Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][CH2:18][NH2:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O1CCCC1.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](Cl)=[O:41])=[CH:35][CH:34]=1>O>[CH2:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:17][CH2:18][NH:19][C:40](=[O:41])[CH2:39][C:36]2[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=2)=[CH:4][C:3]=1[O:2][CH3:1])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Reactant: Cc1ccc(CC(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(CCNC(=O)Cc2ccc(C)cc2)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 154.9 %

Procedure:
15.26 g (59.3 mmol) of crude 2-(3-methoxy-4-benzyloxyphenyl)ethylamine, 9.09 g (89.0 mmol) of triethylamine and 100 ml of tetrahydrofuran were mixed and cooled to about 0° C. and then 5.44 g (32.28 mmol) of (4-methylphenyl)acetyl chloride was added dropwise thereto. The mixture was stirred at 0° C. for 30 minutes and further at room temperature for 3 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochloric acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 19.48 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(4-methylphenyl)acetamide.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([C@@H:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[N:20]=2)[CH3:17])[CH:13]=[CH:14][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]([C@@H:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[N:20]=2)[CH3:17])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1cccc(N)c1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@H](Nc1cncc(Cl)n1)c1cccc(NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
To a solution of benzaldehyde (0.1 mL, 1 mmol) and N-[(1S)-1-(3-aminophenyl)ethyl]-6-chloropyrazin-2-amine (248 mg, 1 mmol) in dichloroethane (5 mL) was added sodium triacetoxyborohydride (300 mg, 1.4 mmol) in one portion and the mixture was stirred at room temperature for 16 hours. After this time a solution of saturated aqueous sodium hydrogen carbonate (20 mL) was added and the mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate (2×20 mL) and the extracts washed with brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure to give N-{(1S)-1-[3-(benzylamino)phenyl]ethyl}-6-chloropyrazin-2-amine (330 mg, 97%) as an off white solid of reasonable purity.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:28][C@H:27]([CH2:29]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:41][NH:42][CH3:43]>C1COCC1>[CH3:41][N:42]([CH2:29][C@@H:27]1[CH2:26][C@H:25]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)[N:9]=2)[CH2:28]1)[CH3:43]
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3nc(-c4cccc(OCc5ccccc5)c4)c4c(N)nccn43)C2)cc1
Solvent: C1CCOC1
Product: CN(C)C[C@H]1C[C@@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)C1
Temperature: 50 °C

Procedure:
A sealed tube containing a solution of cis-toluene-4-sulfonic acid 3-[8-amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclobutylmethyl ester (100 mg, 0.18 mmol) in THF (3 mL) was charged with dimethylamine solution (1.8 mL, 3.6 mmol, 2.0 M in THF), sealed, and heated at 50° C. overnight. The mixture was concentrated and the residue was diluted with ethyl acetate (40 mL), washed with sat. aq. NaHCO3 (2×15 mL) and brine (2×15 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was recrystallized to afford a white solid; LC-MS (ES, Pos.): m/z 428 [MH+]; 1H NMR (CDCl3, 400 MHz) δ 2.23 (s, 6H), 2.24-2.32 (m, 2H), 2.42 (d, J=6.1 Hz, 2H), 2.61-2.69 (m, 3H), 3.64 (m, 1H), 4.98 (br s, 2H, NH2), 5.15 (s, 2H), 7.00-7.04 (m, 2H), 7.12 (d, J=5.0 Hz, 1H), 7.23-7.27 (m, 2H), 7.31-7.46 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:18]=1.N[C@@H](CC1C=CC=CC=1)CO>CCCCCCC>[Cl:1][C:2]1[C:3]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][C:5]2[O:10][C@H:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:18]=1
Reactant: CC(C)(C)c1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Agent: N[C@H](CO)Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(C)c1cc2c(cc1Cl)C=C(C(=O)O)[C@@H](C(F)(F)F)O2
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a solution of 6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (Example 8)(11.4 g, 34.1 mmol) and (S)(-)-2-amino-3-phenyl-1-propanol (2.57 g, 17.00 mmol) was added n-heptane (200 mL) and the mixture set aside for 16 hours. The resulting suspension was filtered yielding a solid (3.8 g). This solid was recrystallized from 2-butanone (20 mL) and n-heptane (200 mL) yielding upon filtration a white solid (3.0 g). This solid was dissolved in ethyl acetate (100 mL) and washed with 1 N HCl (50 mL) and brine (2×50 mL), dried over MgSO4 and concentrated in vacuo yielding a white solid. This solid was recrystallized from n-heptane yielding the title compound of high optical purity as a crystalline solid (1.7 g, 30%): mp 175.4-176.9° C. 1H NMR (acetone-d6 /300 MHz) 7.86 (s, 1H), 7.52 (s, 1H), 7.12 (s, 1H), 5.83 (q, 1H, J=7.1 Hz), 1.48 (s, 9H). Anal. Calc'd for C15H14O3F3Cl: C, 53.83; H, 4.22; N, 0.0; Cl, 10.59. Found: C, 53.78; H, 4.20; N, 0.0; Cl, 10.65. This compound was determined to have an optical purity of greater than 90% ee. Chiral purity was determined as describe in Example 66.
Reaction SMILES: [CH2:1]([C:3]1([OH:13])[CH2:8][CH2:7][CH:6]([C:9]([F:12])([F:11])[F:10])[CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CN(C)C1C=CN=CC=1.CC(C)=O>[C:21]([O:13][C:3]1([CH2:1][CH3:2])[CH2:4][CH2:5][CH:6]([C:9]([F:10])([F:12])[F:11])[CH2:7][CH2:8]1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: C=C(C)C(=O)Cl
Reactant: CCC1(O)CCC(C(F)(F)F)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=C(C)C(=O)OC1(CC)CCC(C(F)(F)F)CC1
Yield: 75.7 %

Procedure:
A four-necked flask equipped with a stirrer, a thermometer, and a dropping funnel was charged with 7.9 g (0.04 mol) of 1-ethyl-4-trifluoromethylcyclohexanol, 0.2 g of 4-dimethylaminopyridine, 4.9 g of triethylamine, and 20 g of acetone. The mixture was stirred to obtain a solution. A solution prepared by dissolving 4.6 g (0.044 mol) of methacrylic acid chloride in 5 g of acetone was added to the solution at 4° C. over 30 minutes. The mixture was stirred at 4° C. for 3 hours to obtain a reaction mixture. The reaction mixture was washed with water to obtain 8.0 g of 1-ethyl-4-(trifluoromethyl)cyclohexyl methacrylate (hereinafter may be referred to as “compound (M-3)” ((M-3) in Table 1)). The yield of 1-ethyl-4-(trifluoromethyl)cyclohexyl methacrylate with respect to 1-ethyl-4-trifluoromethylcyclohexanol was 76%.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([SH:11])=[N:9][N:10]=1)=O)C.[CH3:12][NH:13][CH3:14]>>[CH3:12][N:13]([CH3:14])[C:4]([C:6]1[O:7][C:8]([SH:11])=[N:9][N:10]=1)=[O:3]
Reactant: CCOC(=O)c1nnc(S)o1
Reactant: CNC
Product: CN(C)C(=O)c1nnc(S)o1

Procedure:
This product (m.p. 185°-187° C.) was prepared by reacting 2-ethoxycarbonyl-1,3,4-oxadiazole-5-thiol with dimethylamine in a manner similar to that described in the procedure of Example XVI, Part C as hereinafter set forth.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:17][CH2:18][Cl:19])[C:5]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8]>Cl>[Cl:1][CH2:2][CH2:3][N:4]([CH2:17][CH2:18][Cl:19])[C:5]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(C)cc(C)c1N(CCCl)CCCl
Agent: Cl
Product: Cc1cc(C)c(N(CCCl)CCCl)c(C(=O)O)c1

Procedure:
A suspension of methyl 2-bis(2'-chloroethyl)amino-3,5-dimethylbenzoate (5.6 g, 0.018 mol) in concentrated HCl (37% w/w in H2O, 150 mL) was heated to refluxing under N2 for 8 hours. The reaction mixture was treated with ice/H2O (200 mL), extracted wit chloroform (3×150 mL). The organic solution was concentrated to given the product 2-bis(2'-chloroethyl)amino-3,5-dimethylbenzoic acid as a white solid (5.1 g, 96%). 1H NMR (300 MHz, CDCl3): 8.01 (d, J=1.5 Hz, 1H), 7.23 (dd, J=1.5, 0.6 Hz, 1H), 3.6 (m, 8H), 2.43 (s, 3H), 2.35 (s, 3H). ESMS calcd (C13H17Cl2NO2): 289.1; found: 290.1 (M+H)+.
Reaction SMILES: C(OC(=O)N[N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:18]3[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[C:20]([Cl:35])[C:19]3=[O:36])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C>CS(C)=O.O>[Cl:35][C:20]1[C:19](=[O:36])[N:18]([CH2:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][CH:9]=[CH:10]3)[C:23]([CH3:24])=[CH:22][C:21]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(ccn2NC(=O)OC(C)(C)C)c1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2[nH]ccc2c1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]indole-1-carbamic acid tert-butyl ester (1.08 g, 2.1 mmol) dissolved in 40 mL of DMSO was stirred at 120° C. for 20 hours. The reaction was cooled to room temperature, diluted with water, and washed 5 times with ethyl acetate. The combined organics were washed 1 time with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. 1H NMR (300 MHz, DMSO-d6) δ 11.1 (br s, 1H), 7.67 (d, J=6.7 Hz, 1H), 7.36-7.32 (m, 2H), 7.23 (s, 1H), 7.18 (d, J=2.3 Hz, 1H), 6.93 (dd, J=8.4, 1.2 Hz, 1H), 6.57 (s, 1H), 6.38 (s, 1H), 5.37 (s, 2H), 5.29 (s, 2H), 2.35 (s, 3H).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C@@H:8]2[CH2:12][C@H:11]([C:13]([O:15]CC)=[O:14])[C@H:10]([CH2:18][CH3:19])[CH2:9]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>>[CH:1]1([S:4]([NH:7][C@@H:8]2[CH2:12][C@H:11]([C:13]([OH:15])=[O:14])[C@H:10]([CH2:18][CH3:19])[CH2:9]2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)[C@H]1C[C@@H](NS(=O)(=O)C2CC2)C[C@H]1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask containing (1S,2R,4S)-ethyl 4-(cyclopropanesulfonamido)-2-ethylcyclopentane-carboxylate (11.1 g, 38.4 mmol, prepared using K from Preparation #Y.1, cyclopropanesulfonyl chloride and TEA, AA [Table 2, Method 1, Rt=9.5 min, or =negative]) was added aqueous NaOH (1 N, 210 mL, 210 mmol). After stirring at ambient temperature for about 8 h, the reaction was acidified to about pH 1 using 6 N aqueous HCl and extracted with DCM (3×150 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give (1S,2R,4S)-4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylic acid with 25 mol % DCM as an excipient (10.7 g, 99%): LC/MS (Table 1, Method a) Rt=1.71 min; MS m/z: 260 (M−H)−.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH:11]([C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])O)=[N:7][CH:6]=1)=[O:4].S(=O)(=O)(O)O.[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[CH:28]([NH:31][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])=[N:7][CH:6]=1)=[O:4])([CH3:30])[CH3:29]
Reactant: CC(C)N
Reactant: CCCCc1noc(C)c1C(O)Cc1ncc(C(=O)OC)s1
Agent: O=S(=O)(O)O
Product: CCCCc1noc(C)c1/C=C/c1ncc(C(=O)NC(C)C)s1
Temperature: 90 °C
Yield: 32.6 %

Procedure:
2-[2-(3-Butyl-5-methyl-isoxazol-4-yl)-2-hydroxy-ethyl]-thiazole-5-carboxylic acid methyl ester (30 mg, 0.092 mmol) was stirred with concentrated sulfuric acid (0.1 mL) for 30 min, then the reaction mixture quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried, filtered and concentrated, then dissolved in toluene (0.5 mL) and isopropylamine (22 mg, 0.37 mmol) and TBD (13 mg, 0.092 mmol) added. The reaction mixture was then heated at 90° C. for 15 h and then the reaction mixture was concentrated then purified by chromatography (silica, 0 to 3% methanol in dichloromethane) to give the title compound (10 mg, 34%) as a pale yellow oil. MS: m/e=334.3 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:13][C:11](=[O:12])[N-:10][C:8]2=[O:9])=[CH:3][CH:2]=1.[Na+].OC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.NC(CO)(CO)CO>C(O)C>[CH:17]1[CH:18]=[CH:19][C:14]([C:7]2([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)[NH:13][C:11]([OH:12])=[N:10][C:8]2=[O:9])=[CH:15][CH:16]=1
Reactant: O=C1[N-]C(=O)C(c2ccccc2)(c2ccccc2)N1
Agent: NC(CO)(CO)CO
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: [Na+]
Solvent: CCO
Product: O=C1N=C(O)NC1(c1ccccc1)c1ccccc1
Reaction time: 0.12 h

Procedure:
A drug phenytoin composition is prepared as follows: first, 2,580 g of polyethylene oxide having a weight-average molecular weight of 200,000 is passed through a 40-mesh screen. Then, 1,290 g of the screened polyethylene oxide is placed into the bowl of a mixer. Then, 2,400 g of sodium phenytoin is placed in the bowl over the polyethylene oxide. Next, 300 g of polyvinylpyrrolidone of 40,000 viscosity-average molecular weight is passed through a 40-mesh screen and added to the mixer. The remaining 1,290 g of polyethylene oxide is then added to the bowl. Next, 300 g of sorbitol and 360 g of tromethamine USP (2-amino-2-hydroxymethyl-1,3-propanediol) is passed through a 40-mesh screen and added to the mixer. The addition of the dry ingredients into the bowl is performed with the sodium phenytoin located between the two layers of polyethylene oxide. The ingredients are mixed for 5 minutes to produce a homogenous blend. The granulation process is initiated by the gradual addition of 3,200 g of ethyl alcohol to the mixer with continuous mixing. Mixing is continued over a period of 5 to 10 minutes to effect a consistency to change the dry powder to granules. The wet granulation is dried at 40° C. for 16 hours and then passed through a fluid air mill with a 7-mesh screen for size reduction. Next, the size reduced granules are placed into a blender. Then, 60 g of magnesium stearate that has been passed through a 60-mesh screen is added to the granulation, and all the ingredients mixed for a minute. This preparation provides a phenytoin composition comprising sodium phenytoin, polyethylene oxide, polyvinylpyrrolidone, tromethamine, sorbitol and magnesium stearate, useful for the therapeutic management of epilepsies.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=2)[CH2:12][NH:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[C:5]([Cl:28])=[CH:4][N:3]=1>O.CO.C(O)(=O)C.[Fe]>[NH2:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[C:14]([NH:13][CH2:12][C:11]1[CH:25]=[CH:26][CH:27]=[C:9]([NH:8][C:6]2[C:5]([Cl:28])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:10]=1)=[O:24]
Reactant: O=C(NCc1cccc(Nc2nc(Cl)ncc2Cl)c1)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Nc1cccc(C(=O)NCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 117.2 %

Procedure:
To a solution N-{3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}-3-nitrobenzamide (400.0 mg, 0.956 mmol) in water (0.7 mL), methanol (3.7 mL) and acetic acid (1.5 mL) was added iron (130 mg, 2.4 mmol) powder in small quantities. When the addition was completed, the very cloudy mixture was stirred at 0° C. for 1 h and then heat at 40° C. for 3 h. The mixture was filtered, and the cake was washed with MeOH/EtOAc. The filtrate was concentrated and the residue was diluted with H2O, then the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as an off-white powder (435 mg). LCMS for C18H15Cl2N5O (M+H)+: m/z=388.0, 390.0, 392.0. 1H NMR (400 MHz, CD3OD): δ 8.20 (s, 1H), 7.59 (t, J=2.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.24 (m, 2H), 7.20 (m, 2H), 6.93 (m, 1H), 4.60 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](O)=O)=O)(C)(C)C.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[NH2:26]>>[F:25][C:21]1[C:20]2[N:26]=[C:15]([CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)[NH:18][C:19]=2[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: Nc1cccc(F)c1N
Product: Fc1cccc2[nH]c(CC3CCCCN3)nc12
Yield: 61.6 %

Procedure:
(RS)-2-Carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.93 g) was heated with 1,2-diamino-3-fluorobenzene (1.00 g) (Kirk, K. L, J. Org. Chem., 1969, 34, 384) as described in Description 18 to afford the title compound (1.14 g).
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14](=[O:28])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[C:17]=2[F:27])[CH2:12][C@:11]2([CH2:29][O:30]C3CCCCO3)[C@H:9]1[CH2:10]2)=O)(C)(C)C.[ClH:37]>O1CCOCC1>[ClH:37].[F:27][C:17]1[C:18]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:14]([C@@H:13]1[CH2:12][C@:11]2([CH2:29][OH:30])[C@@H:9]([CH2:10]2)[NH:8]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)Nc2cccc(OC(F)(F)F)c2F)C[C@@]2(COC3CCCCO3)C[C@@H]12
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(OC(F)(F)F)c1F)[C@@H]1C[C@@]2(CO)C[C@H]2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1R,3S,5S)-3-(2-fluoro-3-trifluoromethoxy-phenylcarbamoyl)-5-(tetrahydro-pyran-2-yloxymethyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (105 mg, 0.19 mmol) in dioxane (0.5 mL) was added HCl (4 N in dioxane, 481 μL, 1.92 mmol). The mixture was stirred at RT for 4 h, solvent was removed under reduced pressure and the material thus obtained was used without further purification in the next step. MS (UPLC/MS): 335.2 [M+H]+, 333.2 [M−H]−, 379.6 [M+HCOO]−.
Reaction SMILES: O[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[C:3]([OH:5])=[O:4].CN(C)C=O.S(Cl)([Cl:23])=O>>[Cl:23][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[C:3]([OH:5])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(O)Cc1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=C(O)C(Cl)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To a magnetically stirred solution of α-hydroxy-2-nitrobenzenepropanoic acid (1.00 g, 4.74 mmol) in N,N-dimethylformamide (2 ml, 25.85 mmol) cooled in ice was added thionyl chloride (12 ml, 164.5 mmol) slowly dropwise. The cooling bath was removed and the solution was left at room temperature (20° C.) overnight. The solution was evaporated to a solid. Ice and dichloromethane were added and the mixture was stirred magnetically for one hour, during which time it warmed to room temperature. The layers were separated and the organic phase was washed six times with water. The dried (MgSO4) solution was evaporated to a syrup which was subjected to an oil pump vacuum; yield 1.09 g Examination of the syrup on the μ-Bondapak C18 chromatographic column (Waters Associates) using a solvent system containing 90% of 0.1N ammonium acetate, pH 4.0 buffer and 10% acetonitrile revealed three components. The major component, which was present to the extent of 74% of the mixture, was separated on a Waters Associates Prep. 500 unit using a C18 cartridge and the solvent system mentioned above. Appropriate fractions were evaporated to a syrup below room temperature. The syrup was mixed with dilute hydrochloric acid and chloroform. The organic phase was washed twice with saturated brine and dried (MgSO4). The solution was evaporated to a syrup which crystallized spontaneously (0.48 g, 44%). Crystallization from chloroform-cyclohexane gave 0.33 g (31%) of the titled product; m.p. 108°-109°; MH+ 230 (1 Cl, CI mode); λmaxKBr 1707, 1725 (COOH), pmr (CDCl3) δ3.22-3.96 (8 lines, AB part of an ABX system, --CH2 --), 4.60-4.88 (q centered at 4.76, width 14 Hz, "J" 6 Hz, X part of ABX system, >CHCl), 7.32-8.16 (m, aromatic).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8](Br)[CH:7]=1)=[O:5])[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.O.O.O.C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC.O.CCO>[CH2:1]([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)OCC)n2n1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)OCC)n2n1
Temperature: 80 °C

Procedure:
A suspension of the product of Step 1 (0.145 g, 0.407 mmol), 3-pyridylboronic acid (0.092 g, 0.750 mmol), sodium acetate trihydrate (0.308 g, 2.08 mmol), and 0.013 g Pd(dppf)Cl2-DCM in a mixture of 7:3:2 DME/water/EtOH (6 mL) was heated to 80° C. for 30 min in a closed vial in a CEM microwave reactor. The reaction was then partitioned between saturated sodium bicarbonate and DCM and the organic layer was collected. The aqueous layer was extracted with DCM (2×25 mL) and the combined organic layers were then extracted with 1N HCl (3×10 mL). The combined aqueous extracts were then neutralized with solid sodium bicarbonate and extracted with DCM (3×20 mL). The combined organic layers were then dried over sodium sulfate and evaporated in vacuo to give 2-(3-ethyl-ureido)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester as a powder. MS (APCI+)=355.2
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=1.[C:25]1(=[O:30])[CH2:29][CH2:28][CH:27]=[CH:26]1.[Cl-].[NH4+]>C1COCC1.CCCCCC.C(OCC)(=O)C.C1CCCCC1.C(OCC)(=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH:27]2[CH2:28][CH2:29][C:25](=[O:30])[CH2:26]2)[C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:19]=1
Reactant: O=C1C=CCC1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(c1ccc(Cl)cc1)C1CCC(=O)C1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
Under argon, 14.8 ml (105.6 mmol) of diisopropylamine were initially charged in 150 ml of THF, the mixture was cooled to −30° C. and 42.3 ml (105.75 mmol) of a 2.5 M solution of n-butyllithium in hexane were added slowly. The reaction solution was then warmed to −20° C., 15 g (81.25 mmol) of methyl (4-chlorophenyl)acetate, dissolved in 90 ml of THF, were added slowly and the mixture was stirred at this temperature for 2 h. The reaction solution was then cooled to −78° C., and 7.2 ml (86.1 mmol) of 2-cyclopentene-1-one, dissolved in 60 ml of THF, were added slowly. After the addition had ended, the solution was stirred at this temperature for 1 h. After TLC check (mobile phase cyclohexane/ethyl acetate 9:1), saturated ammonium chloride solution was added and the mixture was taken up in ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave 15.65 g (58.67 mmol, 72% of theory) of the title compound as a yellowish oil.