Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:40])[CH:15]([N:26]3[CH2:30][C:29]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])=[CH:28][C:27]3=[O:39])[CH2:16][CH:17]([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:40])[CH:15]([N:26]2[CH2:30][C:29]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])=[CH:28][C:27]2=[O:39])[CH2:16][CH:17]([C:22]([F:23])([F:25])[F:24])[C:18]([F:20])([F:19])[F:21])=[N:9]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC(C(F)(F)F)C(F)(F)F)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)C(CC(C(F)(F)F)C(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Yield: 87.6 %

Procedure:
In a round bottom flask was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (32 mg, 0.05 mmol), methanol (2 mL) and p-toluenesulfonic acid hydrate (5 mg, 0.15 mmol) and stirred at 25° C. for 48 h. The mixture was concentrated in vacuo and then taken up in ethyl acetate/methanol and concentrated in vacuo with silica gel (1.5 g). Purification by Biotage flash chromatography (AnaLogix SF15-12 g column, 100% ethyl acetate to 10% methanol/ethyl acetate) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (25 mg, 84%) as a colorless gum: HR-ES-MS m/z calculated for C22H21N4O5ClF6 [M+H]+ 571.1178, observed 571.1177; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.20-2.37 (m, 1H), 2.38-2.48 (m, 1H), 3.21-3.32 (m, 2H), 3.71-3.82 (m, 1H), 3.82-3.98 (m, 2H), 4.10 (dd, J=13.6, 4.0 Hz, 1H), 4.29 (d, J=17.9 Hz, 1H), 4.45 (d, J=17.9 Hz, 1H), 4.71 (t, J=5.5 Hz, 1H), 4.89 (s, 1H), 4.89-4.98 (m, 2H), 6.43 (d, J=2.1 Hz, 1H), 7.31-7.42 (m, 1H), 7.43-7.53 (m, 3H), 7.56 (d, J=2.1 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 10.91 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=O)[CH2:10]1.Cl.[NH2:18][CH2:19][C:20]#[C:21][CH3:22].O1CCCC1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:10][C:11]2[N:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:12]=2[C:13](=[O:15])[CH2:14]1
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Reactant: CC#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1C1CC(=O)c2c(C)ccnc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To a mixture of 5-(2-methoxyphenyl)-1,3-cyclohexanedione (1.0 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieves 4A (2 g) and tetrahydrofuran (20 ml) was added triethylamine (0.48 g). The mixture was stirred at room temperature for 1 hour, refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was stirred for 4 hours at 220° C. and cooled, to which was added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give oil of 7-(2-methoxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:26])[CH:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:15][C:16]=1[O:17]C.N1CCOCC1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([Cl:11])[C:3]=1[CH:12]1[C:13](=[O:26])[CH:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:15][C:16]1=[O:17]
Reactant: CC#Cc1cc(Cl)c(C2=C(OC)CC(Cc3ccccn3)C2=O)c(Cl)c1
Solvent: C1COCCN1
Product: CC#Cc1cc(Cl)c(C2C(=O)CC(Cc3ccccn3)C2=O)c(Cl)c1
Temperature: 10 °C
Yield: 35.5 %

Procedure:
A mixture of 2-(2,6-dichloro-4-prop-1-ynyl-phenyl)-3-methoxy-5-(2-pyridylmethyl)cyclopent-2-en-1-one (41 mg, 0.106 mmol) and morpholine (1 ml) were heated at 10°C. for 4 hours. The reaction was cooled to room temperature and evaporated to dryness under reduced pressure. The residue was partitioned between EtOAc (10 ml) and saturated aqueous NH4Cl (10 ml). The organic phase was washed with further saturated aqueous NH4Cl (5 ml), brine (5 ml), dried over MgSO4, filtered and evaporated to dryness under reduced pressure. The crude product was purified on the FractionLynx to give the desired product (14 mg, 36%). 1H NMR (400 MHz, CDCl3) δ ppm 8.50 (d, 1H), 7.85 (dd, 1H), 7.40 (d, 1H), 7.35-7.30 (m, 3H), 6.10 (br, 1H), 3.40-3.25 (m, 3H), 3.05 (dd, 1H), 2.40 (dd, 1H), 2.05 (s, 3H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11](=[N:13][OH:14])[NH2:12])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C(C1C=C(S(N)(=O)=O)C=CC=1)#N.[CH3:27][O:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36](O)=O)[CH:33]=[CH:32][C:31]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH3:45]>>[CH3:27][O:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36]2[O:14][N:13]=[C:11]([C:7]3[CH:6]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:10]=[CH:9][CH:8]=3)[N:12]=2)[CH:33]=[CH:32][C:31]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH3:45]
Reactant: NC(=NO)c1cccc(S(N)(=O)=O)c1
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Agent: N#Cc1cccc(S(N)(=O)=O)c1
Product: COCc1cc(-c2nc(-c3cccc(S(N)(=O)=O)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was obtained following procedure and work up described for example 107, step 1, but starting from 3-(aminosulfonyl)-N′-hydroxybenzenecarboximidamide, prepared as described in WO 2006/013104 A1 from 3-cyanobenzene-1-sulfonamide (Maybridge; GK 03054), (1.50 g; 6.97 mmol) and Intermediate 28 (1.79 g; 6.97 mmol), followed by a recrystallization from DCM gave the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.58-8.57 (m, 1H), 8.35-8.32 (m, 2H), 8.20-8.17 (m, 1H), 8.08-8.05 (m, 1H), 7.83 (t, J=7.8 Hz, 1H), 7.59 (bs, 2H), 7.43 (d, J=8 Hz, 1H), 7.36-7.27 (m, 3H), 7.16-7.13 (m, 1H), 4.23 (d, J=12.6 Hz, 1H), 4.16 (d, J=12.6 Hz, 1H), 3.25 (s, 3H), 2.03 (s, 3H). LC/MS (Method B): 436.3 (M+H)+. HPLC (Method A) Rt 5.37 min (purity: 99.6%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([F:24])=[CH:6][C:7]2[C:8]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.I[CH3:26]>CN(C=O)C>[Br:3][C:4]1[C:5]([F:24])=[CH:6][C:7]2[C:8]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:14][CH2:13][C:9]=3[N:10]([CH3:26])[C:11]=2[CH:12]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Br)c(F)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3cc(F)c(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 80.2 %

Procedure:
Sodium hydride (60% weight dispersion in mineral oil, 150 mg, 3.66 mmol) was added to a solution of tert-butyl 7-bromo-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.9 g, 2.44 mmol) in 20 ml of DMF, and the mixture was stirred for 40 min at ambient temperature. Iodomethane (0.25 mL, 3.66 mmol) was added, and the resulting suspension was stirred for 2 h. The resulting mixture was concentrated under reduced pressure to ⅓ of initial volume and treated with water (20 mL). The resulting precipitate was collected by filtration, sequentially washed with water and diethyl ether and dried under vacuum to afford the title compound (0.75 g, 83%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J=5.4 Hz, 1H), 7.17 (d, J=9.3 Hz, 1H), 4.45 (br s, 2H), 3.81 (br m, 2H), 3.60 (s, 3H), 2.78 (br m, 2H), 1.52 (s, 9H); ESI MS m/z 383 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:70]([NH2:74])[CH:71]([CH3:73])[CH3:72]>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:74][CH2:70][CH:71]([CH3:73])[CH3:72])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NCC(C)C)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and isobutylamine (10.0 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (12.6 mg, 44%). LC-MS m/z 577 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]([CH3:15])[CH2:8][C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1)(=O)C.[OH-].[Na+]>O>[C:9]1([CH2:8][CH:7]([CH3:15])[CH2:6][CH2:5][OH:4])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: CC(=O)OCCC(C)CC1=CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CCO)CC1=CCCCC1
Temperature: 92.5 °C
Reaction time: 11 h
Yield: 93 %

Procedure:
4-(cyclohex-1-en-1-yl)-3-methylbutyl acetate (2.1 kg, 10.0 mols, purity: 98%) sodium hydroxide (420 g, 10.5 mols) and water (8400 ml) were mixed together and heated at 90-95° C. under stirring for 10-12 h. The reaction mixture was cooled to 35° C. The aqueous phase was separated from the organic phase. The organic phase was washed once with 5% w/w aqueous NaCl and twice with water. The crude product was fractionated under reduced pressure to provide 4-(cyclohex-1-en-1-yl)-3-methyl butan-1-ol (1.5 kg, yield: 93%; GC purity: 99% sum of the isomers).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10](F)=[N:11][CH:12]=[CH:13][CH:14]=2)[C:3]=1[F:16].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:4]=2[C:3]=1[F:16]
Reactant: Nc1cnc(Cl)c(F)c1-c1cccnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1c(Cl)ncc2[nH]c3ncccc3c12
Temperature: 40 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
A solution of 6′-chloro-2,5′-difluoro-[3,4′]bipyridinyl-3′-ylamine (70 g, 290 mmol) in THF (300 mL) was added dropwise to a solution of sodium bis(trimethylsilyl)amide (720 mL, 1M in THF, 720 mmol) at such a rate that the reaction temperature was maintained at 40° C. When the addition was complete the mixture was stirred for ca. 1 hour at ambient temperature. The bulk of the solvent was evaporated in-vacuo and the residue poured into ice-cold 1N hydrochloric acid. The resulting slurry was filtered and the solid washed with water. The filter cake was collected and triturated with acetone followed by diethyl ether to afford the title compound as a beige solid (40.9 g, 64%). The trituration liquors were evaporated and the residue triturated with methanol followed by diethyl ether to afford a second crop of title compound as a brown solid (6.1 g, 10%). Total yield=47 g, 74%. 1H NMR (400 MHz, DMSO-d6): 13.24 (s, 1H), 8.91 (d, J=2.5 Hz, 1H), 8.77 (dd, J=4.8, 1.7 Hz, 1H), 8.65 (dd, J=7.9, 1.7 Hz, 1H), 7.50 (dd, J=7.9, 4.8 Hz, 1H).
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]4)=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]4)=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1ccc2cc(OCCCc3nnnn3C3CCCCC3)ccc2[nH]1
Agent: [Pd]
Solvent: CO
Product: O=C1CCc2cc(OCCCc3nnnn3C3CCCCC3)ccc2N1
Reaction time: 8 h
Yield: 59.7 %

Procedure:
Into 500 ml of methanol, 2.5 g of 6-[3-(1-cyclohexyltetrazol-5-yl)propoxy]carbostyril is added, then 0.1 of palladium black is added into the mixture and the reaction is carried out under 2.5 atoms of H2 -pressure at 50° C. for 8 hours. After the reaction is completed, the catalyst is removed by filtration and the filtrate is concentrated to dryness. The residue is recrystallized from chloroform-petroleum ether to obtain 1.5 g of 6-[3-(1-cyclohexyltetrazol-5-yl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals. Melting point: 154.4°-155.5° C.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[F-].[Ca+2:22].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[S:27](=[O:31])(=[O:30])([OH:29])[OH:28]>>[S:27]([O-:31])([O-:30])(=[O:29])=[O:28].[Ca+2:22].[P:1](=[O:2])([OH:5])([OH:4])[OH:3]
Reactant: O=S(=O)(O)O
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Product: O=S(=O)([O-])[O-]

Procedure:
A process for preparing wet process phosphoric acid from phosphate rock containing acid insoluble heat labile iron sulfide and organic compounds wherein phosphate rock is heated to give a heated rock and the heated rock is reacted with a mixture of sulfuric acid and phosphoric acid to form calcium sulfate and phosphoric acid, comprising
Reaction SMILES: C([O:8][C:9]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>CO.C(OCC)(=O)C.[C].[Pd]>[O:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[C:25]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:32]=[C:33]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:34]=[CH:35][C:9]=2[OH:8])[CH:26]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccco2)cc1NC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccco2)cc1NC(=O)c1cc(N2CCOCC2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(morpholin-4-yl)benzamido)-4-(furan-2-yl)benzoate (0.14 g) in methanol (2.0 mL) and ethyl acetate (2.0 mL), 10% palladium-carbon (0.029 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour. Chloroform was added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 85-75% hexane/ethyl acetate] to obtain 0.085 g of tert-butyl 4-(furan-2-yl)-2-(2-hydroxy-5-(morpholin-4-yl)benzamido)benzoate as a yellow solid.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+].C[O:13][CH:14](OC)[CH2:15]Cl>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH2:1]([O:9][CH2:15][CH:14]=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: COC(CCl)OC
Reactant: CCCCCCCCO
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCOCC=O
Yield: 50.6 %

Procedure:
A mixture of 130 grams of n-octanol, 60 grams of granular sodium hydroxide, 4 grams of Aliquat 336® (registered trademark of General Mills Chemicals, Inc.) and 110 grams of chloro acetaldehyde dimethyl acetal are heated to reflux for 4 hours. The reaction mass is cooled and 200 ml of water are added thereto with vigorous stirring. After all solids are dissolved, the aqueous phase is distilled to yield 87 grams of n-octanol (boiling point 60° C. at 1.4 mm Hg pressure) and 77 grams of n-octyl oxyacetaldehyde (boiling point 90° C. at 1.8 mm Hg). The conversion based on chloroacetaldehyde dimethyl acetal is 40% and the yield based on n-octanol is 83%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18]O)[C@@H:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Se:39]C#N)([O-:32])=[O:31].C(P(CCCC)CCCC)CCC.[Na+].[Cl-]>C1COCC1>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18][Se:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N+:30]([O-:32])=[O:31])[C@@H:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:3])([CH3:2])[CH3:4]
Reactant: N#C[Se]c1ccccc1[N+](=O)[O-]
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CCO)[C@H]1Oc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CC[Se]c2ccccc2[N+](=O)[O-])[C@H]1Oc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
To a solution of tert-butyl((3S,7R,8R,9S)-7-(2-hydroxyethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)carbamate (227 mg, 0.557 mmol) in anhydrous THF (5.6 mL) at 0° C. (ice water bath) were added 1-nitro-2-selenocyanatobenzene (177 mg, 0.780 mmol) and tributylphosphine (223 μl, 0.891 mmol). The resulting solution was stirred for 3 h and then treated with additional 1-nitro-2-selenocyanatobenzene and tributylphospine (53 mg and 67 μL, respectively). The reaction was stirred for an additional 1 h, then poured into 20 mL sat. NaCl solution and extracted with 3×20 mL EtOAc. The organic extracts were combined, dried over MgSO4, filtered, and concentrated to provide a brown oil, which was purified by column chromatography on SiO2 (2→20% acetone/hexanes) to provide the title compound as a bright yellow solid (294 mg, 89%): 1H NMR (400 MHz, CDCl3) δ 8.24 (dt, J=8.2, 1.0 Hz, 1H), 7.36-7.19 (m, 5H), 7.00-6.92 (m, 1H), 6.92-6.84 (m, 2H), 5.16-4.98 (m, 2H), 4.21 (t, J=8.5 Hz, 2H), 3.05-2.76 (m, 2H), 2.30 (dt, J=13.2, 6.7 Hz, 1H), 1.94 (tdq, J=28.6, 14.1, 8.4, 6.4 Hz, 3H), 1.78-1.64 (m, 2H), 1.60 (d, J=4.5 Hz, 1H), 1.45 (s, 9H), 1.30 (d, J=6.5 Hz, 3H), 1.27-1.13 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 173.23, 159.12, 154.89, 146.86, 133.45, 133.21, 129.76, 128.95, 126.41, 125.29, 121.34, 115.33, 80.99, 79.97, 74.59, 52.99, 43.60, 34.00, 29.99, 28.58, 28.33, 24.24, 19.15, 18.29; ESIMS m/z 593.2 ([M+Na]+).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[CH2:35][OH:36]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][C@@H:31]4[CH2:35][OH:36])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Reactant: OC[C@H]1CCCN1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCC[C@@H]5CO)c34)cc2Cl)cn1
Yield: 45 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and (R)-2-pyrrolidinemethanol to give the title compound in 45% yield; NMR Spectrum: 1.50-1.81 (m, 4H), 2.33 (dd, 1H), 2.45 (s, 3H), 2.58 (m, 1H), 2.74-2.79 (m, 1H), 3.11-3.19 (m, 1H), 3.24-3.32 (m, 3H), 4.44 (t, 2H), 7.20 (d, 1H), 7.27 (br s, 2H), 7.73 (d, 1H), 8.14 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 496 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([C:39](O)=[O:40])[C:33]2=[O:42])=[CH:28][C:27]=1[CH3:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:39]([C:34]5[C:33](=[O:42])[N:32]([C:29]6[CH:30]=[CH:31][C:26]([F:25])=[C:27]([CH3:43])[CH:28]=6)[C:37]([CH3:38])=[CH:36][CH:35]=5)=[O:40])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1cc(-n2c(C)ccc(C(=O)O)c2=O)ccc1F
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-n2c(C)ccc(C(=O)Nc3ccc(Oc4ccc5nc(NC(=O)C6CC6)cn5c4)c(F)c3)c2=O)ccc1F
Yield: 43.9 %

Procedure:
A solution (5 mL) of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (131 mg, 0.40 mmol), 1-(4-fluoro-3-methylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (125 mg, 0.48 mmol), HATU (183 mg, 0.48 mmol) and N,N-diisopropylethylamine (103 mg, 0.80 mmol) in N,N-dimethylformamide was stirred at room temperature for 5 hr. The reaction solution was divided into two layers with tetrahydrofuran and sodium hydrogen carbonate saturated aqueous solution and the aqueous layer was subjected to extraction (3 times) with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica) and recrystallized from ethanol to give the title compound (100 mg, 44%) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[O:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][N:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([N:18]2[CH2:17][CH2:16][O:15][CH2:20][CH2:19]2)=[N:22][CH:23]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1ccc(N2CCOCC2)nc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(N2CCOCC2)nc1
Yield: 56.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-morpholinonicotinamide was obtained following Method C starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.042 g, 0.178 mmol), 6-morpholinonicotinoyl chloride (0.045 g; 0.178 mmol), and triethylamine (0.062 mL; 0.446 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent 1 to 10% methanol in dichloromethane) furnished 0.039 g (57%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-morpholinonicotinamide as a solid.