Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]2[O:9][C:10]3[C:15]([C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH:19]=[CH:18][N:17]=4)=[CH:14][CH:13]=[CH:12][C:11]=3[C:6]2=[CH:5][CH:4]=1)[CH3:2].[CH:28]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH:1]([C:3]1[N:8]=[C:7]2[O:9][C:10]3[C:15]([C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH:19]=[CH:18][N:17]=4)=[CH:14][CH:13]=[CH:12][C:11]=3[C:6]2=[CH:5][CH:4]=1)([CH3:28])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCc1ccc2c(n1)oc1c(-c3cc(-c4ccccc4)ccn3)cccc12
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(n1)oc1c(-c3cc(-c4ccccc4)ccn3)cccc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2-ethyl-8-(4-phenylpyridin-2-yl)benzofuro[2,3-b]pyridine (5.15 g, 14.70 mmol) was charged into the reaction mixture with 120 mL of THF. This mixture was cooled to −78° C. Lithium diisopropylamide in THF (9.19 mL, 18.37 mmol) was added dropwise to the cooled reaction mixture over a 10 minute period. The reaction mixture was then stirred for 2 hours at −78° C. Iodomethane (3.13 g, 22.05 mmol) was then dissolved in 10 mL of THF. This solution was then added via syringe to the cold reaction mixture. Stirring was continued as the reaction mixture was allowed to gradually warm to room temperature overnight. The reaction mixture was quenched with aqueous ammonium chloride then was extracted 2×300 mL ethyl acetate. The organics were combined, were washed with aqueous LiCl then were dried over magnesium sulfate. These organics were then filtered and concentrated under vacuum. The crude residue was dissolved in DCM and was loaded onto a silica gel column. The column was eluted with 3-4% ethyl acetate/DCM. Clean product fractions were combined and solvents were evaporated yielding 2-isopropyl-8-(4-phenylpyridin-2-yl)benzofuro[2,3-b]pyridine (4.1 g, 11.25 mmol, 77% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:5](Cl)=[CH:6][CH:7]=1.[CH3:15][S-:16].[Na+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:5]([S:16][CH3:15])=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)ccc(Cl)c1C1=NOCC1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CSc1ccc(Cl)c(C)c1C1=NOCC1
Reaction time: 8 h

Procedure:
20 g (0.083 mol) of 3-(3,6-dichloro-2-methylphenyl)-4,5-dihydroisoxazole are dissolved in 120 ml of NMP. At 0° C., 6.7 g (0.09 mol) of sodium thiomethoxide are added over a period of 40 min, and the mixture is then stirred overnight. The reaction mixture is stirred into 360 ml of water and extracted four times with 70 ml of toluene, the combined organic phases are washed once with 70 ml of water and the organic phase is concentrated. The residue (an isomer mixture) is distilled at 150-170° C. under a reduced pressure of 1 mbar. The main fraction is purified chromatographically. This gives 4.5 g of a product which is 83% pure (17% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH:5]=[N:6][OH:7].ClN1C(=O)CCC1=O.[OH:20][CH2:21][C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:28][C:22]([CH2:21][OH:20])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:7][N:6]=2)[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: ON=Cc1cc(Cl)cc(Cl)c1
Reactant: C=C(CO)C(=O)OCC
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CO)CC(c2cc(Cl)cc(Cl)c2)=NO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.00 g (15.8 mmol) of 3,5-dichlorobenzaldehyde oxime were stirred in 100 ml of DMF together with 2.21 g (16.6 mmol) of N-chlorosuccinimide at RT for 4 h. 3.08 g (23.7 mmol) of ethyl 2-(hydroxymethyl)acrylate and 2.40 g (23.7 mmol) of triethylamine were then added, and the mixture was stirred at RT for 18 h. The reaction solution was concentrated under reduced pressure, and CH2Cl2 and water were then added. The aqueous phase was re-extracted once with CH2Cl2, and the combined organic phases were washed twice with water, dried over Na2SO4, filtered and concentrated. After chromatography on silica gel using n-heptane:ethyl acetate (3:1), the product was obtained. Yield: 3.10 g (62%)
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH:16]=O)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:27][S:28][CH2:29][CH2:30][CH2:31][O:32][NH2:33]>C(Cl)Cl.CO>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:33]/[O:32][CH2:31][CH2:30][CH2:29][S:28][CH3:27])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CSCCCON
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Solvent: ClCCl
Solvent: CO
Product: CSCCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
The title compound was obtained by a procedure similar to that in Step B of Example 9 using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide obtained in Step F of Example 1 as a starting material and O-(3-methylsulfanyl-propyl)-hydroxylamine obtained in Step B as a reagent. Namely, 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (76 mg, 0.158 mmol) was dissolved in a mixed solvent of methylene chloride (5 mL) and methanol (1 mL). O-(3-Methylsulfanyl-propyl)-hydroxylamine (100 μL) was added thereto, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to give a pale yellow crude product. The residue was triturated with a proper amount of ethyl acetate:hexane (1:9) to give (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-propoxyimino)-methyl]-benzamide (88.8 mg, 96%) as a white solid.
Reaction SMILES: [O-:1][P:2]([O-:5])([O-:4])=[O:3].[O-][P:7]([O-:10])([O-:9])=[O:8].[O-][P:12]([O-:15])([O-])=[O:13].[F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[P:22](=O)(O)(O)[OH:23]>O>[O:3]=[P:2]12[O:5][P:7]3([O:10][P:12]([O:15][P:22]([O:9]3)([O:4]1)=[O:23])(=[O:13])[O:1]2)=[O:8]
Reactant: O=P(O)(O)O
Reactant: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Agent: [F-]
Solvent: O
Product: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3

Procedure:
The above objects are provided by a continuous slurry process for the production of granulated fertilizers comprising the steps of (a) continuously introducing into a pre-reactor comminuted phosphate rock, phosphoric acid in an amount sufficient to provide a ratio of P2O5 to CaO of 0.7 to 1.0 and water in an amount sufficient to dilute the phosphoric acid to not less than 38%, (b) heating the mixture with continuous agitation, while (c) continuously transferring the mixture to a digester, (d) heating the mixture in the digester with agitation for a length of time sufficient to form a slurry, while, (e) continuously withdrawing slurry as an overflow stream, (f) splitting the withdrawn slurry stream into two streams, (g) recycling one stream to the pre-reactor or to the digester, (h) delivering the other stream to a granulator and mixing with other dry fertilizer ingredients, thereby producing fertilizer granules, and (i) drying the granules.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Cl[CH2:45][CH:46]1[O:50][C:49](=[O:51])[NH:48][CH2:47]1.BrCC1OC(C(F)(F)F)=CC=1>>[O:51]=[C:49]1[NH:48][CH2:47][CH:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])[O:50]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1NCC(CCl)O1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1NCC(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)O1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 5-chloromethyl-2-oxazolidinone to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, [(2-oxo-1,3-oxazolidin-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (32%) as a colorless solid: mp 197-198° C.; 1H NMR (300 MHz, DMSO-d6) δ7.58 (s, 1H), 7.37-7.29 (m, 1H), 7.26-7.20 (m, 1H), 7.19-7.13 (m, 1H), 7.09-7.01 (m, 1H), 6.49-6.39 (m, 2H), 4.98-4.75 (m, 2H), 4.74-4.66 (m, 1H), 4.54-4.45 (m, 2H), 4.15-3.84 (m, 2H), 3.67-3.56 (m, 1H), 3.31-3.23 (m, 1H), 3.02-2.90 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.9, 177.6, 161.2, 160.6, 160.5, 158.3, 142.6 (2C), 132.2, 132.0, 128.7, 128.6, 123.5, 123.4, 123.0, 120.6, 120.5, 119.9, 119.0, 118.9, 109.7, 109.6, 92.5, 92.4, 79.8, 73.3, 73.2, 72.1, 56.8, 43.1, 42.7, 42.6, 28.4; MS (ES+) m/z 379.3 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:12]C)=[O:11])[CH2:7][C:6]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:17][C:5]=2[CH2:4][N:3]1[CH2:29][C:30]([F:33])([F:32])[F:31].[OH-].[Na+].Cl>O1CCOCC1>[O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:17][C:5]=2[CH2:4][N:3]1[CH2:29][C:30]([F:33])([F:31])[F:32]
Reactant: COC(=O)C[C@@H]1Cc2ccc(OCCCNc3ccccn3)cc2CN(CC(F)(F)F)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C[C@@H]1Cc2ccc(OCCCNc3ccccn3)cc2CN(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a stirred solution of methyl (S)-3-oxo-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (19.50 g, 42 mmol) in dioxane (150 mL) was added aqueous 1 N NaOH (75 mL, 75 mmol). The cloudy reaction was stirred at RT for 2 h, then the resulting homogeneous solution was neutralized with aqueous 1 N HCl (75 mL, 75 mmol). The solution was concentrated to near dryness by rotary evaporation to precipitate out the product. The supernatant was decanted off and the remaining gummy solid was redissolved in methanol. The clear solution was then reconcentrated by rotary evaporation. The remaining solid was triturated with a small volume of water, filtered and dried under vacuum to give the title compound (16.38 g, 86%) as a white powder. HPLC (Hamilton PRP-1®, 25% CH3CN/H2O containing 0.1% TFA) k′=3.1; [α]D−112.3° (c, 1.0, MeOH); MS (ES) m/e 452.3 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 7.95 (dd, 1H), 7.34 (dt, 1H), 7.02 (d, J=9.2 Hz, 1H), 6.81 (m, 2H), 6.58 (t, 1H), 6.47 (m, 2H), 5.30 (d, J=16.5 Hz, 1H), 4.27-4.13 (m, 2H), 4.15 (d, J=16.5 Hz, 1H), 4.02 (t, 1H), 3.78 (m, 1H), 3.37 (m, 2H), 3.00 (dd, 1 H), 2.69 (dd, 1H), 2.65 (dd, 1H), 2.41 (dd, 1H), 1.96 (ddd, 2 H). Anal. Calcd for C22H24F3N3O4: C, 58.53; H, 5.36; N, 9.31. Found: C, 58.37; H, 5.42; N, 9.20.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[CH:21]=[CH:22][C:23]=1[CH3:24]>C(O)(C)C>[ClH:2].[CH3:24][C:23]1[CH:22]=[CH:21][C:20]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)=[CH:19][C:18]=1[NH:17][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccc(C(=O)Nc2ccc(C)c(N)c2)cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(C(=O)Nc2ccc(C)c(Nc3ccnc4cc(OC)c(OC)cc34)c2)cc1OC
Temperature: 85 °C
Yield: 23.6 %

Procedure:
Hydrochloric acid (0.15 ml) was added to a mixture of 4-chloro-6,7-dimethoxy quinoline (335 mg) and N-(3-amino-4-methylphenyl)-3,4-dimethoxybenzamide (472 mg) in isopropanol (8 ml) and heated to 85° C. for 18 hours. After cooling to room temperature the precipitated solid was isolated and washed with isohexane to yield the title compound as a solid (180 mg, 24%); NMR: 2.31 (s, 3H), 3.82 (s, 6H), 3.97 (s, 3H), 3.99 (s, 3H), 6.75 (m, 1H), 7.06 (m, 1H), 7.25 (m, 1H), 7.42 (m, 2H), 7.51 (m, 1H), 7.55 (m, 1H), 7.64 (m, 1H), 8.1 (s, 1H), 8.36 (m, 1H), 9.84 (s, 1H), 10.61 (s, 1H); m/s: M+H+ 474.
Reaction SMILES: [C:1]1([C:7]2[S:11][N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:16]I.[N+]([O-])(O)=O>CCOC(C)=O>[I:16][C:8]1[C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][S:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: II
Reactant: COC(=O)c1cc(-c2ccccc2)sn1
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])O
Product: COC(=O)c1nsc(-c2ccccc2)c1I
Temperature: 80 °C
Yield: 21.4 %

Procedure:
To methyl 5-phenylisothiazole-3-carboxylate (500 mg, 2.280 mmol) in a tube were added iodine (579 mg, 2.280 mmol) and nitric acid (2.280 mmol). The resulting mixture was heated to 80° C. for 1 h. After the reaction was cooled to room temperature, EtOAc (50 mL) was added. The resulting mixture was washed with saturated Na2S2O3 solution until the brown color disappeared. The organic layer was concentrated. HPLC and flash chromatography yielded methyl 4-iodo-5-phenylisothiazole-3-carboxylate (168 mg, 0.487 mmol, 21.34% yield). The compound had an LC/MS M+1=345.9.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([N:15]=[C:16]=[S:17])[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([N:15]2[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:16]2=[S:17])[CH:14]=1
Reactant: COc1ccc(Cl)cc1N=C=S
Reactant: CCNCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2cc(Cl)ccc2OC)C1=S
Yield: 53.3 %

Procedure:
A mixture N-ethyl glycine (9.2 g), 5-chloro-2-methoxyphenyl-isothiocyanate (10 g), triethylamine (10.1 g), methylene chloride (150 mL) was heated at reflux for 3.5 hours. The mixture was evaporated to dryness. The residue collected, washed with hot ethanol and dried. Title compound (7.6 g) was obtained as a creamy solid, m.p. 171°-174° C. Anal. Calcd. for. C12H13Cl N2O2S: C, 50.61; H, 4.60; N, 9.84. Found: C, 50.33; H, 4.50; N, 9.69. Mass spectrum (EI, M.+) m/z 284/286.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH:23]3[CH2:25][O:24]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH:23]([OH:24])[CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCNCC1
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCC2CO2)CC1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCC(O)CN2CCCCC2)CC1

Procedure:
In analogy to the procedure described for example 167D, (rac)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-oxiranyl-ethyl)-[1,4]diazepan-5-one and piperidine gave the title compound as yellow oil. MS: 468.1 (MH+, 2Cl).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.[O:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([NH:19][C:32]([CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[O:33])[CH2:17][CH2:18]2)[CH2:7][CH2:6]1
Reactant: O=C(O)C1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(Oc3cc(F)c(F)cc3F)CC2)CC1
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(Oc3cc(F)c(F)cc3F)CC2)CC1)C1CCOCC1

Procedure:
According to the synthesis of example 19 the title compound was prepared from Trans(4-{2-[4-(2,4,5-trifluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-amine and tetrahydro-pyran-4-carboxylic acid. Preparative HPLC on reversed phase eluting with acetonitrile/water yielded the title compound. MS (m/e): 469.5 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[CH2:10]([CH2:12][NH2:13])[OH:11].CO>C(OCC)(=O)C>[NH2:9][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:13][CH2:12][CH2:10][OH:11])[CH:3]=1
Reactant: Cc1nc(N)cc(Cl)n1
Reactant: NCCO
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(N)cc(NCCO)n1
Temperature: 250 °C
Yield: 39.7 %

Procedure:
A mixture of 6-chloro-2-methylpyrimidin-4-ylamine (717 mg, 5.0 mmol) and ethanolamine (0.602 mL, 10.0 mmol) were heated at 250° C. in a microwave for 30 seconds. After cooling, the residue was dissolved in ethyl acetate, containing a small amount of methanol and was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a white solid (334 mg, 40% yield). 1H NMR (400 MHz, DMSO-d6): δ 6.45 (br s, 1H), 5.98 (br s, 2H), 5.25 (s, 1H), 3.47 (t, J=6.0 Hz, 2H), 3.23-3.14 (m, 2H), 2.12 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19]C)=[O:18])=[CH:10][C:9]([NH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[N:8][CH:7]=2)#[N:2].CO.[OH-].[Li+]>O1CCCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([OH:19])=[O:18])=[CH:10][C:9]([NH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[N:8][CH:7]=2)#[N:2]
Reactant: COC(=O)c1cccc(Nc2c(C#N)cnc3cnc(NCCN4CCOCC4)cc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1cccc(C(=O)O)c1

Procedure:
To methyl 3-(3-cyano-6-(2-morpholinoethylamino)-1,7-naphthyridin-4-ylamino)benzoate in tetrahydrofuran (12 mL) was added methyl alcohol (4.5 mL) and lithium hydroxide (1 N, 4.5 mL). After 12 hr the solvents were evaporated and the crude mixture was purified by preparative HPLC to give 3-(3-cyano-6-(2-morpholinoethylamino)-1,7-naphthyridin-4-ylamino)benzoic acid in quantitative yield.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@@H:12]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:16][C@@H:15]2[O:34]C(C)(C)[O:36][C@H:14]2[C@@H:13]1[OH:39])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([O:8][NH:9][C:10]([C@H:12]1[C@@H:13]([OH:39])[C@H:14]([OH:36])[C@@H:15]([OH:34])[CH2:16][N:17]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)(=[O:19])=[O:20])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)O[C@H]2[C@H](O)[C@H](C(=O)NOCc3ccccc3)N(S(=O)(=O)c3ccc(Oc4ccccc4)cc3)C[C@@H]2O1
Solvent: CO
Product: O=C(NOCc1ccccc1)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
The above compound (5-2) (1.5 g) was dissolved in methanol (30 mL) and a cation exchange resin (Muromac, 3.4 g) was added, and then the mixture was stirred overnight at room temperature. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (chloroform:methanol=20:1→10:1) to obtain the titled compound (1.1 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][NH:13][CH2:14][CH2:15][OH:16]>C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:5]([O:4][C:2]([N:13]([CH2:14][CH2:15][OH:16])[CH3:12])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNCCO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCO)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 96.8 %

Procedure:
Benzyl chloroformate (19 g, 111.1 mmol) in THF (20 mL) was added dropwise over 15 min to a stirred solution of 2-(methylamino)ethanol (10 g, 133.3 mmol) in THF (100 mL) and aqueous sodium carbonate (100 mL) at 0° C. The reaction mixture was stirred at 0° C. for 12 h and then extracted with EtOAc (2×200 mL). The organic layer was washed with aqueous sodium carbonate (200 mL) and dried (potassium carbonate) and solvent was removed under reduced pressure to give the title compound (22.5 g, 97% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[C:3]=1[CH:21]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:22]([O:24]C)=[O:23].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[C:3]=1[CH:21]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:22]([OH:24])=[O:23]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1cnn(C)c1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2sc3c(c2c(-c2cnn(C)c2)c1C(OC(C)(C)C)C(=O)O)CCCC3
Temperature: 60 °C
Yield: 29.3 %

Procedure:
To a solution of methyl 2-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.120 g; 0.281 mmol) in methanol (3.5 mL) was added a solution of sodium hydroxide 10 N (0.350 mL; 3.5 mmol) and the mixture was heated at 60° C. for 18 h. The volatiles were removed under reduced pressure and the residue was dissolved in water, the mixture was then acidified by adding 1N HCl until a precipitate was formed. The solid was filtered, washed with water and dried under reduced pressure. The crude product was suspended in a mixture of acetonitrile and methanol, filtered, washed with acetonitrile and dried under reduced pressure to furnish 0.034 g (29%) of the title compound as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[CH2:11]([O:10][CH2:9][C@@H:8]([NH2:7])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](COCc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
220 mg (644 μmol) of -tert.-butyl-[(2S)-1-(benzyloxy)-3-phenylpropane-2-yl]carbamate (intermediate 30) were dissolved in 11 ml of a 4 N hydrogen chloride solution diluted in dioxane and stirred for 1 hour at RT. Then, the batch was evaporated and the residue vacuum dried. The yield was 138 mg (77% o. th.) of the title compound.