Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([C:14]2[CH:15]=[N:16][N:17]([CH2:20][CH3:21])[C:18]=2[OH:19])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][S:7]2(=[O:23])=[O:22].ClCCl.C(=O)([O-])[O-].[K+].[K+].[CH2:33]([S:36](Cl)(=[O:38])=[O:37])[CH2:34][CH3:35]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH3:1][C:2]1[C:11]([C:12]([C:14]2[CH:15]=[N:16][N:17]([CH2:20][CH3:21])[C:18]=2[O:19][S:36]([CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][S:7]2(=[O:23])=[O:22]
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)CCCS3(=O)=O)c1O
Reactant: CCCS(=O)(=O)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)Oc1c(C(=O)c2ccc3c(c2C)CCCS3(=O)=O)cnn1CC
Temperature: 25 °C
Yield: 47.5 %

Procedure:
A 30-ml eggplant type flask was charged with 0.30 g (0.86 mmol) of 5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide, 25 ml of dichloromethane, 5 ml of water and 0.14 g (0.86 mmol, 1 equivalent) of potassium carbonate. While the mixture was stirred at room temperature, 0.14 g (0.95 mmol, 1.1 equivalents) of n-propanesulfonyl chloride was dropwise added. 5 mg of benzyltriethylammonium chloride (BTEAC) was added, and the mixture was allowed toreact at the above temperature for 2 hours and then liquid-separated. An aqueous layer was extracted with dichloromethane. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off to give 0.2 g of a crude product, and the crude product was recrystallized from ethanol to give 0.18 g (yield 48%) of 5-methyl-6-(1-ethyl-5-n-propanesulfonyloxypyrazole-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 58).
Reaction SMILES: [CH3:1][Al](C)C.Br[C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH2:13]2)=[N:10][CH:11]=1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C@H:14]1[CH2:15][CH2:16][N:12]([C:9]2[N:8]=[CH:7][C:6]([CH3:1])=[CH:11][N:10]=2)[CH2:13]1
Reactant: Clc1ccc(CN[C@H]2CCN(c3ncc(Br)cn3)C2)c(Cl)c1
Reactant: C[Al](C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1cnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 65 °C

Procedure:
Add trimethylaluminium (2 N in hexanes, 190 μL, 0.32 mmol) and tetrakis(triphenylphosphine)palladium (0) (26 mg, 0.022 mmol) to (S)-[1-(5-bromopyrimidin-2-yl)-pyrrolidin-3-yl]-(2,4-dichlorobenzyl)-amine in dry THF (1.5 mL) and heat at 65° C. for 2 h, then add extra trimethylaluminium (2 N in hexanes, 190 μL, 0.32 mmol) and tetrakis(triphenylphosphine)palladium (0) (26 mg, 0.022 mmol) and heat at 65° C. for 30 min and 48 h at room temperature. Add water and extract with chloroform. Combine the organic layers and wash with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and dissolve the residue in methanol (2 mL) and deposit onto an SCX-2 cartridge; eluting with methanol, then with 2 N ammonia in methanol. Concentrate the ammonia washing and chromatograph the residue by preparative mass guided chromatography to give the title compound as a residue. Treatment of the residue essentially as described in Example 1 gives the title compound as its hydrochloride. 1H NMR (300 MHz, CDCl3) δ 8.16 (2H, s), 7.37 (2H, dd, J=5.09, 3.01 Hz), 7.21 (1H, dd, J=8.29, 2.07 Hz), 3.90 (2H, d, J=4.90 Hz), 3.68-3.83 (2H, m), 3.58 (1H, m), 3.39-3.51 (2H, m), 2.14-2.25 (1H, m), 2.12 (3H, s), 1.84-1.96 (1H, m), MS (ES): m/z=337 [M+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:8][CH:9]=1
Reactant: O=C(O)CCCCc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCCCC(=O)O)nc1
Reaction time: 1 h

Procedure:
A solution of 5-(5-nitropyrid-2-yl)pentanoic acid (6.0 g) in ethanol (140 ml) containing 10% palladium on carbon (0.6 g) was shaken under an atmosphere of hydrogen at 3.4 atmospheres pressure for 1 hour. The catalyst was removed by filtration, the filtrate was evaporated to dryness and the residue was recrystallised from acetonitrile to give the title compound as a cream coloured solid (4.04 g). m.p. 80°-82° C.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:43]([C:40]2[CH:39]=[CH:38][C:37]([O:36][CH3:35])=[CH:42][CH:41]=2)(=[O:45])=[O:44])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Product: COc1ccc(S(=O)(=O)Nc2cc3nc(-c4ccccc4)n(-c4ccccc4)c3cc2OCCCCCC(=O)OC(C)C)cc1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted according to general operating instructions 13 with 4-methoxybenzenesulfonic acid chloride.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH2:15])[C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>[OH-].[Na+].O>[CH2:16]([NH:15][C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(N)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Cl

Procedure:
To a solution of 3-methylsulfonyl-4-chloro-5-aminobenzoic acid (1.25 g.) in 1N sodium hydroxide (5 ml.) is added benzyl bromide (1 ml.). The stirred reaction is heated at 45°-50° C. for 6 hours with the occasional addition of a few drops of 1N sodium hydroxide to maintain a pH of 9. The reaction mixture is diluted with water (50 ml.) and acidified with 1N hydrochloric acid to give 0.9 g. (53 %) of 3-benzylamino-4-chloro-5-methylsulfonylbenzoic acid, m.p. 254°-256.5° C. after recrystallization from nitromethane.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6]C=C[C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[N:21]3)=[C:16]([NH:24][CH2:25][CH2:26][CH2:27][NH2:28])[N:15]=2)=[CH:10][CH:9]=1.COC1C=C(C2C=C3C(C=CC=N3)=C(NCCCN)N=2)C=C(OC)C=1OC.CC1C=C(C2C=C3C(C=CC=N3)=C(NCCCN)N=2)C=CC=1C.NCC(O)CNC1N=C(C2C=CC3C(=CC=CC=3)C=2)C=C2C=1C=CC=N2.NCC(O)CNC1N=C(C2C=CC(C3C=CC=CC=3F)=CC=2)C=C2C=1C=CC=N2.NCC(O)CNC1N=C(C2C=CC(C3C=CC(OC)=CC=3)=CC=2)C=C2C=1C=CC=N2.NCC(O)CNC1N=C(C2C=C(OC)C(OC)=C(OC)C=2)C=C2C=1C=CC=N2.NCC(O)CNC1N=C(C2C=CC(Br)=CC=2)C=C2C=1C=CC=N2.COC1C=CC(C2C=CC(C3C=C4C(C=CC=N4)=C(NCC(C)(C)CN)N=3)=CC=2)=CC=1.CN(C)C1C=CC(C2C=C3C(C=CC=N3)=C(NCC(O)C)N=2)=CC=1.CN(C)C1C=CC(C2C=C3C(C=CC=N3)=C(NCCSCCO)N=2)=CC=1>>[CH:10]1[C:9]2[C:8](=[CH:3][CH:2]=[CH:7][CH:6]=2)[CH:13]=[CH:12][C:11]=1[C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[C:16]([NH:24][CH2:25][CH2:26][CH2:27][NH2:28])[N:15]=1
Reactant: NCCCNc1nc(-c2ccc(-c3ccccc3F)cc2)cc2ncccc12
Agent: CC(O)CNc1nc(-c2ccc(N(C)C)cc2)cc2ncccc12
Agent: CN(C)c1ccc(-c2cc3ncccc3c(NCCSCCO)n2)cc1
Agent: COc1cc(-c2cc3ncccc3c(NCC(O)CN)n2)cc(OC)c1OC
Product: NCCCNc1nc(-c2ccc3ccccc3c2)cc2ncccc12

Procedure:
N-[7-(2′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine; N-[7-(3,4,5-trimethoxyphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine; N-[7-(3,4-dimethylphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine; 1-amino-3-[[7-(2-naphthalenyl)-1,6-naphthyridin-5-yl]amino]-2-propanol; 1-amino-3-[[7-(2′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]amino]-2-propanol; 1-amino-3-[[7-(4′-methoxy[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]amino]-2-propanol; 1-amino-3-[[7-(3,4,5-trimethoxyphenyl)-1,6-naphthyridin-5-yl]amino]-2-propanol; 1-amino-3-[[7-(4-bromophenyl)-1,6-naphthyridin-5-yl]amino]-2-propanol; N-[7-(4′-methoxy[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-2,2-dimethyl-1,3-propanediamine; 1-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]amino]-2-propanol; 2-[[2-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]amino]ethyl]thio]-ethanol;
Reaction SMILES: O1C=CC=C1.[C@@H:6]1([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[O:19])[NH:17][C:15]2=[O:16])[O:13][C@H:10]([CH2:11][OH:12])[C@@H:8]([OH:9])[CH2:7]1.COC1C2OC(C=CC=2C=C2C=COC=12)=O.[CH3:39][O:40][C:41]1[CH:62]=[CH:61][C:44]([C:45](Cl)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)=[CH:43][CH:42]=1>>[CH3:21][C:20]1[C:18](=[O:19])[NH:17][C:15](=[O:16])[N:14]([CH:6]2[O:13][CH:10]([CH2:11][O:12][C:45]([C:44]3[CH:61]=[CH:62][C:41]([O:40][CH3:39])=[CH:42][CH:43]=3)([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:8]([OH:9])[CH2:7]2)[CH:22]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: COc1c2occc2cc2ccc(=O)oc12
Solvent: c1ccoc1
Product: COc1ccc(C(OCC2OC(n3cc(C)c(=O)[nH]c3=O)CC2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
For example, the furan-side monoadduct between thymidine and 8-methoxypsoralen, prepared as described above, is reacted with 4,4'-dimethoxytrityl chloride at room temperature in an appropriate anhydrous solvent to give the 5'-dimethoxytrityl thymidine:8-methoxypsoralen monoadduct. Following purification by high pressure liquid chromatography this compound is reacted with chloro-N,N diisopropylamino methoxyphosphine at room temperature in an appropriate solvent to give the 5'-dimethoxytritylthymidine phosphoramidite: 8-methoxypsoralen monoadduct. This compound is then used as an activated protected nucleoside phosphoramidite in a typical phosphite triester polynucleotide synthesis. The stereochemistry of the 8-methoxypsoralen moiety is correct (i.e. cis-syn) for subsequent crosslink formation when hybridized to the complementary sequence.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:34](O)[CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:45]\[CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH3:53].[C:55]([OH:58])(=[S:57])[CH3:56]>C1COCC1.CCCCCCC>[C:55](=[O:58])([S:57][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:45]\[CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH3:53])[CH3:56]
Reactant: CC(O)=S
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
Triphenylphosphine (21.0 g, 80 mmol) was dissolved in dry THF (170 mL) at 0° C. under inert atmosphere and added DIAD (15.8 mL, 80 mmol) dropwise. After 40 minutes at 0° C. the white suspension was added dropwise to a solution of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-ol (11.5 g, 40 mmol) and thioacetic acid (5.7 mL, 80 mmol) in dry THF (50 mL) during 15 minutes. The resulting turbid mixture was stirred at 0° C. for 30 minutes, followed by ambient temperature for 1.5 hour. Heptane was added (200 mL), the mixture was stirred for ten minutes and the precipitated white solid removed by filtration and rinsed with heptane (150 mL). The residue was concentrated to remove most of the THF and stirred at ambient for 18 hours. The mixture was filtered, concentrated and added heptane (200 mL). The resulting mixture was stirred for 2 hours, filtered and evaporated. The residue was purified by flash chromatography on silica gel, using EtOAc:Heptane (2:98), followed by EtOAc:Heptane (4:96) and finally EtOAc:Heptane (5:95). Concentration of the appropriate fractions provided 11.0 g (79% yield) of the title compound as oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH:23]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[C:27]1=[O:45])([CH3:25])[CH3:24]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:31]3[CH:32]=[C:33]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:45])[N:26]([CH:23]([CH3:25])[CH3:24])[CH2:35][CH2:34]4)[C:16]2=[CH:15][N:14]=1
Reactant: CC(C)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CCN(C(C)C)C5=O)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 8, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one. LCMS (M+H)+=511.9/514.0.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([O:22][CH2:23][CH3:24])[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[O:11])=[C:4]([F:25])[CH:3]=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O>>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:10](=[O:11])[CH:9]([C:5]2[C:6]([F:8])=[CH:7][C:2]([C:27]3[O:26][CH:30]=[CH:29][CH:28]=3)=[CH:3][C:4]=2[F:25])[O:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)#[N:21]
Reactant: OB(O)c1ccco1
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(Br)cc1F
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccco2)cc1F

Procedure:
Analogous to example 247.1, (RS)-2-(4-bromo-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-ethoxy-acetamide (example 248.1) was reacted with 2-furanboronic acid to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-4-furan-2-yl-phenyl)-2-ethoxy-acetamide. Off-white solid. MS 397.0 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:4][C:3]=1[CH2:12][O:13][C:14]1[CH:37]=[CH:36][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:20]2)=[CH:16][CH:15]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:4][C:3]=1[CH2:12][O:13][C:14]1[CH:37]=[CH:36][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:21]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[N:20]2)=[CH:16][CH:15]=1
Reactant: COC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4cccs4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2cccs2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
A mixture of methyl 3-[1-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (633 mg), lithium hydroxide monohydrate (155 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, and 1N hydrochloric acid (3.7 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (581 mg, yield: 95%). This was recrystallized from ethyl acetate-hexane. Melting point: 159–160° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:33])[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[C:17](=[O:28])[C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[C:20](=[O:23])[C:21]=2[CH3:22])[CH:12]=[CH:11][C:10]=1[O:29]C(=O)C.C(=O)([O-])O.[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:33])[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[C:17](=[O:28])[C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[C:20](=[O:23])[C:21]=2[CH3:22])[CH:12]=[CH:11][C:10]=1[OH:29]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccccn3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccccn3)c2)=C(C)C1=O
Yield: 50.8 %

Procedure:
N-(Pyridin-2-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.050 g, 0.111 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.023 g, 0.0564 mmol, 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[C:37]([O:45][C:46](=[O:48])[CH3:47])=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](O)=[O:40])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:39](=[O:40])[C:38]2[CH:42]=[CH:43][CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])[C:37]=2[O:45][C:46](=[O:48])[CH3:47])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3cccnc3)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.5 %

Procedure:
3-Aminopyridine (0.076 g, 0.802 mmol), triethylamine (0.081 g, 0.802 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.136 g, 0.802 mmol) were added to a methylene chloride solution (100 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.100 g, 0.222 mmol, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH2:20])=[O:19])[CH:8]=1)=[O:5].Cl[C:35]1[N:40]=[C:39]([NH2:41])[CH:38]=[CH:37][C:36]=1[F:42].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:41][C:39]1[N:40]=[C:35]([C:22]2[CH:23]=[CH:24][C:2]([Cl:1])=[C:3]([CH:21]=2)[C:4]([NH:6][C:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=[C:9]([C:18]([NH2:20])=[O:19])[CH:8]=2)=[O:5])[C:36]([F:42])=[CH:37][CH:38]=1
Reactant: Nc1ccc(F)c(Cl)n1
Reactant: CC1(C)OB(c2ccc(Cl)c(C(=O)Nc3cc(C(N)=O)nn3-c3ccccc3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(NC(=O)c2cc(-c3nc(N)ccc3F)ccc2Cl)n(-c2ccccc2)n1

Procedure:
A solution of 5-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxamide (Preparation 3, 50 mg, 0.11 mmol), 6-chloro-5-fluoropyridin-2-amine (47 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) and potassium carbonate (30 mg, 0.21 mmol) in dioxane (1.5 mL) and water (1.5 mL) was heated at 110° C. under microwave irradiation for 1 hour. The reaction was poured into water (25 mL) and extracted with EtOAc (2×25 mL). The organic layer was washed with brine (10 mL), dried over magnesium sulphate and concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:20])[C@@H:17]([CH3:19])[NH2:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:21][CH3:22].Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:19][C@H:17]1[NH:18][C:24](=[O:26])[N:15]([C:12]2[CH:13]=[N:14][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:21][CH3:22])[CH:4]=3)=[CH:10][CH:11]=2)[C:16]1=[O:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)ccc1C
Solvent: ClCCl
Product: COc1cc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cn2)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 137.8 %

Procedure:
To a solution of N1-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-D-alaninamide (Intermediate 52, 255 mg) in dry dichloromethane (15 mL), TEA (0.590 mL, 4.23 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (113 mg, 0.381 mmol) in dry dichloromethane (DCM) (5 mL) was slowly added and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with water (10 mL) and extracted with dichloromethane (20 mL). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by silica gel chromatography (Biotage system, 10 g SNAP column) using as eluent a gradient cyclohexane/ethyl acetate from 70/30 to 30/70. This afforded the title compound as a white solid (172 mg, 0.525 mmol).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.C1C(=O)N([Cl:17])C(=O)C1>CC#N>[Cl:17][C:7]1[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: FC(F)(F)c1cc[nH]n1
Solvent: CC#N
Product: FC(F)(F)c1n[nH]cc1Cl
Temperature: 80 °C
Yield: 76.8 %

Procedure:
A mixture of 3-(trifluoromethyl)pyrazole (1.58 g, 11.6 mmol) and NCS (1.55 g, 11.6 mmol) in CH3CN (20 mL) was heated at 80° C. for 3 hrs. It was then cooled to rt, evaporated in vacuo, and purified by flash chromatography (SiO2) with a gradient elution of 0 to 15% EtOAc/CH2Cl2 to afford 4-chloro-3-(trifluoromethyl)pyrazole (1.52 g, 77%).
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH:14]=[CH2:15])(=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].Br[CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>C1COCC1>[C:20]1(=[O:29])[N:19]([CH2:18][CH2:17][CH:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[C:3]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]12
Reactant: C=CCOC(=O)CC(=O)OCC=C
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(=O)C(CCN1C(=O)c2ccccc2C1=O)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
A solution of sodium hydride (4.35 g, 0.18 mol) in freshly distilled THF (100 mL) was cooled to 0° C. and treated with diallyl malonate (35 g, 0.19 mol) over 40 min via a dropping funnel. After stirring at room temperature for 30 min, N-(2-bromoethyl)phthalimide (43.9 g, 0.17 mol) was added to the solution in one portion and the mixture was heated to reflux. After 48 h the solution was cooled to 0° C., quenched with 2N HCl and concentrated to about 20% of its original volume. The concentrate was diluted with ethyl acetate (300 mL) and washed successively with satd. aq. K2CO3 and NaCl. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography (5-25% ethyl acetate:hexanes) provided diallyl (2-phthalimidoethyl)malonate (41.2 g, 67%) as a colorless oil. 1H NMR (300 MHz, CDCl3) d 7.82 (m, 2H), 7.72 (m, 2H), 5.85 (m, 2H), 5.30 (m, 2H), 5.22 (m, 2H), 4.60 (m, 4H), 3.80 (t, J=6.6 Hz, 2H), 3.46 (t, J=7.2 Hz, 1H), 2.30 (dd, J=13.8, 6.9 Hz, 2H).