Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O-]C#N.[K+].COC1C=C([N:30]2[CH2:36][C:34](=O)[NH:33][C:31]2=[O:32])C=CC=1OC.Br.BrCCN>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:12][C:13](=[O:15])[N:30]([CH2:36][CH2:34][NH2:33])[C:31]2=[O:32])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N2CC(=O)NC2=O)cc1OC
Reactant: COc1ccc(NCC(=O)O)cc1OC
Agent: Br
Agent: N#C[O-]
Agent: NCCBr
Product: COc1ccc(N2CC(=O)N(CCN)C2=O)cc1OC

Procedure:
In the same way as in [A] and reacting the N-(3,4-dimethoxyphenyl)glycine (17.2 g, 81 mmoles) with potassium cyanate (6.6 g, 81 mmoles) the 1-(3,4-dimethoxyphenyl)hydantoin was obtained, m.p. 223°-225° C. By reacting the latter (11.23 g, 47.5 mmoles) with 2-bromoethylamine hydrobromide (9.74 g, 47.5 mmoles) as described in [A] the title compound was obtained, m.p. 162°-164° C.
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1NC(C2C3C(=CC=CC=3)C([Br:31])=CC=2)=CN=1)=O)C(C)C.C(N(C(C)C)CC)(C)C.COC(=O)NC(C(N1CC(C#N)CC1C1NC(C2C=CC3C(=CC=C([C:74]4[CH:79]=[CH:78][C:77]([C:80]5[NH:81][C:82]([CH:85]6[CH2:91][C:88]7([CH2:90][CH2:89]7)[CH2:87][N:86]6[C:92](=[O:105])[CH:93]([NH:100][C:101]([O:103][CH3:104])=[O:102])[CH2:94][CH2:95][S:96]([CH3:99])(=[O:98])=[O:97])=[N:83][CH:84]=5)=[CH:76][CH:75]=4)C=3)C=2)=CN=1)=O)C(C)C>>[CH3:104][O:103][C:101](=[O:102])[NH:100][CH:93]([C:92]([N:86]1[CH:85]([C:82]2[NH:81][C:80]([C:77]3[CH:76]=[CH:75][C:74]([Br:31])=[CH:79][CH:78]=3)=[CH:84][N:83]=2)[CH2:91][C:88]2([CH2:90][CH2:89]2)[CH2:87]1)=[O:105])[CH2:94][CH2:95][S:96]([CH3:99])(=[O:98])=[O:97]
Reactant: COC(=O)NC(CCS(C)(=O)=O)C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)c3ccccc23)[nH]1)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(CCS(C)(=O)=O)C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1

Procedure:
Title compound was prepared according to the method employed to prepare (1-{2-[5-(4-Bromonaphthalen-1-yl)-1H-imidazol-2-yl]-pyrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester in Example CK, substituting N-methylmorpholine with five equivalents of diisopropylethylamine.(99%) Example FA: [1-(4-Cyano-2-{5-(6-(4-{2-[5-(4-methanesulfonyl-2-methoxycarbonylamino-butyryl)-5-aza-spiro[2,4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester
Reaction SMILES: [Cl:1][C:2]1[N:3]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([F:12])[C:6]=1[C:7](OCC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:5]([F:12])[C:6]=1[CH2:7][OH:8]
Reactant: CCOC(=O)c1c(F)c(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1c(Cl)c(CO)c(F)c1-c1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A solution (20 mL) of ethyl 2-chloro-4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (250 mg) in tetrahydrofuran was cooled to −70° C., and a 1.5 mol/L solution (6 mL) of diisobutylaluminum hydride in toluene was added dropwise by small portions. The mixture was further stirred at −70° C. for 1 hr, 1 mol/L hydrochloric acid (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a colorless oil (yield 210 mg, 94%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:43]([O:45]C)=[O:44])=[CH:11][C:12]2[CH2:13][CH2:14][CH2:15][C:16]([OH:42])([C:19]3[S:20][C:21]([C:24]4[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([NH:31][C:32]5[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=5)[N:25]=4)=[CH:22][N:23]=3)[C:17]=2[CH:18]=1.[OH-].[K+].Cl>O1CCCC1>[F:8][C:9]1[C:10]([C:43]([OH:45])=[O:44])=[CH:11][C:12]2[CH2:13][CH2:14][CH2:15][C:16]([OH:42])([C:19]3[S:20][C:21]([C:24]4[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([NH:31][C:32]5[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][N:33]=5)[N:25]=4)=[CH:22][N:23]=3)[C:17]=2[CH:18]=1
Reactant: COC(=O)c1cc2c(cc1F)C(O)(c1ncc(-c3cc(C)cc(Nc4cc(C(F)(F)F)ccn4)n3)s1)CCC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C3(O)CCCc4cc(C(=O)O)c(F)cc43)s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a solution of methyl 3-fluoro-5-hydroxy-5-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-5,6,7,8-tetrahydronaphthalene-2-carboxylate, trifluoroacetate salt (200 mg, 0.297 mmol) in tetrahydrofuran (1.2 mL) under argon was added potassium hydroxide (40% aqueous solution, 834 μl, 5.95 mmol), and the reaction was stirred at rt for 16 h. The pH was adjusted to 5 by the addition of aqueous HCl (2.0 M). The resulting mixture was extracted with ethyl acetate (3 times), and the combined organic phases were dried (Na2SO4) and concentrated under reduced pressure to afford (rac)-3-fluoro-5-hydroxy-5-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (115.0 mg, 0.211 mmol, 71% yield) as a light yellow solid. MS ESI calcd for C26H20F4N4O3S [M+H]+ 545, found 545.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9]1([CH3:23])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH:17]=[C:18]([CH:21]=O)[S:19][CH:20]=2)[O:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N-]=C=O>C1COCC1>[CH3:8][C:9]1([CH3:23])[C:13]([CH3:14])([CH3:15])[O:12][B:11]([C:16]2[CH:17]=[C:18]([CH2:21][N:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[S:19][CH:20]=2)[O:10]1
Reactant: C1CCCNCC1
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [N-]=C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2csc(CN3CCCCCC3)c2)OC1(C)C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
A solution of hexahydro-1H-azepine (0.025 g, 0.252 mmol) in THF (1 mL) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (0.05 g, 0.210 mmol) in THF (1 mL) in 1-Dram vial and let stir for 30 minutes. Sodium triacetoxyborohydride (0.225 g, 0.582 mmol) was then added to the mixture and let stir 18 h. The mixture was then agitated for 1 hour with MP-Isocyanate Resin (0.135 g, 0.230 mmol, 1.7 mmol/g) and THF (2 mL). The solution was filtered and the resin was washed with THF (4 mL×2). The combined solution was concentrated, giving 0.055 g (82%) of the title compound.
Reaction SMILES: [S:1]1[C:5]2[C:6]([CH:10]=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1C=CC=CC=1.Cl>[OH-].[Na+]>[S:1]1[C:5]2[C:6]([CH:10]=[CH:13][C:14]([OH:16])=[O:15])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc2nnsc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc2nnsc12
Temperature: 0 °C
Yield: 447.6 %

Procedure:
A mixture of 1.96 g of benzo-1,2,3-thiadiazole-7-carbaldehyde, 1.24 g of malonic acid and 6 ml of pyridine are heated for 26 hours at 120° C., with 2 further additions of 0.6 g portions of malonic acid after 4 and 7 hours. The mixture is then cooled, poured into ice-water and acidified with concentrated hydrochloric acid. The precipitate which has formed is faltered off and dissolved in dilute sodium hydroxide solution, the mixture is washed three times with methylene chloride, and the aqueous phase is subsequently acidified once more, using hydrochloric acid. The precipitate obtained is filtered off, washed with water and dried in vacuo, resulting in 11 g of the title compound of m.p. 199°-202° C.
Reaction SMILES: [NH:1]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:2]([C:17]([O:19]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[NH2:38][C@H:39]([C:47]([NH:49][C@@H:50]([C:52]([OH:54])=[O:53])[CH3:51])=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCOCC1.O>[NH:1]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[C@@H:2]([C:17]([NH:38][C@H:39]([C:47]([NH:49][C@@H:50]([C:52]([OH:54])=[O:53])[CH3:51])=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:19])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C[C@@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
8.0 g (15.0 mmol) of pentafluorophenyl ester of Boc-D-Orn(Z)-OPfp was dissolved in 15 ml dioxane. To this was added with mixing 4.3 g (17.7 mmol) H-Phe-D-Ala-OH dissolved in water with pH 8.5. The reaction mixture was stirred for a day and a night at room temperature. The solvents were evaporated under vacuum, 70 ml ethyl acetate was added, and the mixture was acidified to pH 2-3 by the addition of 2% sulfuric acid solution. The peptide was extracted twice with 70 ml ethyl acetate, washed with saturated sodium chloride solution to neutral pH and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under vacuum leaving a thick oil. The product was crystallized from ethyl acetate with ether and hexane. The yield was 6.92 g (74.4%), and the melting point was 145° C. Rf=0.44 in acetic acid:chloroform;methanol=0.5:16:1. Rf=0.32 in chloroform:ethyl acetate:methanol=6:3:1.
Reaction SMILES: [C:1]([O:5]CC)(=O)[CH:2]=[CH2:3].[CH3:8][C:9]1[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:11][NH:12][C:13]=1[NH2:14]>N1C=CC=CC=1.O>[CH3:8][C:9]1[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:11][N:12]2[CH2:3][CH2:2][C:1](=[O:5])[NH:14][C:13]=12
Reactant: Cc1c(-c2cccnc2)n[nH]c1N
Reactant: C=CC(=O)OCC
Solvent: O
Solvent: c1ccncc1
Product: Cc1c(-c2cccnc2)nn2c1NC(=O)CC2
Temperature: 25 °C

Procedure:
Ethyl acrylate (0.5 mL) was added to a solution of 4-methyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine (300 mg, 1.72 mmol) in pyridine (4 mL) and water (1 mL) and the resulting mixture heated to reflux overnight. After cooling to rt, the solvent was removed in vacuo and the residue re-crystallized from MeOH to give the desired product: MS (m/z): 229.1 [M+H]+, 1HNMR (400 MHz, CD3OD) δ 8.80 (d, 1 H, J=1.2 Hz), 8.53 (dd, 1 H, J=1.2 Hz, J=4.8 Hz), 8.07-8.09 (m, 1 H), 7.52 (dd, 1 H, J=4.8 Hz, J=8.0 Hz), 4.36 (t, 2 H, J=7.2 Hz), 2.94 (t, 2 H, J=7.2 Hz), 2.13 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH2:4]/[N:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18].[SH:22][C@@H:23]([CH2:27][C:28]([OH:30])=[O:29])[C:24](O)=[O:25]>C1(C)C=CC=CC=1>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][NH:14][C:8]1[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=1[CH:6]1[N:5]([CH2:4][CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[C:24](=[O:25])[CH:23]([CH2:27][C:28]([OH:30])=[O:29])[S:22]1
Reactant: O=C(O)C[C@H](S)C(=O)O
Reactant: CN(C)CCNc1c(F)cccc1/C=N/CCC(C)(C)C
Solvent: Cc1ccccc1
Product: CN(C)CCNc1c(F)cccc1C1SC(CC(=O)O)C(=O)N1CCC(C)(C)C

Procedure:
2-((E)-(3,3-dimethylbutylimino)methyl)-N-(2-(dimethylamino)ethyl)-6-fluorobenzenamine (175 mg, 0.5964 mmol) and (S)-2-mercaptosuccinic acid (102 mg, 0.6793 mmol) were stirred in toluene (7 mL) at 80° C. for 24 hours. Crude 2-(2-(2-(2-(dimethylamino)ethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid was obtained as a brown oil and carried on to the next reaction.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH:9]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:8]3[O:7][C:6]=2[C:5](C(O)=O)=[CH:4][C:3]=1[Cl:18].NC1C2C3CCCCC=3OC=2C(C(O)=O)=CC=1Cl.NC1C2C3C=CC=CC=3OC=2C(C(O)=O)=CC=1Cl>>[NH2:1][C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:18]
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1C1CCCCC1O2
Agent: Nc1c(Cl)cc(C(=O)O)c2oc3c(c12)CCCC3
Agent: Nc1c(Cl)cc(C(=O)O)c2oc3ccccc3c12
Product: Nc1c(Cl)ccc2oc3ccccc3c12

Procedure:
When the procedure of Example 16 is followed however, 1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran -4-carboxylic acid is replaced by 1-amino2-chloro-6,7,8,9-tetrahydrodibenzofuran-4-carboxylic acid or 1-amino-2-chlorodibenzofuran-4-carboxylic acid then the captioned products are prepared.
Reaction SMILES: F[C:2]([C:5]1[C:10]([C:11]#[N:12])=[CH:9][N:8]=[CH:7][N:6]=1)([CH3:4])[CH3:3]>C1COCC1.[Ni]>[CH:2]([C:5]1[C:10]([CH2:11][NH2:12])=[CH:9][N:8]=[CH:7][N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(F)c1ncncc1C#N
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)c1ncncc1CN
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 4-(2-fluoropropan-2-yl)pyrimidine-5-carbonitrile (1.0 equiv.) and Raney-nickel in THF (0.5 M) was degassed under vacuum. The resulting mixture was hydrogenated under a fully-inflated balloon at room temperature overnight. The mixture was filtered through a pad of celite and the cake was rinsed with MeOH. The filtrate was concentrated and further dried to give a brown oil, which was purified by silica gel column chromatography (0-20% MeOH in ethyl acetate, 50 g column) to give (30% yield) of pale yellow oil as a 3:2 mixture of the above two products. MS (ESI) m/z 152.0 [M+1]+. MS (ESI) m/z 170.0 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:14]I>C1COCC1>[CH3:14][N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccnc1-c1ccccc1

Procedure:
2-phenylimidazole (5 g) was taken into 150 ml of THF. To this solution 2.3 g of NaH were added. After refluxing for an hour under nitrogen 5.9 g of methyl iodide were added. The reaction mixture was refluxed for another 3 hours under nitrogen and then quenched with 5 ml of water. The solution was evaporated to dryness, and 200 ml of ethylacetate were added. The solution was washed with water and dried over MgSO4. The resulting product was column purified on a SiO2 using dichloromethane methane solvent mixture (95:5). The purified product is colourless oil. 1H NMR (CDCl3) δ 7.55 (2H, d, J=4.5 Hz), 7.34(3H, dd J=5.3, 1.76), 7.01 (1H, d J=1.2 Hz), 6.85 (1H, d 1.2 Hz), 3.6 (3H, s).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+]>>[N+:8]([C:7]1[C:2]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: [O-]c1ccccc1
Agent: [Na+]
Product: O=[N+]([O-])c1cccnc1Oc1ccccc1

Procedure:
In step (2) of Reaction Scheme III, a 2-chloro-3-nitropyridine of Formula XXIX-4 or XXIX-5 is reacted with sodium phenoxide to provide a 3-nitro-2-phenoxypyridine of Formula XXX-4 or XXX-5. Phenol is reacted with sodium hydride in a suitable solvent such as diglyme (bis(2-methoxyethyl) ether) to form the phenoxide. The phenoxide is then reacted at an elevated temperature with a compound of Formula XXIX-4 or XXIX-5. The product can be isolated from the reaction mixture using conventional methods.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH3:17])=[CH:11][C:10]=1[CH3:35])(C)(C)C.[OH-].[Na+]>C1COCC1.CCO>[CH3:35][C:10]1[CH:11]=[C:12]([O:15][CH:16]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH3:17])[CH:13]=[CH:14][C:9]=1[S:8][CH2:7][C:6]([OH:36])=[O:5]
Reactant: Cc1cc(OC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1SCC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(OC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1SCC(=O)O
Reaction time: 5 h

Procedure:
0.143 g (0.28 mmol) of the above prepared [rac]-(2-methyl-4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenylsulfanyl)-acetic acid tert-butyl ester was dissolved in 2.75 ml of THF/EtOH=1/1, treated with 1.38 ml (3 eq.) of 1N NaOH and kept at ambient temperature for 5 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave, since recrystallisation from AcOEt/hexane failed, 0.095 g of the title compound as colorless foam.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][CH:15]([F:17])[F:16])[N:6]=1.[CH2:30]([OH:33])[C:31]#[CH:32].C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH:15]([F:17])[F:16])=[C:7]([C:5]2[N:6]=[C:2]([C:32]#[C:31][CH2:30][OH:33])[S:3][C:4]=2[NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])[CH:12]=1
Reactant: C#CCO
Reactant: O=C(Nc1sc(Br)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1sc(C#CCO)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (150 mg, 0.3 mmol), bis(triphenylphosphine)palladium(II) dichloride (11 mg, 0.015 mmol), copper(I)iodide (5 mg, 0.024 mmol) in THF (1 mL) was added propargyl alcohol (35 μL, 0.6 mmol) then triethylamine (1 mL) under an atmosphere of nitrogen. The resultant mixture was stirred at 50° C. for 3 hours before being cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The phases were separated and the organic phase washed with brine, dried (Na2SO4) and evaporated. The resultant residue was purified by flash column chromatography on silica eluting with 80% ethyl acetate in cyclohexane to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-(5-chloro-2-difluoromethoxy-phenyl)-2-(3-hydroxy-prop-1-ynyl)-thiazol-5-yl]-amide as a yellow solid (112 mg, 78%). LCMS (Method 3) [M+H]+=476.2, RT=3.19 min.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19](O)=[O:20])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:28]CCl>CN(C)C=O>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]([Cl:28])=[O:20])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: O=C(O)C=Cc1ccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a suspension of 3-[4-(biphenyl-4-sulfonylamino)-phenyl]-acrylic acid (82a) (0.27 g, 0.71 mmol) in dichloromethane (3 ml) oxalyl chloride (0.3 ml, 3.39 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.277 g, 98%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].Cl[C:12]1[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cu].[Cu]I>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: O=C(O)c1ccccc1S
Reactant: COc1cc(Cl)cc(OC)c1
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: COc1cc(OC)cc(Sc2ccccc2C(=O)O)c1
Temperature: 190 °C
Reaction time: 10 h
Yield: 9.7 %

Procedure:
A mixture of thiosalicylic acid (44 g), 5-chloro-1,3-dimethoxybenzene (49.2 g), potassium carbonate (78 g), copper (powder) (4.3 g) and copper(I) iodide (4.3 g) in N-methyl-2-pyrrolidone (390 ml) was stirred at 190° C. for 10 hours. The reaction mixture was treated by the same procedure as in Example 1 to give 8.0 g (10%) of a compound of the indicated formula (10).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH2:40][O:41][CH2:42][CH2:43][O:44]C3CCCCO3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:51][CH3:52])=[O:5])[CH3:2].Cl.C(=O)([O-])O.[Na+]>CO>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:39])([F:37])[F:38])[CH:27]=3)[C:22]([CH2:40][O:41][CH2:42][CH2:43][OH:44])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:51][CH3:52])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(COCCOC3CCCCO3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(COCCO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
(2R*,4S*)-4-[[3,5-Bis(trifluoromethyl)benzyl]-(5-{2-[(tetrahydropyran-2-yl)oxy]ethoxymethyl}pyrimidin-2-yl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg) is dissolved in methanol (5 ml), then thereto is added 1N-hydrochloric acid (1 ml), and the mixture is stirred for 1 hour and 30 minutes. After adding a saturated aqueous sodium hydrogen carbonate solution, the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→1:1) to give (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[(2-hydroxy)ethoxymethyl]-pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (124 mg). MS (m/z): 658 [M+H]+