Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[NH:12][N:11]=1)(=O)N.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C[N:40](C)[CH:41]=[O:42]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:14]=[C:10]3[N:11]([C:41](=[O:42])[NH:40][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=43)[N:12]=2)=[CH:20][CH:19]=1
Reactant: NC(=O)c1ccccc1-c1n[nH]c(-c2ccc(Cl)cc2)n1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=c1[nH]c2ccccc2c2nc(-c3ccc(Cl)cc3)nn12

Procedure:
Seven grams of 3-(2-Carbamoylphenyl)-5-(4-chlorophenyl)-1H-1,2,4-triazole are dissolved in dry dimethylformamide (180 ml) at 50° C. Lead tetraacetate (10.4 g) is added under stirring and the reaction mixture is stirred under nitrogen for ten minutes. The reaction mixture is quenched in crushed ice (500 ml) containing concentrated hydrochloric acid (50 ml). The white solid which forms is collected, washed thoroughly with cold water and recrystallized from 2-methoxyethanol to afford 2-(4-chlorophenyl)-[1,2,4]-triazolo[1,5-c]quinazolin-5(6H)one, mp 315°-318°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]1[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]1=[O:28].[H][H].CCOCC>[Pt].C(OCC)(=O)C.C(Cl)Cl>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:12]2[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]2=[O:28])[CH:4]=1
Reactant: [H][H]
Reactant: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Agent: [Pt]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N)c(F)cc2Cl)c1=O

Procedure:
A mixture of isopropyl 3-(2-chloro-4-fluoro-5-nitrophenyl)tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (34.8 g, 0.0835 mol) and 5% platinum on carbon (3.48 g) in ethyl acetate is hydrogenated until about 90 psi of hydrogen is taken up. The reaction mixture is then filtered and concentrated in vacuo to obtain a foam. Column chromatography of the foam using silica gel and 10% to 20% ether in methylene chloride solutions gives a yellow foam which contains two compounds. A mixture of the foam and 5% platinum on carbon (3.5 g) in ethyl acetate is hydrogenated until 5 psi of hydrogen is taken up. The reaction mixture is then filtered and concentrated in vacuo to give the title product as a yellow foam which is identified by NMR spectral analyses.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)=[O:26]>CN(C=O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14](=[O:15])[CH2:13][C:2]([CH2:24][C:25]([C:27]2[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=2)=[O:26])([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:17][CH:18]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: COC(=O)CC(=O)OC
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC(=O)c1ccc(F)cc1)(CC(=O)c1ccc(S(C)(=O)=O)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
To a solution of 7.18 mL (63 mmol) of dimethyl malonate in 160 mL of DMF at 0° C. under an atmosphere of nitrogen was added 3.0 g (75 mmol) of sodium hydride (60% suspension in oil). The reaction was stirred at ambient temperature for 15 minutes (or until the gas evolution has ceased), cooled to -20° C., and treated with 15 g (69 mmol) of 2-bromo-4'-fluoroacetophenone (Aldrich) in one portion. The mixture was stirred at ambient temperature for 1 hour and then cooled to 0° C.; another 75 mmol of sodium hydride was added and the resulting mixture stirred at ambient temperature for 15 minutes (or until the gas evolution has ceased). The reaction was recooled to -20° C. and treated with 19.1 g (69 mmol) of 2-bromo-4'-(methylsulfonyl)acetophenone (prepared in Step 3). The reaction was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was partitioned between water and ethyl acetate; the ethyl acetate phase was dried (MgSO4) and reconcentrated in vacuo. The residue was chromatographed on silica gel to give 13.8 g (51%) of dimethyl 2-[2-(4-fluorophenyl)-2-oxoethyl]-2-[2-[4-(methylsulfonyl)phenyl]-2-oxoethyl]propanedioate as an oil: NMR (CDCl3) δ 3.06 (s, 3H), 3.76 (s, 6H), 4.03 (s, 2H), 4.08 (s, 2H), 7.13 (t, J=8.6 Hz, 2H), 7.97-8.05 [m with d at 8.03 (J=8.7 Hz), 4H], 8.14 (d, J=8.5 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-:3])=[O:2].[Br:14][CH2:15][CH2:16][CH3:17]>C(O)C>[Br-:14].[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N+:8]([CH2:15][CH2:16][CH3:17])=[CH:9]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2cnccc12
Reactant: CCCBr
Solvent: CCO
Product: CCC[n+]1ccc2c([N+](=O)[O-])cccc2c1
Product: [Br-]
Temperature: 25 °C
Yield: 48.1 %

Procedure:
5-Nitroisoquinoline (10.0 g) and 1-bromopropane (7.8 g) were refluxed in ethanol (200 ml) for five days. On cooling to room temperature, a yellow powdery precipitate formed. This was collected by vacuum filtration and purified by recrystallization from ethanol to yield 8.2 g of the desired 5-nitro-2-n-propylisoquinolinium bromide as yellow, crystalline needles, m.p. 206.5°-209.5° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1)#[CH:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=1>C(N(CC)CC)C.C(Cl)Cl.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>[Cl:11][C:12]1[CH:13]=[C:14]([C:2]#[C:1][C:3]2[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: C#Cc1nc(C)ccc1N
Reactant: Clc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N)c(C#Cc2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
To a solution of Cul (5.0 mg, 28 μmol) in triethylamine (5 ml) were added (2-ethynyl-6-methyl-pyridin-3-yl)amine (75 mg, 0.57 mmol described in Example 7), (PPh3)2PdCl2 (20 mg, 28 μmol), and 1-chloro-3-iodobenzene (135 mg, 0.57 mmol). The reaction mixture was stirred at room temperature for 4 h. The solvent was evaporated to afford a brown oil which was taken up in DCM and the solution was washed with water. The aqueous phase was extracted twice with DCM. The organic phases were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (hexane/ethyl acetate 7:3) to yield 54 mg (0.22 mmol, 39%) of (2-(3-chloro-phenylethynyl)-6-methyl-pyridin-3-yl)amine as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32].C(O)C(N)(CO)CO>ClCCCl>[CH3:1][C:2]1[C:7]([NH:8][C:31]([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)=[O:32])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=C(Cl)c1cccs1
Agent: NC(CO)(CO)CO
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.4 %

Procedure:
To a solution of 2-methyl-6-[(3R)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]pyridin-3-amine (22.7 mg, 0.09 mmol) in DCE (1 mL) was added pyridine (0.22 mL, 2.7 mmol) followed by a solution of thiophene-2-carbonyl chloride (40 mg, 0.27 mmol) in DCE (1 mL) and stirred at ambient temperature for 5 hours. To this mixture was then added trisamine resin (200 mg, 0.8 mmol, 4 mmol/g loading), stirred for 30 min, filtered and concentrated to afford a crude solid which was purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to obtain 7.8 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C@H:3]([C:7](O)=[O:8])[CH:4]([CH3:6])[CH3:5].[OH:11][C@@H:12]([C@H:40]([OH:55])[C@H:41]([OH:54])[C@@H:42]([NH:45][C:46](=[O:53])[C@H:47]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH2:48])[CH2:43][OH:44])[C:13]([NH:15][C@H:16]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:17][C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:14].C(N(CC)CC)C.O>CN(C)C=O>[OH:11][C@@H:12]([C@H:40]([OH:55])[C@H:41]([OH:54])[C@@H:42]([NH:45][C:46](=[O:53])[C@H:47]([CH2:49][CH:50]([CH3:51])[CH3:52])[NH:48][C:7](=[O:8])[C@H:3]([CH:4]([CH3:6])[CH3:5])[N:2]([CH3:10])[CH3:1])[CH2:43][OH:44])[C:13]([NH:15][C@H:16]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:17][C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[O:14]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](C(C)C)N(C)C)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
To a solution of N,N-dimethyl-L-valine (58 mg) and diphenylmethyl (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-leucyl)aminohexanoyl]amino-3-phenylpropionate (250 mg) in dimethylformamide (4 ml) were added diethyl cyanophosophonate (82 mg) and triethylamine (0.14 ml) and the mixture was stirred at room temperature for 18 hours. After addition of water, the whole was extracted with ethyl acetate and the extract was washed with saturated brine, followed by drying over anhydrous sodium sulfate. Removal of the organic solvent gave a residue, which was recrystallized from ehtyl acetate-hexane to afford the title compound (282 mg).
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[C:12]2[CH:13]=[C:14]([C:18]([N:20]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:19])[CH:15]=[CH:16][CH:17]=2)[C@@H:6]([CH3:34])[CH2:5]1)[CH:2]=[CH2:3].[C:35]([O:39][CH2:40][CH3:41])(=[O:38])[CH:36]=[CH2:37]>C(O)C>[CH2:40]([O:39][C:35](=[O:38])[CH2:36][CH2:37][N:23]1[CH2:24][CH2:25][CH2:26][N:20]([C:18](=[O:19])[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C@@H:11]([N:7]3[CH2:8][C@@H:9]([CH3:10])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][C@@H:6]3[CH3:34])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)[CH:13]=2)[CH2:21][CH2:22]1)[CH3:41]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCCNCC3)c2)C[C@H]1C
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCCN(CCC(=O)OCC)CC3)c2)C[C@H]1C
Temperature: 25 °C
Yield: 62.5 %

Procedure:
The compound of Example 2 (362 mg) and ethyl acrylate (81 mg) in ethanol (10 mL) was refluxed for 4 h. TLC of reaction solution indicated a new spot and starting material. Additional ethyl acrylate (65 mg) was added to the reaction solution. The reaction was refluxed for another 6 h. After being cooled to room temperature, the reaction solution was dried by rotary evaporator. The remaining residual was purified by silica gel chromatography conducted on CombiFlash™ Sq 16× (gradient: 100% CH2Cl2 to 10% MeOH in CH2Cl2) to give 3-(4-{3-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-[1,4]diazepan-1-yl)-propionic acid ethyl ester (275 mg; 63%). 1H NMR (300 MHz, CDCl3) δ 7.59-7.47 (m, 1H), 7.39-7.22 (m, 3H), 7.09 (m, 1H), 6.63 (m, 3H), 5.89 (m, 1H), 5.21 (m, 3H), 4.14 (q, 2H, J=7.0 Hz), 3.76-3.63 (m, 2H), 3.44-3.34 (m, 3H), 2.95-2.76 (m, 5H), 2.72-2.39 (m, 8H), 2.17 (dd, 1H, J=10.0, 10.0 Hz), 2.00 (dd, 1H, J=11.0, 11.0 Hz), 1.92 (m, 1H), 1.69 (m, 1H), 1.25 (t, 3H, J=7.0 Hz), 1.15 (d, 3H, J=6.0 Hz), 1.02 (d, 3H, J=5.5 Hz); MS (FAB, glycerol) m/z: 563 (M++1), 409, 209, 153; Found C, 68.59; H, 8.30; N, 9.64. Calc. (C33H46N4O4 0.2 CH2Cl2) C, 68.78; H, 8.07; N, 9.66.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([O-:21])=[O:20])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([CH3:25])([CH3:24])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:26]1[CH:28]([CH:29](O)C#N)[CH2:27]1.C([BH3-])#N.[Na+].[C:37](O)(=O)[CH3:38]>C(#N)C>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:14]([CH2:29][CH:28]3[CH2:27][CH2:26]3)[C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:37][CH3:38])=[O:20])=[CH:22][CH:23]=3)[CH:12]=2)[C:7]([CH3:25])([CH3:24])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: N#CC(O)C1CC1
Reactant: CC(=O)O
Reactant: CC(C)N1CCC(C)(C)c2ccc(Nc3ccc(C(=O)[O-])cc3)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(N(CC2CC2)c2ccc3c(c2)N(C(C)C)CCC3(C)C)cc1
Yield: 75 %

Procedure:
A solution of 4-[(1-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)amino]benzoate (Compound 34, 9.4 mg, 0.0256 mmol), cyclopropylcarboxaldehyde (8.99 mg, 0.1282 mmol), sodium cyanoborohydride (8.06 mg, 0.1282 mmol), acetic acid (0.125 mL), and acetonitrile (1 mL) was stirred at room temperature for 3 days. The solvent was removed and the residue was purified by silica gel chromatography (10% ethyl acetate in hexane, Rf=0.48) to give the title compound (8.03 mg, 75%) as a solid: PNMR (300 MHz, CDCl3): δ0.19 (m, 2 H), 0.49 (m, 2 H), 1.16 (d, 6 H, J=6.5 Hz), 1.30 (s, 6 H), 1.35 (t, 3 H, J=7.1 Hz), 1.73 (t, 2 H, J=6.0 Hz), 3.17 (t, 2 H, J=6.0 Hz), 3.56 (d, 2 H, J=6.5 Hz), 3.99 (sp, 1 H, J=6.6 Hz), 4.31 (q, 2 H, J=7.1 Hz), 6.43 (dd, 1 H, J=8.1, 2.0 Hz), 6.53 (d, 1 H, J=3.6 Hz), 7.71 (d, 2 H, J=9.0 Hz), 7.18 (d, 1 H, J=8.0 Hz), 7.83 (d, 2 H, J=9.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([C:25](OCC)=[O:26])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[NH2:30][CH:31]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]1>C(O)C>[NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([C:25]([NH:30][CH:31]3[CH2:35][CH2:34][NH:33][CH2:32]3)=[O:26])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:15])=[O:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CCOC(=O)c1nnc(-c2nc(-c3ccc(S(=O)(=O)C(C)C)cc3)cnc2N)o1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(C(=O)NC4CCNC4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
To a suspension of ethyl 5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazole-2-carboxylate (100 mg, 0.34 mmol) in ethanol (2 mL), tert-butyl 3-aminopyrrolidine-1-carboxylate (49.1 mg, 0.26 mmol) was added and the resulting mixture heated under reflux overnight. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was taken up in CH2Cl2 (2.0 mL) and TFA (400 μL) was added and the reaction mixture stirred overnight at room temperature. The reaction mixture was passed through a bicarbonate cartridge and the filtrate concentrated in vacuo. The residue was passed through a TsOH cartridge eluting the product with 2M Ammonia in methanol (5 mL). The solid was triturated form acetonitrile to give the product as a yellow solid (44.94 mg, 41%); 1H NMR (400.0 MHz, DMSO) d 1.19 (d, 6H), 1.75 (s, 1H), 2.00 (d, 1H), 2.73-2.78 (m, 2H), 2.94 (s, 1H), 2.95 (dd, 1H), 3.47 (t, 1H), 4.40 (br s, 1H), 7.85 (br s, 2H), 7.98 (d, 2H), 8.32-8.34 (m, 2H), 9.09 (s, 1H) and 9.46 (d, 1H) ppm; MS (ES+) 458.22
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([C:20]([OH:22])=O)[N:17]([CH3:19])[N:18]=[C:11]12.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:46]([NH:49][CH2:50][CH:51]1[CH2:53][CH2:52]1)[CH2:47][CH3:48]>ClCCl.C(N(CC)CC)C>[CH:51]1([CH2:50][N:49]([CH2:46][CH2:47][CH3:48])[C:20]([C:16]2[N:17]([CH3:19])[N:18]=[C:11]3[C:12]=2[CH2:13][CH2:14][CH2:15][N:10]3[C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[Cl:1])=[O:22])[CH2:53][CH2:52]1
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3C(=O)O)c(Cl)c1
Reactant: CCCNCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCN(CC1CC1)C(=O)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 25 °C

Procedure:
7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (107.0 mg), 1-hydroxybenzotriazole hydrate (50.3 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (72.5 mg), triethylamine (93 μL), and N-propylcyclopropanemethylamine (49 μL) were combined in 4 mL of dichloromethane and stirred at room temperature over night. The reaction mixture was then partitioned between ethyl acetate and 1M hydrochloric acid. The ethyl acetate solution was washed with aqueous sodium bicarbonate, dried with magnesium sulfate, and concentrated. The crude product was chromatographed on silica gel eluting with an acetone/hexane gradient giving a solid. Recrystallization from hexane provided 75.6 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylic acid cyclopropylmethylpropylamide, mp 120.6-122.0° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH2:15]([O:22][C:23]([N:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
An ice-cooled solution containing 4-piperidinol (5 g, 50 mMoles) and triethylamine (7 ml, 50 mMoles) in dichloromethane (50 ml) was cautiously treated with benzylchloroformate (7.5 ml, 50 mMoles) and allowed to stir for 2 hours. Dichloromethane (25 ml) was added and the solution was washed sequentially with water (2×40 ml) and saturated brine (50 ml), then dried (MgSO4) and concentrated under reduced pressure. The residue was purified by vacuum flash chromatography, eluting with a gradient of 50-100% ether in hexane to give N-benzyloxycarbonyl piperidin-4-ol (7.5 g) as a colourless oil; NMR (d6DMSO): 1.2-1.4 (m,2H), 1.6-1.8 (m,2H), 3.0-3.2 (m,2H), 3.6-3.8 (m,3H), 4.7 (d,2H), 5.1 (2,2H), 7.3 (m,5H); m/e 236 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH:15]=[C:14]1[C:23]([O:25]CC)=[O:24])(=[O:12])=[O:11].[OH-].[Li+].Cl>O.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:22][CH2:21][C:16]2([O:17][CH2:18][CH2:19][O:20]2)[CH:15]=[C:14]1[C:23]([OH:25])=[O:24])(=[O:12])=[O:11]
Reactant: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OCCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OCCO2
Temperature: 50 °C
Reaction time: 7 h
Yield: 85.1 %

Procedure:
1.8 g (4.29 mmol) of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 1 was dissolved in 60 ml of a water-tetrahydrofuran (1:1) solution, and 900 mg (21.45 mmol) of lithium hydroxide was added thereto, followed by stirring for 7 hours at 50° C. The reaction solution was cooled with ice, it was then made acidic by addition of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was washed with hexane to give 1.43 g of the title compound as a pale brown powder (yield: 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH:5]=[C:6]([F:27])[C:7]=1[O:8][CH2:9][C:10]1[C:11]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[N:12][S:13][C:14]=1[C:15]([F:18])([F:17])[F:16].COC1C=CC(C(N)=O)=CN=1.O1CCCC1.[Li+].[OH-]>O>[F:1][C:2]1[CH:3]=[C:4]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:5]=[C:6]([F:27])[C:7]=1[O:8][CH2:9][C:10]1[C:11]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[N:12][S:13][C:14]=1[C:15]([F:16])([F:17])[F:18]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc(OC)nc3)nsc2C(F)(F)F)c(F)c1
Agent: COc1ccc(C(N)=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)cn1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 3-(3,5-difluoro-4-[[3-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]phenyl)propanoate (prepared according to the procedure following Example 1 step 1-5 using 6-methoxynicotinamide as starting material) (50 mg, 0.10 mmol, 1.00 equiv), tetrahydrofuran (1 mL), LiOH (50 mg, 2.09 mmol, 20.98 equiv), water (1 mL). The resulting solution was stirred overnight at 20° C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 6 with hydrogen chloride (2 mol/L). The solids were collected by filtration. The crude product (20 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Reversed Column, C18 silica gel; mobile phase, 0.05% TFA/ACN=1/4 increasing to 0.05% TFA/ACN=0/1 within 20 min; Detector, UV 254 nm. This resulted in 8.8 mg (18%) of 3-(3,5-difluoro-4-((3-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)phenyl)propanoic acid as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.51 (s, 1H), 8.06 (d, J=6.3 Hz, 1H), 6.80-6.89 (m, 3H), 5.19 (s, 2H), 3.96 (s, 3H), 2.83 (t, J=7.5 Hz, 2H), 2.56 (t, J=7.5 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C20H15F5N2O4S, 475.1 (M+H). found 475.1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C(N(CCCC)CCCC)CCC.CN(C=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:15][O:14][C:10](=[O:13])/[CH:11]=[CH:12]/[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)/C=C/c1ccc(OC)cc1
Yield: 70 %

Procedure:
Table 1, Entry 1. In the reaction tube were mixed 4-iodoanisole (0.234 g, 1.0 mmol), methyl acrylate (0.108 g, 1.25 mmol), palladium acetate (0.00225 g, 0.01 mmol), tri-n-butylamine (0.185 g, 1.0 mmol) and 0.50 ml DMF.under nitrogen. The contents of the flask were irradiated for 3.50 min with an effect of 60 W. After cooling, the product mixture was poured into 25 ml water and was extracted three times with 25 ml DCM. The combined extracts were washed with 25 ml water and concentrated to an oil. The crude product was purified by column chromatography on silica gel using i-hexane/diethyl ether (4/1) as the eluent. The yield was 70% (white solid).