Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26]([NH:13][CH:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Reactant: NC1CCCCCCCCCCC1
Product: O=C(CSCC(=O)NC1CCCCCCCCCCC1)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 1-(ii), cyclododecylamine was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-[(([2-(cyclododecylamino)-2-oxoethyl]sulfanyl)acetyl)amino]benzoic acid.methyl ester (yield: 95%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[OH-].[Na+].[I:13]I>CO>[I:13][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH3:10])[C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: Cc1cc(C=O)ccc1O
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C=O)cc(I)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
At 5° C., to a stirred solution containing commercial 4-hydroxy-3-methylbenzaldehyde (4.65 g, 34.1 mmol) and sodium hydroxide (2.73 g, 68.25 mmol) in MeOH (171 mL) was added iodine (10.8 g, 42.7 mmol). The reaction was stirred for 16 h, eventually warming to ambient temperature. The reaction was quenched with 1N HCl (200 mL) and extracted with ether. The ethereal extracts were washed with 10% Na2S2O3 (3×), with brine (3×), dried (MgSO4) and concentrated. Purification on Biotage KP-Sil eluting with 70% CH2Cl2/pet. ether to give 7.28 g (81%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ 2.30 (s, 3H), 7.65 (d, J=1.02 Hz, 1H), 8.09 (d, J=1.91 Hz, 1H), 9.74 (s, 1H), 10.25 (s, 1H).
Reaction SMILES: [C:1]([O-])([O-])=[O:2].[K+].[K+].Cl[CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][N:10]=1.[CH3:17][O:18][C:19]1[C:24](C)=[CH:23][C:22]([N:26]2[C:31](=[O:32])[N:30](CC3C(F)=CC(F)=CC=3F)[C:29]3[CH:43]=[CH:44][CH:45]=[CH:46][C:28]=3[S:27]2(=[O:48])=[O:47])=[CH:21][C:20]=1C>CN(C=O)C>[CH3:15][C:14]1[C:9]([CH2:8][N:30]2[C:29]3[CH:43]=[CH:44][CH:45]=[CH:46][C:28]=3[S:27](=[O:47])(=[O:48])[N:26]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[C:24]([O:2][CH3:1])[CH:23]=3)[C:31]2=[O:32])=[N:10][CH:11]=[C:12]([CH3:16])[CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Reactant: Cc1cnc(CCl)c(C)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)N(Cc3ncc(C)cc3C)c3ccccc3S2(=O)=O)cc1OC

Procedure:
The title compound (89 mg, 0.20 mmol) was prepared from (IntA1) (167 mg, 0.50 mmol), K2CO3 (207 mg, 1.5 mmol) and 2-(chloromethyl)-3,5-dimethylpyridine (93 mg, 0.6 mmol) in DMF (5 mL) using the methods of (115).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:15]=[N:14][CH:13]=[C:12]([CH3:16])[N:11]=1.[CH:17](=[O:26])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[OH:26][CH:17]([CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[C:12]([CH3:16])[N:11]=1
Reactant: O=CC=Cc1ccccc1
Reactant: Cc1cncc(C)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cncc(CC(O)C=Cc2ccccc2)n1
Temperature: 25 °C

Procedure:
To a solution of lithium diisopropylamide (1.5 Molar, 73.3 mL, 0.11 mole) in 150 mL of tetrahydrofuran at -78° C. is added slowly a solution of 2,6-dimethylpyrazine (10.8 g, 0.1 mole) in 100 mL of tetrahydrofuran. The mixture is allowed to warm to room temperature and then cooled to -78° C. A solution of cinnamaldehyde (14.5 g, 0.11 mole) in 100 mL of tetrahydrofuran is added dropwise over 15 minutes. The reaction product mixture is then worked up according to the procedures of Example I to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:33]([O-])=O)=[C:4]([OH:32])[C:5]([NH:9][C:10](=[O:31])[CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:24][CH3:25])([CH3:23])[CH3:22])=[CH:17][C:16]=2[C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])[CH2:12][CH3:13])=[CH:6][C:7]=1[Cl:8].S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH2:44]>C(O)(C)C>[Cl:8][C:7]1[C:2]2=[N:1][C:11](=[O:14])[CH2:12][C:13](=[O:44])[N:33]=[C:3]2[C:4]([OH:32])=[C:5]([NH:9][C:10](=[O:31])[CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:24][CH3:25])([CH3:22])[CH3:23])=[CH:17][C:16]=2[C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])[CH2:12][CH3:13])[CH:6]=1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c(N)c([N+](=O)[O-])c1O
Reactant: O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c2c(c1O)=NC(=O)CC(=O)N=2

Procedure:
In a mixture of 200 ml of water and 40 ml of isopropanol was dispersed 20 g of the 3-amino-4-chloro-2-nitro-6-[2-(2,4-di-t-amylphenoxy)butanoylamino]phenol prepared in (4) above, and 100 g of sodium hydrosulfite was slowly added to the dispersion while stirring and heating on a steam bath. After refluxing, the reaction mixture was concentrated, and the precipitated solid was collected by filtration, washed with water, and dried to provide 17 g of the desired compound.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.N1C=CC=CC=1.[C:26]1([CH2:32][S:33](Cl)(=[O:35])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[N:7]=[C:6]([NH:8][S:33]([CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:35])=[O:34])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cnc2[nH]cc(Cc3ccc(NS(=O)(=O)Cc4ccccc4)nc3F)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
In a vial, 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (137, 157 mg, 0.614 mmol) was mixed with 4 mL of dichloromethane and pyridine (149 μL, 1.84 mmol) and cooled to 0° C. in an ice water bath. Phenyl-methanesulfonyl chloride (139, 0.234 g, 1.23 mmol) was added and the reaction stirred at 0° C. for 1 hour, then warmed to room temperature and stirred overnight. Aqueous saturated sodium bicarbonate was added and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 0-10% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a yellow solid (P-2181, 39 mg). MS (ESI) [M+H]+=411.1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10])[OH:22]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccc(F)cc1Br
Product: COc1ccc(F)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 92.6 %

Procedure:
With 16.9 g of 2-bromo-4-fluoroanisol and 10.0 g of 5-chloroisatin as starting materials, 15.7 g of the title compound (yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][N:6]([S:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])(=[O:10])=[O:9])[CH:5]([CH2:20][C:21](O)=[O:22])[C:4](=[O:24])[NH:3]1.[CH:26]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(Cl)CCl.CCOC(C)=O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:26]1([NH:33][C:21](=[O:22])[CH2:20][CH:5]2[C:4](=[O:24])[NH:3][C:2]([CH3:1])([CH3:25])[CH2:7][N:6]2[S:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])(=[O:9])=[O:10])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1cc(C)c(S(=O)(=O)N2CC(C)(C)NC(=O)C2CC(=O)O)c(C)c1
Reactant: NC1CCCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)N2CC(C)(C)NC(=O)C2CC(=O)NC2CCCCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (5,5-dimethyl-3-oxo-1-(2,4,6-trimethylbenzene-sulfonyl)piperazin-2-yl)acetic acid (0.32 g, 0.94 mmol) in DMF (3 mL) was added cycloheptyl amine (0.5 mL), EDC (0.5 g, 2.5 mmol), and DMAP (0.3 g, 2.6 mmol). The mixture was stirred at RT overnight. TLC indicated that the reaction was not complete. Additional EDC (0.3 g) was added and the mixture was heated at 65° C. for 1 h. The mixture was cooled to RT. EtOAc (80 mL) was added and mixture was washed with dilute HCl in brine. The EtOAc solution was dried and evaporated to give the crude compound. Column chromatograph purification (silica gel, 0-2% MeOH/CH2Cl2) gave the titled compound. MS: 464.1 (M+1)+.
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7]([CH3:10])=[N:8][CH:9]=1.CCN(CC)CC.[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25]>CCOC(C)=O.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>[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[C:25][C:4]1[CH:9]=[N:8][C:7]([CH3:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ncc(C#CCN(C)C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A 12 L reactor equipped with an overhead stirrer and N2 bubbler was charged with a solution of 5-bromo-2-methyl-3-nitropyridine (945 g, 4.35 mol) in EtOAc (5.7 L, 6 vol). To the reaction mixture, Pd(PPh3)2Cl2 (15.4 g, 0.022 mol, 0.005 equiv), CuI (8.28 g, 0.0435 mol, 0.01 equiv) and Et3N (3 L, 21.75 mol, 5 equiv) were added. Nitrogen was bubbled through the solution for 15 min and 3-dimethylamino-1-propyne (556 mL, 5.22 mol, 1.2 equiv) was added. The reaction-temperature setting was increased to 60° C. stepwise. The maximum temperature attained was 66° C. The reaction was continued for 3 h at this temperature (60° C.) and was judged complete by HPLC analysis. The reaction was cooled to ambient temperature and the inorganic salts were filtered off by passing the reaction mixture through a pad of celite. The filter cake was washed with EtOAc (2 L, 2 vol). The filtrate was transferred into a 20 L separatory funnel. The EtOAc layer was washed with 5% aqueous Na2CO3 solution (2×5 L, 5 vol). The layers were separated. The EtOAc layer was then washed with 10% brine in water (5 L, 5 vol). The layers were separated and the EtOAc layer was pumped down to a low volume (ca. 2 L, 2 vol) under reduced pressure. IPA (5 L, 5 vol) was added to the solution and the solvent was again evaporated to a low volume (ca. 2 L, 2 vol). The solution of N,N-dimethyl-3-(6-methyl-5-nitropyridin-3-yl)prop-2-yn-1-amine was subjected to hydrogenation in two batches using the procedure described in step 2, below.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:33])[CH2:22][C:23]4[CH:32]=[CH:31][C:26]5[C:27](=[O:30])[O:28][CH2:29][C:25]=5[CH:24]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.Cl.N1(C(=O)CC2C=CC(N3C=NN=N3)=CC=2)CCNC[CH2:36]1.C1(=O)C2C=C3C(=CC=2CO1)CC(=O)CC3>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:33][CH2:36][C:32]5[C:23](=[CH:24][C:25]6[CH2:29][O:28][C:27](=[O:30])[C:26]=6[CH:31]=5)[CH2:22]4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(Cc1ccc2c(c1)COC2=O)N1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2)CC1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Agent: Cl
Agent: O=C1CCc2cc3c(cc2C1)COC3=O
Product: O=C1OCc2cc3c(cc21)CCC(N1CCN(C(=O)Cc2ccc(-n4cnnn4)cc2)CC1)C3

Procedure:
6-(4-{[4-(1H-Tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)-5,6,7,8-tetrahydronaphtho[2,3-c]furan-1(3H)-one was prepared in an analogous fashion to that described above for the synthesis of 5-[2-(4-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)propyl]-2-benzofuran-1(3H)-one starting from 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride and 7,8-dihydronaphtho[2,3-c]furan-1,6(3H, 5H)-dione. LC/MS: [(M+1)]+=459.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33]>>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:32]([N:31]([CH3:35])[CH3:30])=[O:33])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C)C(=O)Cl
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: CN(C)C(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Yield: 80.3 %

Procedure:
The compound (0.15 g) obtained in Example 1 and N,N-dimethylcarbamic acid chloride (0.074 g) were reacted and treated in the same manner as in the method described in Example 6 to obtain the title compound as colorless oil (0.13 g, 80%).
Reaction SMILES: ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Br:34])[C:28]([OH:30])=O.[NH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].C(N(CC)C(C)C)(C)C>O1CCOCC1.CO>[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Br:34])[C:28]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:30]
Reactant: NCCCCCC(=O)O
Reactant: O=C(O)c1ccc(Br)c(Br)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)CCCCCNC(=O)c1ccc(Br)c(Br)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.6 %

Procedure:
Added N-hydroxysuccinimide (0.69 g, 6 mmol) followed by 1,3-dicyclohexylcarbodiimide (1.24 g, 6 mmol) to a stirred solution of 3,4-dibromobenzoic acid (1.4 g, 5 mmol) in anhydrous dioxane (40 mL). Stirred suspension for 6 hours at room temperature. Filtered precipitate from solution and washed with dioxane (3×5 mL). Combined filtrate and washes and concentrated in vacuo to afford a white solid. Dissolved solid in methanol (50 mL) and added 6-aminohexanoic acid (1.31 g, 10 mmol) and N,N-diisopropylethylamine (1.74 mL, 10 mmol). Stirred for 24 hours at room temperature. Concentrated solution on a rotary evaporator and dissolved residue in 0.1 N NaOH (150 mL). Filtered precipitate from solution and washed with water (2×10 mL). Combined filtrate and washes and acidified with conc. HCl (1.5 mL). Extracted filtrate with ether (2×50 mL), washed extract with brine (2×30 mL) and dried over anhydrous MgSO4. Removed solvent in vacuo to afford a white solid. Obtained 1.78 g (91% yield) of N-(3,4-di-bromobenzoyl)-6-aminohexanoic acid. 1H NMR (300 MHz, DMSO-d6): δ11.99 (s, 1H), 8.61 (triplet, J=6 Hz, 1H), 8.16 (doublet, J=1.8 Hz, 1H), 7.84(doublet, J=8.1 Hz, 1H), 7.73(doublet of doublets, J=1.8, 8.1 Hz, 1H), 3.2 (doublet of triplets, J=6,6, 6.0 Hz, 2H), 2.18 (triplet, J=7.3 Hz, 2H), 1.49 (multiplet, 4H), 1.28 (multiplet, 2H). 13C NMR (300 MHz, DMSO-d6): δ174.71, 164.03, 135.64, 133.98, 132.31, 128.22, 127.20, 124.14, 33.60, 28.65, 26.00, 24.22.
Reaction SMILES: O1CCOCC1.Br[C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[N:13][C:12]=12.[CH3:18][O:19][C:20]([C:22]1[S:23][C:24]([CH3:36])=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:26]=1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>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.O>[CH3:18][O:19][C:20]([C:22]1[S:23][C:24]([CH3:36])=[C:25]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[N:13][C:12]=23)[CH:26]=1)=[O:21]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)s1
Reactant: Clc1cnc2c(Br)cnn2c1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cnn3cc(Cl)cnc23)c(C)s1
Temperature: 100 °C
Yield: 67.7 %

Procedure:
To a flask containing 1,4-dioxane (58.1 mL) and water (19.4 mL) was added 3-bromo-6-chloropyrazolo[1,5-a]pyrimidine (3.60 g, 15.5 mmol), methyl-5-methyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-carboxylate (4.37 g, 15.5 mmol), palladium tetrakis (895 mg, 0.774 mmol), and sodium carbonate (4.92 g, 46.5 mmol). The reaction mixture was sealed and degassed with N2 for 15 min. The reaction mixture was then heated to 100° C. for 2 h. The reaction was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (dichloromethane:hexane:ethyl acetate 20:75:5 to 20:60:20) to afford the title compound (3.23 g, 10.5 mmol). LRMS (APCI) calc'd for (C13H10ClN3O2S) [M+H]+, 308.0; found 308.0.
Reaction SMILES: [N:1]1([C:6]2[N:15]=[C:9]3[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][N:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH3:29])[C:25]=1[C:26](O)=[O:27])=[O:20])[CH3:17].CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH3:29])[C:25]=1[C:26](=[O:27])[NH:14][C:11]1[CH:12]=[CH:13][N:8]2[N:7]=[C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:15]=[C:9]2[CH:10]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: Nc1ccn2nc(N3CCCC3)nc2c1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Yield: 88 %

Procedure:
A mixture of 2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (197 mg, 969 μmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (231 mg, 1.16 mmol), propylphosphonic anhydride (50% in ethyl acetate, 1.43 ml, 2.42 mmol) and N,N-diisopropylethylamine (494 μl, 2.91 mmol) in tetrahydrofuran (10 ml) was refluxed for 18 hours. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 1-methyl-5-(2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester (327 mg, 88.0%) as a light brown solid. mp: 233-234° C., MS: m/z=384.5 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[CH3:17])[NH2:13].[K+].[Br-]>>[CH3:9][C:10]1[CH:11]=[C:12]([NH:13][C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[NH:2])[CH:14]=[CH:15][C:16]=1[CH3:17]
Reactant: N#Cc1cccnc1
Reactant: Cc1ccc(N)cc1C
Agent: [Br-]
Agent: [K+]
Product: Cc1ccc(NC(=N)c2cccnc2)cc1C
Yield: 84 %

Procedure:
The title compound was prepared from 3-cyanopyridine (8.6 g, 83 mmol) and 3,4-dimetylaniline (10 g, 83 mmol) by following the procedure described in preparation 10 (15.6 g, yield 84%, mp 132-134 C, purity 99.7% by HPLC). 1H-NMR (CDCl3):δ 2.24-2.26 (d, 6H), 4.92 (bs, 2H, D2O exchangeable), 6.72-6.74 (d, 1H), 6.78 (s, 1H), 7.11-7.13 (d, 1H), 7.36-74 (m, 1H), 8.22-8.24 (d, 1H), 8.69-8.7 (d, 1H), 9.06 (d, 1H). IR (KBr) cm−1: 3313, 3142, 2997, 2958, 2918, 1651. MS m/z:226.1 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:16])[CH:8]([C:11]([O:13]CC)=O)[C:9]#[N:10].[CH:17]1[C:22]([NH2:23])=[CH:21][CH:20]=[C:19]([OH:24])[CH:18]=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:16])[CH:8]([C:11](=[O:13])[NH:23][C:22]1[CH:17]=[CH:18][C:19]([OH:24])=[CH:20][CH:21]=1)[C:9]#[N:10]
Reactant: Nc1ccc(O)cc1
Reactant: CCOC(=O)C(C#N)C(=O)c1cccn1C
Solvent: Cc1ccccc1C
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccc(O)cc1

Procedure:
The mixture of 5.7 g of 1-methyl-β-oxo-α-ethoxycarbonyl-2-pyrrolpropionitrile, 3,6 g of p-aminophenol and 300 ml of xylene is refluxed for 2 hours and filtered hot. The filtrate is chilled, the crystals formed collected and recrystallized from methanol, to yield the 1-methyl-β-oxo-α-(p-hydroxyphenylcarbamoyl)-2-pyrrolpropionitrile melting at 182°-184°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11].[H-].[Na+].[CH2:41]([O:44][P:45]([O:51][CH2:52][C:53]1[C:61]([CH3:62])=[CH:60][CH:59]=[CH:58][C:54]=1[C:55](Cl)=[O:56])([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH:42]=[CH2:43]>O1CCCC1>[CH2:48]([O:47][P:45]([O:51][CH2:52][C:53]1[C:61]([CH3:62])=[CH:60][CH:59]=[CH:58][C:54]=1[C:55]([O:38][C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11])=[O:56])([O:44][CH2:41][CH:42]=[CH2:43])=[O:46])[CH:49]=[CH2:50]
Reactant: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1C(=O)Cl
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1C(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Yield: 69 %

Procedure:
According to a similar procedure to that described in Example 1-(12), 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (976.6 mg, 1.80 mmol) described in Reference example 1, sodium hydride (55% dispersion in mineral oil; 94.2 mg, 1.96 mmol), and 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methylbenzoyl chloride obtained above were reacted in tetrahydrofuran (10 ml), and the reaction mixture was worked up to afford, after extraction, the title compound as a crude oil. The crude oil was subjected to chromatography on a silica gel (100 g) column (eluent; ethyl acetate:hexane=3:2˜4:1) to afford the title compound (1.0641 g, 69% yield) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[O:8])=[C:5]([CH3:19])[C:4](C(O)=O)=[C:3]1[CH2:23][C:24]([OH:26])=[O:25]>FC(F)(F)C(O)=O>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[N:10]([CH3:18])[C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)=[O:8])=[C:5]([CH3:19])[CH:4]=[C:3]1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: Cc1c(C(=O)O)c(CC(=O)O)n(C)c1C(=O)c1ccc(C(F)(F)F)n1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(C(F)(F)F)n1C
Yield: 67 %

Procedure:
A mixture of 1.87 g (5 mmole) of 1,4-dimethyl-3-hydroxycarbonyl-5-(1-methyl-5-trifluoromethylpyrrol-2-oyl)pyrrole-2-acetic acid is heated together with 10 ml trifluoroacetic acid at 80° C. for thirty minutes. TFA is removed in vacuo. The residue is crystallized from ethyl acetate/hexane. After drying, 1.1 g of 1,4-dimethyl-5-(1-methyl-5-trifluoromethylpyrrol-2-oyl)pyrrole-2-acetic acid is obtained.