Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH2:35][CH2:36][O:37][CH3:38])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].[CH2:41](O)C>O1CCCC1.ClCCl>[CH:21]1([CH:20]=[C:19]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH2:35][CH2:36][O:37][CH2:38][CH3:41])(=[O:33])=[O:34])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COCCS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOCCS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Yield: 90 %

Procedure:
A mixture of 1-benzenesulfonyl-2-{2-cyclopentyl-1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-vinyl}-1H-pyrrolo[2,3-b]pyridine (1.3 g, 2.36 mmol) in ethanol (10 mL), tetrahydrofuran (20 mL) and an aqueous sodium hydroxide solution (10%, 6 mL) was heated at 50° C. for 5 h. The mixture was diluted with dichloromethane (150 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{2-cyclopentyl-1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-vinyl}-1H-pyrrolo[2,3-b]pyridine (900 mg, 90%): LC/MS m/e calcd for C24H28N2O3S [M+H]+ 425.57, observed 425.4.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:26]C(=O)OC(C)(C)C)[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:21][C:15]=2[N:14]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[NH2:26][C@H:12]([C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:21][C:15]=2[N:14]=1)[CH2:11][CH2:10][CH2:9][OH:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCOCc1ccccc1)c1nc2cc(C(C)(C)C)ccc2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc2[nH]c([C@@H](N)CCCO)nc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 16.8 %

Procedure:
Wet 5% Pd/C (150 mg) was added to a solution of tert-butyl [(1S)-4-(benzyloxy)-1-(5-tert-butyl-1H-benzimidazol-2-yl)butyl]carbamate (Preparation 35, 390 mg, 0.864) in EtOAc (150 mL) and stirred for 48 hours at room temperature under an H2 balloon pressure. The reaction was filtered through celite and the filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 30-40% EtOAc in petroleum ether. The resulting solid was suspended in dioxane (4 mL) and treated with 4N HCl in dioxane (4 mL) at 0° C. The reaction was stirred warming to room temperature for 3 hours. The reaction was concentrated in vacuo and purified through an SCX cartridge to furnish the title compound (38 mg, 45%).
Reaction SMILES: [O-2].[Sm+3:2].[O-2].[O-2].[Sm+3].[N+:6]([O-:9])([OH:8])=[O:7]>>[N+:6]([O-:9])([O-:8])=[O:7].[Sm+3:2].[N+:6]([O-:9])([O-:8])=[O:7].[N+:6]([O-:9])([O-:8])=[O:7]
Reactant: O=[N+]([O-])O
Agent: [O-2]
Agent: [Sm+3]
Product: O=[N+]([O-])[O-]
Reaction time: 1 h
Yield: 60 %

Procedure:
Slightly excess samarium oxide was dissolved in concentrated nitric acid under heating to effect the reaction. After 1 hour, the reaction liquid was filtered and the filtrate was cooled to precipitate crystalline samarium nitrate. Yield: 60%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=S)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:24][CH2:25][CH:26]([OH:32])[CH2:27][C:28]([F:31])([F:30])[F:29].C(N(CC)CC)C>C(O)C.[Hg](Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=[N:24][CH2:25][CH:26]([OH:32])[CH2:27][C:28]([F:31])([F:30])[F:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC(O)CC(F)(F)F
Reactant: C[C@H]1NC(=S)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Agent: Cl
Agent: Cl[Hg]Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@H]1NC(=NCC(O)CC(F)(F)F)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl[(3S,5S,6R)-6-methyl-5-phenyl-2-thioxopiperidin-3-yl]carbamate (75 mg, 0.23 mmol) in ethanol (2.3 mL) was added 1-amino-4,4,4-trifluorobutan-2-ol hydrochloride (105 mg, 0.59 mmol), mercury(II) chloride (83 mg, 0.30 mmol), and triethylamine (78 μL, 0.56 mmol). The mixture was stirred 30 min, filtered, and then concentrated, giving the crude title compound. MS 430.3 (M+1).
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CC[O:9]CC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=2)=[CH:22][C:21]=1[F:39])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].OO>C1COCC1.CCO>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:28][C@@H:27]2[OH:9])=[CH:22][C:21]=1[F:39])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(OCc3ccccc3)c(F)c2)CC1
Agent: FB(F)F
Agent: OO
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCc3ccccc3)c(F)c2)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To sodium borohydride (2.282 g, 60.3 mmol) in THF (81 ml) at 0° C. was added boron trifluoride diethyl etherate (9.86 ml, 78 mmol) dropwise via addition funnel. The ice bath was removed and the solution was allowed to warm to rt and stir for 1 h. The reaction was chilled to 0° C., then tert-butyl 4-(4-(benzyloxy)-3-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (7.46 g, 19.5 mmol) in THF (8.11 ml) was added dropwise via additional funnel. After complete additional, the reaction was allowed to warm to rt and was stirred for 2 h. The reaction was cooled to 0° C. and quenched with water (16.2 ml) until the effervescence subsided. To this mixture was sequentially added aqueous 10% sodium hydroxide (14.2 ml, 38.9 mmol), aqueous 30% hydrogen peroxide (13.91 ml, 136 mmol) and EtOH (16.2 ml). The resulting mixture was stirred at rt for 16 h. The mixture was diluted with ice water and extracted with dichloromethane. The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to afford (±)-rel-(3R,4R)-tert-butyl 4-(4-(benzyloxy)-3-fluorophenyl)-3-hydroxypiperidine-1-carboxylate (7.32 g, 94% yield) as a white solid: LC-MS [M+H]+=328.2; 1H NMR (500 MHz, DMSO-d6) δ 7.53-7.28 (m, 5H), 7.18-7.07 (m, 2H), 6.97 (d, J=8.2 Hz, 1H), 5.14 (s, 2H), 4.82 (d, J=5.6 Hz, 1H), 4.10 (br. s., 1H), 3.95 (br. s., 1H), 3.40 (tt, J=10.2, 5.2 Hz, 1H), 2.81-2.60 (m, 1H), 2.46-2.35 (m, 1H), 1.66 (dd, J=13.4, 3.1 Hz, 1H), 1.59-1.46 (m, 1H), 1.42 (s, 9H).
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([CH3:23])([CH3:22])[S:20](=[O:25])(=[O:24])[CH2:19][C@:18]([C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=2F)([CH3:26])[N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=O)(C)(C)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:47][C:48]1([CH3:51])[O:50][CH2:49]1.[NH4+].[Cl-]>C1COCC1.CC(O)(C)C.CC(C)([O-])C.[K+]>[CH3:22][C:21]1([CH3:23])[S:20](=[O:25])(=[O:24])[C@@H:19]2[CH2:47][C:48]([CH3:51])([CH3:49])[O:50][C:28]3[CH:29]=[CH:30][C:31]([N+:33]([O-:35])=[O:34])=[CH:32][C:27]=3[C@@:18]2([CH3:26])[N:17]=[C:16]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C1(C)C
Reactant: CC1(C)CO1
Agent: CC(C)(C)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OC(C)(C)C[C@H]2S(=O)(=O)C1(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 13.7 %

Procedure:
To a 25-mL RBF was added tert-butyl N-tert-butoxycarbonyl-N-[(3R)-3-(2-fluoro-5-nitro-phenyl)-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate (450 mg, 0.850 mmol) in THF (5.6 ml). The reaction solution was cooled to −78° C., then LHMDS (1.0M in THF; 2124 μl, 2.124 mmol) was added slowly. The brown solution was stirred for 15 min, then 1,1-dimethyloxirane (377 μl, 4.25 mmol) was added at −78° C. The reaction mixture was stirred from −78° C. to RT by removing dry-ice bath. 35 min later, it was quenched by 8 mL sat. aq. NH4Cl. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with satd NaCl and dried over MgSO4. The solution was filtered and concentrated to give the crude material as a brown oil. The crude mixture was dissolved in 6 ml tBuOH and potassium tert-butoxide, 1.0M solution in THF (2.5 ml, 2.55 mmol). It was stirred at RT. 20 min later, 8 mL of aq. NH4Cl was added and extracted with EtOAc. The organic extract was concentrated and was purified using 40 g Puriflash column in 20% to 35% to 50% EtOAc/Heptanes to give 56 mg of tert-butyl ((4aR,11bR)-3,3,6,6,11b-pentamethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (13% yield, less polar by TLC), and 90 mg of tert-butyl ((4aS,11bR)-3,3,6,6,11b-pentamethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (22% yield, containing impurity, more polar by TLC). MS m/z=504.0 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[C:4]([CH3:10])[CH:3]=1.[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:16]2[CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:12]([CH3:11])[CH2:17]2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(N)ncc1C=O
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc(N)ncc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
A mixture of 6-amino-4-methyl-3-pyridinecarbaldehyde (D99) (0.053 g, 0.39 mmol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.117 g, 0.58 mmol) and sodium tri(acetoxy)borohydride (0.206 g, 0.97 mmol) in 1,2-DCE (10 mL) was sonicated to aid dissolution of the starting material then stirred at room temperature overnight. Saturated aqueous NaHCO3 (30 mL) was added and the mixture was stirred for 24 h. The reaction mixture was extracted with DCM (3×10 mL) and the organics were dried and concentrated to give the crude title compound as an oil (0.067 g) which was used in the next step without further purification. MS (ES): MH+ 321.3, MNa+ 343.3.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4]([CH3:15])=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH:23]=[CH2:24]>CN(C)C=O>[CH2:24]([O:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4]([CH3:15])=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2)[CH:23]=[CH2:22]
Reactant: Cc1c(C)c2c(O)ccc(C)c2[nH]c1=O
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C)c2[nH]c(=O)c(C)c(C)c12
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
5-Hydroxy-3,4,8-trimethylcarbostyril (3.30 g, 16.3 mmol) was dissolved in N,N-dimethylformamide (100 ml), to which potassium carbonate (2.70 g, 19.6 mmol) and allyl iodide (2.91 g, 17.9 mmol) were added. The mixture was stirred in a bath of 75° C. for 8 hours. The reaction mixture was cooled, and the insoluble matter was removed by filtration. The filtrate was subjected to distillation under reduced pressure for removing the solvent. The residue was recrystallized from chloroform--n-hexane. As a result, 2.84 g of the title compound was obtained as pale yellow needles (71.7%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[NH2:11][CH2:12][CH2:13][N:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])=[CH:18][C:17](=[O:30])[NH:16][C:15]1=[S:31].Cl.[N:33]1([C:38](N)=[NH:39])C=CC=N1>CN(C=O)C.CCO>[CH3:29][O:28][C:21]1[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=1[C:19]1[N:14]([CH2:13][CH2:12][N:11]=[C:38]([NH2:39])[NH2:33])[C:15](=[S:31])[NH:16][C:17](=[O:30])[CH:18]=1
Reactant: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCN)c(OC)c1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCN=C(N)N)c(OC)c1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.22 mL, 1.3 mmol) was added to a suspension of 1-(2-aminoethyl)-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one hydrochloride (181.6 mg, 0.528 mmol) (the product of Example 6) and 1H-pyrazole-1-carboxamidine hydrochloride (90.6 mg, 0.618 mmol) in DMF (0.55 mL). After heating for 1 h at 55° C., the reaction mixture was cooled to ambient temperature, diluted with EtOH (1.6 mL), and the solid product collected by vacuum filtration, rinsing with additional EtOH. The isolated solid was re-suspended in EtOH (2.1 mL) for 3 h at r.t. before being collected again by vacuum filtration and rinsing with additional EtOH. The desired product was obtained, after drying, as a colorless solid. Solubility data for this product is consistent with it being in its zwitterionic form.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Cl[C:15]1[N:20]=[C:19]([NH:21][CH3:22])[C:18]([Cl:23])=[CH:17][N:16]=1>>[Cl:23][C:18]1[C:19]([NH:21][CH3:22])=[N:20][C:15]([NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][C:3]=2[O:12][CH3:13])=[N:16][CH:17]=1
Reactant: CNC(=O)c1ccc(N)c(OC)c1
Reactant: CNc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccc(Nc2ncc(Cl)c(NC)n2)c(OC)c1

Procedure:
4-(5-Chloro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide was prepared by the procedure described in Example 7 using 4-amino-3-methoxy-N-methylbenzamide and 2,5-dichloro-N-methylpyrimidin-4-amine. 1H NMR δ (ppm) (CDCl3): 8.58 (1H, d, J=8.4), 7.95-7.92 (1H, m), 7.70 (1H, s), 7.45 (1H, d, J=1.9), 6.09 (1H, s), 5.30 (1H, s), 4.03-3.95 (3H, m), 3.15-3.09 (3H, m), 3.02 (3H, t, J=4.8).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH:8]([N:10]=[CH:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[NH2:9].[OH-].[K+]>C(O)=O>[CH:5]([N:15]1[CH2:16][CH2:17][N:12]([CH:11]=[N:10][NH:8][NH2:9])[CH2:13][CH2:14]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: NNN=CN1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Product: NNN=CN1CCN(C=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
12.7 ml of acetic acid anhydride are added dropwise to 42 ml of ice-cooled formic acid, the mixture is stirred for ca. 1 hour and 16 g of the benzylidene derivative of 1-(hydrazinoimino-methyl) piperazine in 42 ml of formic acid are added dropwise. The mixture is left for ca. 2 hours at 0° and the solvent is evaporated off. The residue is treated with water and the pH of the mixture obtained is adjusted to pH 11 by addition of 10N KOH. The mixture is extracted with dichloromethane, the dichloromethane phase is dried and the solvent is evaporated off. The benzylidene derivative of 1-formyl4-(hydrazinoiminomethyl)piperazine is obtained in the form of a white powder.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:18][C:14]1[C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 475 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 9.05-6.65 (m, 9H), 4.80-2.75 (m, 5H), 1.70-0.65 (m, 8H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:12][C:13]1[N:14]=[C:15]([OH:23])[C:16]2[S:22][CH2:21][CH2:20][CH2:19][C:17]=2[N:18]=1>C1COCC1.CN(C=O)C>[CH2:3]([O:10][CH2:12][C:13]1[N:14]=[C:15]([OH:23])[C:16]2[S:22][CH2:21][CH2:20][CH2:19][C:17]=2[N:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Oc1nc(CCl)nc2c1SCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Oc1nc(COCc2ccccc2)nc2c1SCCC2

Procedure:
Sodium hydride (0.68 g 53% mineral oil) was suspended in THF (80 ml) and 1.5 ml of benzyl alcohol was added dropwise with stirring. To this clear solution was added product from Example 3, Step A (2.6 g) dissolved in 25 ml of DMF. After stirring for 2 hours at 25° C. the reaction mixture was heated at reflux for 10 minutes. The solvent was removed in vacuo, water was added to the residue followed by enough diluted HCl to render the solution slightly acidic and it was extracted with ethyl acetate. The ethyl acetate layer was dried and evaporated to give title compound as an oil that was used directly in Step B.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:13](=[O:24])[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])[CH:3]=1.[CH2:25](O)[CH:26]=[CH2:27]>OS(O)(=O)=O>[CH2:27]([O:9][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([NH2:1])=[CH:3][C:4]=1[C:13](=[O:24])[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[CH:26]=[CH2:25]
Reactant: Nc1ccc(OCC(=O)O)c(C(=O)NCc2ccc(Br)cc2F)c1
Reactant: C=CCO
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)COc1ccc(N)cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 20 %

Procedure:
[4-Amino-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy] acetic acid (0.62g, 1.56 mmol) was dissolved in allyl alcohol (15 mL, 0.1 M). This solution was treated with 7 drops of concentrated H2SO4 and stirred at room temperature for 48 h. The reaction was concentrated, redissolved in ethyl acetate, washed with H2SO, saturated aq NaCl (3×), dried over Na2SO4 and filtered. The filtrate was treated with decolorizing charcoal, boiled for 10 minutes, cooled to room temperature, filtered and concentrated. The crude solid was recrystallized from heptane and ethyl acetate to give [4-amino-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid allyl ester as a light orange solid (0.13 g, 20%). 1H NMR (DMSO-d6, 300 MHz) δ 8.92 (br t, J=5.4 Hz, 1H), 7.49-7.80 (m, 4H); 6.84 (d, J=8.7 Hz, 1 H), 6.63 (br dd, J1=8.7 Hz, J2=2.7 Hz, 1H), 5.95-5.79 (m, 1H), 5.29 (br d, J=17.1 Hz, 1H), 5.19 (br d, J=10.5 Hz, 1 H), 4.91 (br s, 1H), 4.83 (br s, 2H), 4.61 (br d, J=5.4 Hz, 1 H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[NH2:16][C:17]([NH2:19])=[O:18].Cl>C(O)C>[OH:18][C:17]1[N:19]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[N:16]=1
Reactant: NC(N)=O
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Solvent: CCO
Product: Oc1nc(-c2ccccc2)cc(C(F)(F)F)n1
Yield: 41.9 %

Procedure:
4,4,4-Trifluoro-1-phenyl-1,3-butanedione (10.8 g) and urea (6.01 g) were dissolved in ethanol (25 mL) and concentrated hydrochloric acid (5 mL) was added. The mixture was heated under reflux for 2.5 hr. The reaction solution was concentrated under reduced pressure, and water was added. The mixture washed with chloroform. A saturated a aqueous sodium hydrogen carbonate solution was added to the a aqueous layer and the precipitate was collected by filtration to give 2-hydroxy-4-phenyl-6-trifluoromethylpyrimidine (5.03 g) as a pale-pink crystalline powder.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:34]([NH:33][C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=4)=[O:35])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-trifluoromethylphenyl isocyanate (0.170 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 55.4 mg (15.7%) of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([C:7]1[C:15]2[CH:14]=[CH:13][C:12](=[O:16])[N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[S:9][C:8]=1[C:23]([O:25]CC)=[O:24])=[O:6].[OH-].[Na+]>CCO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([C:7]1[C:15]2[CH:14]=[CH:13][C:12](=[O:16])[N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[S:9][C:8]=1[C:23]([OH:25])=[O:24])=[O:6]
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1C(=O)c1cccc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C(=O)c2c(C(=O)O)sc3c2ccc(=O)n3-c2ccccc2)c1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of Example 1 (4.23 g, 10 mmol) and 0.25M NaOH(aq) (48 ml, 12 mmol) in EtOH (100 ml) was heated at reflux for 1 h. The solution was cooled to r.t. and the solvent removed in vacuo. The residue was dissolved in water (ca. 10 ml) and poured into 2M HCl(aq) (200 ml). The precipitate was filtered and dried in vacuo to give the title compound as a white solid (3.17 g, 81%). δH (DMSO-d6) 7.64-7.53 (7H, m), 7.48-7.43 (2H, m), 7.39 (1H, t, J 7.6 Hz), 6.49 (1H, d, J 9.6 Hz), 2.32 (3H, s). LCMS (ES+) RT 3.19 minutes, 390 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:20][C:21](=O)[C:22](F)(F)F)[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ICC[N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][S:37]1(=[O:43])=[O:42]>CN(C)C=O.C1(C)C=CC=CC=1>[O:42]=[S:37]1(=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41][N:36]1[CH2:22][CH2:21][NH:20][C:11]1[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:10]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NC(=O)C(F)(F)F
Reactant: O=S1(=O)CCCCN1CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN1CCCCS1(=O)=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 5-[(4-fluorophenyl)methyl]-3-[(trifluoroacetyl)amino]-2-pyridinecarboxylate (304 mg, 0.821 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (535 mg, 1.64 mmol) and 2-(2-iodoethyl)tetrahydro-2H-1,2-thiazine 1,1-dioxide (356 mg, 1.23 mmol), respectively. The reaction mixture was stirred at 80° C. for 5 hours. Additional cesium carbonate (535 mg, 1.64 mmol) and 2-(2-iodoethyl)tetrahydro-2H-1,2-thiazine 1,1-dioxide (356 mg, 1.23 mmol) were added and the reaction mixture was stirred overnight at 80° C. The reaction mixture was cooled and diluted with toluene. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by flash chromatography (0 to 5%, methanol in dichloromethane) to provide ethyl 3-{[2-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)ethyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate, which was slightly contaminated and taken on to the next step.