3.5 hours with a BMN conversion of 99.6% in two hours. The reactor is cooled, vented, and the reactor contents at 60° C. are transferred for workup, to a 30-gallon glass lined reactor equipped with a 6-inch column. The 20-gallon reactor is then charged with 12.5 kg of DEK, which is then heated to 60° C. and transferred to the 30-gallon reactor.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1.[O:17]1[CH2:29][CH:18]1[CH2:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>O1CCOCC1>[C:10]([C:9]1[CH:13]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:14])[O:4][CH2:3][C:2]([NH:1][CH2:29][CH:18]([OH:17])[CH2:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24])([CH3:16])[CH3:15])(=[O:11])[NH2:12]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: CC(C)(N)COc1ccc(O)c(C(N)=O)c1
Solvent: C1COCCO1
Product: CC(C)(COc1ccc(O)c(C(N)=O)c1)NCC(O)COc1ccccc1C#N

Procedure:
The solution of 2.24 g of 5-(2-amino-2-methylpropoxy)salicylamide in 30 ml of dioxan is refluxed for 7 hours after the addition of 2.3 g of 2-(2,3-epoxypropoxy)-benzonitrile, and then concentrated by evaporation. The residue is divided between 10 ml of 2N hydrochloric acid and 100 ml of ethyl acetate. The acidic aqueous phase is rendered alkaline with concentrated ammonia solution, the base is extracted with ethyl acetate and the solvent is evaporated off, whereupon an oil is obtained from which, by crystallisation from isopropanol and recrystallisation from ethyl acetate, 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1,1-dimethylethylamino]-3-(2-cyanophenoxy)propan-2-ol having a melting point of 125°-126° is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:11]([C@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:28](Cl)([Cl:30])=[O:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:11]([C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:28]([Cl:30])=[O:29])=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(Cn2ncnc2[C@H]2CCCN2)cc1
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cl)N1CCC[C@@H]1c1ncnn1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 75.8 %

Procedure:
A solution of (R)-1-(4-chlorobenzyl)-5-(pyrrolidin-2-yl)-1H-1,2,4-triazole (216 mg, 0.82 mmol) and DIEA (233 mg, 1.90 mmol) in 5 mL of dry DCM was cooled to −20° C. under Ar, and a solution of phosgene (0.89 mL of 20% solution in toluene, 0.89 mmol) was added. The reaction mixture was stirred at RT for 2.5 days and the solvent was evaporated in vacuo. The residue was purified by chromatography (silica gel, hexane:EtOAc (1:1)) to give 202 mg of the desired product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=3)[N:14]=[CH:13][CH:12]=2)[OH:10])[CH2:4][CH2:3]1.[N:23]1[C:32]2[NH:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:26]=[CH:25][C:24]=1[CH:33]=O.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(Cl)Cl.C(O)C>[CH3:22][O:21][C:18]1[N:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[C@@H:9]([OH:10])[CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:33][C:24]2[CH:25]=[CH:26][C:27]3[CH2:28][CH2:29][CH2:30][NH:31][C:32]=3[N:23]=2)[CH2:3][CH2:4]1
Reactant: O=Cc1ccc2c(n1)NCCC2
Reactant: COc1ccc2nccc([C@@H](O)CN3CCC(N)CC3)c2n1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2nccc([C@@H](O)CN3CCC(NCc4ccc5c(n4)NCCC5)CC3)c2n1
Reaction time: 36 h
Yield: 83 %

Procedure:
To a stirred solution of (R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol (2f) (0.30 g, 1.0 mmole) in CH2Cl2 (25 mL) and dry ethanol (10 mL) at RT was added 5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carboxaldehyde (prepared according to the procedure of WO 98/08840, 0.17 g, 1.0 mmole) and granular Na2SO4 (approximately 200 mg). After 36 h, the reaction was filtered through a sintered-glass funnel and the filtrate was concentrated. The remaining residue was dissolved in dry ethanol and reacted with NaBH4 (0.04 g, 1.0 mmole). After 12 h at RT, the reaction was concentrated under vacuum and the residue was dissolved in a mixture of H2O (2 mL) and saturated aqueous NaHCO3 (10 mL). The aqueous solution was extracted with EtOAc (2×50 mL) and the combined organic phases were washed with brine then were dried over Na2SO4. Flash chromatography on silica gel (9:1 CHCl3/MeOH containing 5% NH4OH) afforded the title compound (0.37 g, 83%) as a white solid:
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([N:16](C(F)(F)C(F)C(F)(F)F)CC)C>N>[C:1]12([C:11]([NH2:16])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: *CC*
Agent: N
Product: NC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
1-Adamantanecarboxylic acid (10.8 g, 0.06 mole) was added to N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine (13.4 g, 0.06 mole) contained in a wide mouth polyethylene bottle with magnetic stirring. The acid dissolved immediately during which time a highly exothermic reaction occurred. The reaction mixture was allowed to cool to room temperature and cold aqueous ammonia (250 ml) was added slowly. A heavy precipitate of the amide appeared almost immediately. After the addition was complete, the reaction mixture was stirred for about fifteen minutes. The 1-adamantanecarboxamide was collected and washed copiously with water followed by ethyl ether and dried. Yield: 10.7 g, 100%; mp 189.4-190.2° C. (Lit. mp 189° C., Stetter, et. al., Chem. Ber., 1960, 226-230). The analytical sample was recrystallized from cyclohexane and sublimed. Anal. Calcd. for C11H17NO: C, 73.76; H, 9.49; N, 7.82. Found: C, 73.67; H. 9.60; N, 7.78.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[N:9]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:6]([NH2:5])[N:7]=2)[CH:10]=1
Reactant: O=C(Nc1nc2ccc(F)cn2c1-c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1nc2ccc(F)cn2c1-c1ccccc1
Temperature: 100 °C

Procedure:
2,2,2-trifluoro-N-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)acetamide (compound k, 0.190 g, 0.0006 mol) was dissolved in methanol (8.0 mL) and water (2 ml). To this was added potassium carbonate (0.2 g, 0.002 mol). The reaction was heated in the microwave at 100° C. for 45 min. The solvent concentrated and residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The layers were separated and the organic layer was dried (magnesium sulfate) then chromatographed on silica (55:40:5, DCM:acetonitrle:MeOH) to give 6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-amine Rf 0.40, (55:40:5, DCM:acetonitrle:MeOH); MS m/z 228 (M+H).
Reaction SMILES: FC1C(O[C:9](=[O:27])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[C:11]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[Cl:26])=C(F)C(F)=C(F)C=1F.[NH2:32][O:33][CH2:34][CH2:35][OH:36].C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:26][C:20]1[CH:21]=[C:22]([I:25])[CH:23]=[CH:24][C:19]=1[NH:18][C:11]1[C:12]([F:17])=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:9]([NH:32][O:33][CH2:34][CH2:35][OH:36])=[O:27]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(F)c(F)c1Nc1ccc(I)cc1Cl
Reactant: NOCCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1Cl
Yield: 89.6 %

Procedure:
To a solution of 2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid pentafluorophenyl ester (10.0 g, 17.4 mmol) in anhydrous dimethylformamide (36 mL) was added 2-(aminooxy)-ethanol (1.6 g, 20.8 mmol) and N,N-diisopropylethylamine (6.0 mL, 34.8 mmol). The resultant solution was stirred at ambient temperature for 16 h. The reaction mixture was concentrated to 20% volume then diluted with ethyl acetate (360 mL). The resultant solution was washed with water (6×60 mL) and brine (2×60 mL). The organics were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a white solid that was purified on silica gel. Elution with ethyl acetate-methanol (9:1) afforded 2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (7.31 g, 90%) as a white solid. Recrystallization from methanol afforded analytically pure material, identical in all respects to the material prepared by method A.