Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]([O:18][CH2:19][C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:15]=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([O:18][CH2:19][C@H:20]3[CH2:24][CH2:23][CH2:22][N:21]3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:15]=[N:16][CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(-c2cccc(N)c2)c1
Yield: 148.3 %

Procedure:
To a solution of 3-aminophenylboronic acid (366 mg, 2.36 mmol, Aldrich Chem. Co.) and 5-bromo-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)-pyridine (560 mg, 1.57 mmol) in toluene (10 mL) was added Pd(0) (58 mg) and Na2CO3 (5 mL of a 2M solution), and the mixture was heated at reflux. The solvent was removed under vacuum, and the residue was extracted with ethyl acetate and chloroform. The organic extracts were dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate hexane 1:1 to afford to give the title compound (860 mg, 100% yield). MS (DCI/NH3) m/z 370 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 1.48 (s, 9h), 1.84-2.13 (m, 4H), 3.28-3.51 (m, 2H), 3.70-4.08 (m, 2H), 4.08-4.29 (m, 2H), 6.70-6.75 (m, 1H), 6.85-7.03 (m, 2H), 7.31-7.50 (m, 2H), 7.50-7.72 (m, 1H), 8.29 (d, J=3.0, 1H), 8.443 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:28]([O:31][CH2:32][C:33]1[C:34]([N:42]2[CH2:53][CH2:52][N:51]3[C:44](=[CH:45][C:46]4[CH2:47][C:48]([CH3:55])([CH3:54])[CH2:49][C:50]=43)[C:43]2=[O:56])=[N:35][CH:36]=[CH:37][C:38]=1B(O)O)(=[O:30])[CH3:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[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].CC#N.O>[C:28]([O:31][CH2:32][C:33]1[C:34]([N:42]2[CH2:53][CH2:52][N:51]3[C:44](=[CH:45][C:46]4[CH2:47][C:48]([CH3:55])([CH3:54])[CH2:49][C:50]=43)[C:43]2=[O:56])=[N:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:17][CH2:18][CH2:19][NH:20][C:21]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:27])[N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cccc(OCCNC(=O)OC(C)(C)C)n2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cccc(OCCNC(=O)OC(C)(C)C)n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 95 °C
Yield: 49.3 %

Procedure:
A 50 mL round-bottomed flask equipped with a reflux condenser was charged with 101b (500 mg, 1.14 mmol), [4-(dihydroxyboranyl)-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-3-yl]methyl acetate 101c (452 mg, 1.14 mmol), K3PO4 (483 mg, 2.28 mmol), NaOAc (187 mg, 2.28 mmol), Pd(dppf)Cl2 (42 mg, 0.057 mmol), and CH3CN/H2O (20.0/0.5 mL). The system was subject to three cycles of vacuum/argon flush then heated at 95° C. under N2 for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica-gel column-chromatography eluting with DCM/MeOH (70:1 to 30:1) to afford 101d (400 mg, 50%) as yellow solid. MS-ESI: [M+H]+ 712.3
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][CH2:7][C@H:8]1[O:13][C@H:12]([CH2:14]I)[CH2:11][C@H:9]1[OH:10])([CH3:4])[CH3:3].[N-:28]=[N+:29]=[N-:30].[Li+]>CN(C)C=O.O>[N:28]([CH2:14][C@H:12]1[O:13][C@H:8]([CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:1])[CH3:4])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:9]([OH:10])[CH2:11]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@H](CI)C[C@H]1O)(c1ccccc1)c1ccccc1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CN=[N+]=[N-])C[C@H]1O)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A solution, under argon, of 5.0 g of product from Example 275 in 10 ml of dry N,N-dimethylformamide is treated with 0.986 g of lithium azide. The mixture is stirred at 80° C. for 1 hour followed by room temperature for 18 hours. The reaction is diluted with water, extracted with diethyl ether, concentrated in vacuo, purified by chromatography (silica gel: 5-50% ethyl acetate/hexane) to give 4.0 g of the desired product.
Reaction SMILES: [C:1]([N:4]([C:7]1[CH:8]=[C:9]2[C:20](=[CH:21][CH:22]=1)[C:12]1[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=1[CH2:10]2)[CH2:5][CH3:6])(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCCC1>[CH2:1]([N:4]([C:7]1[CH:8]=[C:9]2[C:20](=[CH:21][CH:22]=1)[C:12]1[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=1[CH2:10]2)[CH2:5][CH3:6])[CH3:2]
Reactant: CCN(C(C)=O)c1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Temperature: 50 °C
Yield: 73.5 %

Procedure:
5,10-Dihydro-2-(N-Acetyl-N-ethylamino)indeno[1,2-b]indole (0.5 g, 1.7 mM) in dry tetrahydrofuran (80 cm3), protected under an atmosphere of nitrogen, was treated with lithium aluminum hydride (0.3 g) during 1 hour. The reaction mixture was then heated to 50° C. for a further 1 hour, cooled, and saturated sodium potassium tartrate (5 cm3) added. The solvent layer was decanted from the aqueous residue, and the latter washed with tetrahydrofuran (3×8 cm3). The combined organic phase and washing were filtered through phase transfer paper and evaporated to yield a yellow solid. This was crystallised from 95% ethanol to afford the title compound 0.35 g as pale yellow prisms, M.p. 204°-206° C. After column chromatography (silica: ethyl acetate/60°-80° petrol), the M.p. of the compound was raised to 205°-206° C. (0.26 g, 55%).
Reaction SMILES: OC1C=CC(C=O)=CC=1.C1(CCO)CC1.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O[C@@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]1>>[O:22]([C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H]1CC[C@@H](O)CC1
Reactant: Oc1ccccc1
Agent: O=Cc1ccc(O)cc1
Agent: OCCC1CC1
Product: COC(=O)[C@H]1CC[C@H](Oc2ccccc2)CC1

Procedure:
Instead of 4-hydroxybenzaldehyde and 2-cyclopropylethanol, phenol (1.43 g) and methyl cis-4-hydroxycyclohexanecarboxylate (2.00 g) were respectively used and treated by the same technique as in Reference Example 11-1 to give methyl trans-4-phenoxycyclohexanecarboxylate as a colorless oil (1.33 g).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C1(C)C=CC=CC=1>[CH3:8][N:9]([CH2:10][CH2:11][N:43]1[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]1)[C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CCN(C)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-[methyl-(4-nitro-phenyl)-amino]-ethyl ester TFA salt (74 mg, 0.21 mmol) in toluene (1 mL) is added triethylamine (50 μL) and N-methylpiperazine (70 μL, 0.63 mmol). The mixture is shaken in 70° C. block shaker overnight. The reaction mixture is concentrated and purified by reverse phase high performance liquid chromatography to give methyl-[2-(4-methyl-piperazin-1-yl)-ethyl]-(4-nitro-phenyl)-amine as a tri-TFA salt (98 mg, 98%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[N:4][C:5]([O:8]C)=[CH:6][CH:7]=1.[I-].[Na+].C[Si](Cl)(C)C.CO>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[N:4][C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1
Reactant: COc1ccc(F)c(NCc2cccc(F)c2)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Oc1ccc(F)c(NCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
3-fluoro-N-(3-fluorobenzyl)-6-methoxypyridin-2-amine (0.100 g, 0.400 mmol) was dissolved in anhydrous CH3CN (1.6 mL). This mixture was treated with sodium iodide (0.301 g, 2.01 mmol) followed by trimethylsilylchloride (0.257 mL, 0.218 g, 2.01 mmol). The resulting reaction mixture was then heated at reflux for 2 hr. The reaction mixture was then treated with MeOH (1 ml), and the resulting mixture was stirred at ambient temperature for 2 hr, and then concentrated in vacuo. The resulting residue was dissolved in EtOAc (25 ml) and partitioned with H2O (25 ml). The H2O layer was extracted with EtOAc (2×25 ml). The organic layers were combined and washed with brine (1×25 ml). The organic layer was dried (Na2SO4), filtered, and the solvent removed in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 10 EtOAc/90 hexanes to 60 EtOAc/40 hexanes gave 0.060 g (64%) of 5-fluoro-6-(3-fluorobenzylamino)pyridine-2-ol. LCMS (m/z): 237.2 (MH+), retention time=0.74 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:37]=2[S:38][C:39]=1[C:40]([N:18]([CH2:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1)=[O:41]
Reactant: COc1ccc(-c2ccc(C#N)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2ccc(C#N)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 13 (300 mg, 0.70 mmol) is treated with acid chloride 8 (214 mg, 0.80 mmol) using Method D to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH:29]=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[C:33]1=[O:47].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH2:29][N:44]3[CH2:45][CH2:46][CH:41]([N:34]4[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[N:32]([CH3:31])[C:33]4=[O:47])[CH2:42][CH2:43]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Reactant: Cn1c(=O)n(C2CCNCC2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1c(=O)n(C2CCN(CCCn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCN(C(=O)OC(C)(C)C)C4)CC2)c2ccccc21
Reaction time: 0.33 h
Yield: 8.4 %

Procedure:
To a stirred solution of 1-(3-oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.99 g, 23.6 mmol) in CH2Cl2 (20 mL) were added 1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.60 g, 25.9 mmol) and glacial AcOH (0.13 mL, 23.6 mmol) in that order and stirred for 20 min. NaBH(OAc)3 (0.65 g, 30.6 mmol) was added and stirred under nitrogen for 2 h. Saturated NaHCO3 (20 mL) was added and stirred for 30 min, and the layers were separated. The organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. MPLC of the crude afforded the desired compound as a white solid (1.27 g, 85%). TLC (silica, 7% MeOH/CH2Cl2): Rf=0.35. MS (electrospray): exact mass calculated for C34H41F3N6O3, 638.32. m/z found, 639.3 [M+H]+, 661.2 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.81 (br d, J=8.0 Hz, 2H), 7.68 (br s, 2H), 7.25 (dd, J=1.6, 7.5 Hz, 1H), 7.15-7.07 (m, 2H), 7.02(dd, J=1.6, 7.9 Hz, 1H), 4.70 (br s, 2H), 4.38 (tt, J=4.2, 12.4 Hz, 1H), 4.18 (t, J=6.8 Hz, 2H), 3.82 (s, 2H), 3.45 (s, 3H), 3.07 (d, J=11.6 Hz, 2H), 2.84 (t, J=5.5 Hz, 2H), 2.53-2.42 (m, 2H), 2.44 (t, J=6.7 Hz, 2H), 2.21-2.03 (m, 4H), 1.84 (d, J=12.0 Hz, 2H), 1.52 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].[CH3:19][Mg]Br>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]([OH:14])[CH3:19]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C=O)c1Cl
Reactant: C[Mg]Br
Product: Cc1ccc(Cl)c(Nc2ccccc2C(C)O)c1Cl

Procedure:
The desired compound is prepared by reaction of 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde, prepared as in step 1, with methylmagnesium bromide.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14](OCC)=[O:15])[N:6]=1.[NH4+:23].CO>O>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]([NH2:23])=[O:15])[N:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1nc(Cc2ccccc2F)n2ccccc12
Solvent: O
Solvent: CO
Product: NC(=O)c1nc(Cc2ccccc2F)n2ccccc12

Procedure:
560 mg (1.88 mmol) of ethyl 3-(2-fluorobenzyl)imidazo[1,5-a]pyridine-1-carboxylate from example 7A are heated in 55 ml of 33% strength aqueous ammonium solution in a microwave at 130° C. for 3 h. The mixture is diluted with water, and, after addition of some methanol, extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. 229 mg (87.5% purity, 40% of theory) of the desired compound are obtained as greenish crystals which are reacted without further purification.
Reaction SMILES: ClC1C=CC(C2C3CN([C:16]4[N:25]=[C:24]5[C:19]([C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22][N:23]5[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[CH:18][C:17]=4[F:38])CC3ON=2)=CC=1.C(O)(C(F)(F)F)=O.FC(F)(F)C(O)=O.[F:53][C:54]([F:70])([F:69])[C:55]1[N:60]=[CH:59][C:58]([C:61]2[C@@H:65]3[CH2:66][NH:67][CH2:68][C@@H:64]3[O:63][N:62]=2)=[CH:57][CH:56]=1>>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[N:23]1[C:24]2[C:19](=[CH:18][C:17]([F:38])=[C:16]([N:67]3[CH2:68][CH:64]4[CH:65]([C:61]([C:58]5[CH:59]=[N:60][C:55]([C:54]([F:69])([F:53])[F:70])=[CH:56][CH:57]=5)=[N:62][O:63]4)[CH2:66]3)[N:25]=2)[C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5ccc(Cl)cc5)C4C3)c(F)cc2c1=O
Reactant: FC(F)(F)c1ccc(C2=NO[C@H]3CNC[C@@H]23)cn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5ccc(C(F)(F)F)nc5)C4C3)c(F)cc2c1=O

Procedure:
The title compound was prepared in an analogous manner to acid 101, but using a suitably substituted TFA salt 4d. Acid 103 was isolated as a gold solid.
Reaction SMILES: [C:1]([C:9]1[NH:13][C:12]([C:14](OC(=O)C)([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([C:9]1[NH:13][C:12]([CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(OC(C)=O)(C(=O)OCC)c1ccc(C(=O)c2ccccc2)[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)c2ccccc2)[nH]1
Temperature: 40 °C
Reaction time: 24 h
Yield: 49.6 %

Procedure:
To a solution of diethyl (5-benzoylpyrrol-2-yl)-acetoxymethanedicarboxylate (142 mg, 0.367 mmol) and triethylsilane (102 mg, 0.440 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (84 mg, 0.734 mmol). The reaction mixture was stirred at 40° C. for 24 hours. Additional triethyl silane (51 mg, 0.220 mmol) and trifluoroacetic acid (84 mg, 0.734 mmol) was added. The reaction mixture was stirred at 40° C. for an additional 24 hours. The mixture was cooled to room temperature, washed with cold 10% aqueous sodium hydroxide and saturated aqueous sodium chloride, and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with hexane/ethyl acetate (87:13) to provide 60 mg (50%) of diethyl (5-benzoylpyrrol-2-yl)methane-dicarboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>[Pt]=O.C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)cc1
Agent: O=[Pt]
Solvent: ClC(Cl)Cl
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)cc1
Reaction time: 1 h
Yield: 47.1 %

Procedure:
A mixture of 5.00 g (0.0137 m) of 1-[(p-nitrophenyl)sulfonyl]-4-(p-fluorophenyl)piperazine, 0.2 g of platinum oxide, and 150 ml of chloroform is shaken under hydrogen on a Parr hydrogenation apparatus for one hour. The mixture is then filtered through a sintered glass funnel containing activated carbon and sand to remove the catalyst. The filtrate is concentrated in vacuo and then extracted with methylene chloride/aqueous sodium bicarbonate. The organic layer is filtered through anhydrous sodium sulfate and taken to dryness. The residue is crystallized from methanol to give 2.16 g of 1-[(p-aminophenyl)sulfonyl]-4-(p-fluorophenyl)piperazine containing a minor impurity. Recrystallization from methanol gives an analytical sample with a melting point of 180.5°-181.5° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=O.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[CH:46]=[CH:45][C:19]([CH2:20][N:21]2[C@@H:29]3[C@@H:25]([CH2:26][CH2:27][CH2:28]3)[C:24]([OH:30])=[C:23]([C:31]3[NH:36][C:35]4[CH:37]=[CH:38][C:39](I)=[CH:40][C:34]=4[S:33](=[O:43])(=[O:42])[N:32]=3)[C:22]2=[O:44])=[CH:18][CH:17]=1.N1CCCCC1>[Cu](I)I>[O:42]=[S:33]1(=[O:43])[C:34]2[CH:40]=[C:39]([N:1]3[CH2:8][CH2:7][CH2:6][CH2:2][CH2:3]3)[CH:38]=[CH:37][C:35]=2[NH:36][C:31]([C:23]2[C:22](=[O:44])[N:21]([CH2:20][C:19]3[CH:45]=[CH:46][C:16]([F:15])=[CH:17][CH:18]=3)[C@@H:29]3[C@H:25]([C:24]=2[OH:30])[CH2:26][CH2:27][CH2:28]3)=[N:32]1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCNCC1
Product: O=C1C(C2=NS(=O)(=O)c3cc(N4CCCCC4)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 60 h
Yield: 147.6 %

Procedure:
A reaction flask was charged with L-proline (24.3 mg, 0.21 mmol), potassium carbonate (146.3 mg, 1.06 mmol), copper iodide (21 mg, 0.11 mmol) and (4aR,7aS)-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1,4a,5,6,7,7a-hexahydro-[1]pyrindin-2-one (prepared as described in Example 39c, 300 mg, 0.53 mmol). The flask was degassed and backfilled with nitrogen, and then anhydrous dimethylsulfoxide (5 mL) was added followed by addition of piperidine (0.16 mL, 1.60 mmol). The resulting suspension was vigorously stirred at 90° C. for 60 h, and then allowed to cool to 25° C. The mixture was passed through a plug of Celite and rinsed with 10% methanol/dichloromethane. The filtrate was concentrated in vacuo, and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 40%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (4aR,7aS)-3-(1,1-dioxo-7-piperidin-1-yl-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(4-fluoro-benzyl)-4-hydroxy-1,4a,5,6,7,7a-hexahydro-[1]pyrindin-2-one (160 mg, 0.31 mmol, 58%), as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.40-1.63 (9H, m), 1.96 (2H, m), 2.06 (1H, m), 3.23 (4H, m), 3.32 (1H, m), 3.83 (1H, m), 4.45 (1H, d, J=15.6 Hz), 4.89 (1H, d, J=14.8 Hz), 7.14 (3H, m), 7.32-7.44 (4H, m), 13.86 (1H, s). LC-MS (ESI) calcd for C27H29FN4O4S 524.19, found 525.3 [M+H+]. e.e. >97% based on the e.e. of the commercially available (1R,2S)-2-amino-cyclopentanecarboxylic acid (Example 40a).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:19]([O:23][C:24]([NH:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C1C=CC=CN=1)C>C(O)C>[C:19]([O:23][C:24]([NH:26][C@H:27]1[CH2:28][CH2:29][C@H:30]([NH:33][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:3]=2)[CH2:31][CH2:32]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Agent: CN(C)c1ccccn1
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Ethyl 4-chloro-2-phenyl-5-pyrimidinecarboxylate and N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine were reacted in ethanol in the presence of dimethylaminopyridine in the same manner as in Reference Example 3-49 to obtain N-tert-butoxycarbonyl-trans-4-(5-ethoxycarbonyl-2-phenyl-4-pyrimidinylamino)cyclohexylamine.
Reaction SMILES: [O:1]1[CH2:6][C:5](=S)[NH:4][C:3](=[O:8])[NH:2]1.[NH:9]1[CH2:15][C:13](=[O:14])[NH:12][C:10]1=[O:11]>O1CCOCC1>[O:8]=[C:3]1[N:4]=[C:5]([N:9]2[CH2:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:6][O:1][NH:2]1
Reactant: O=C1NOCC(=S)N1
Reactant: O=C1CNC(=O)N1
Solvent: C1COCCO1
Product: O=C1CN(C2=NC(=O)NOC2)C(=O)N1
Temperature: 25 °C
Reaction time: 17 h
Yield: 40.4 %

Procedure:
To a solution of 1.0 g (0.0075 mole) of 6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione in 50 ml of freshly distilled dry dioxane is added 0.77 g (0.0077 mole) of hydantoin. After stirring at room temperature for 17 hours, the solution is filtered, washed with chloroform and dried to give a yield of 0.6 g (41 percent) of 1-(3,6-dihydro-3-oxo-2H-1,2,4-oxadiazin-5-yl)-2,4-imidazolidinedione.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:22]=[CH:23][CH:24]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=3)=[O:31])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Product: COc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)c1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=429.04.