Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH2:13])=[CH:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:20]I>O1CCCC1.O>[I:20][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[NH2:13]
Reactant: COc1ccc2ccc(N)cc2c1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2ccc(N)c(I)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a mixture of 7-methoxynaphthalen-2-amine (5 g, 29 mmol) and sodium carbonate (6.1 g, 57.6 mmol) in tetrahydrofuran (200 ml) and water (20 ml) was added iodine (7.0 g, 27.67 mmol) in portions at 0° C. The resulting solution was stirred overnight at room temperature and then diluted with water (250 ml), extracted with ethyl acetate (3×200 ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 5% ethyl acetate in petroleum ether to afford 1-iodo-7-methoxynaphthalen-2-amine as a yellow solid (5.2 g, 60%). (ES, m/z): [M+H]+ 300.1; 1H NMR (300 MHz, CDCl3): δ 7.54 (dd, J=8.7, 5.4 Hz, 2H), 7.30 (d, J=2.4 Hz, 1H), 6.91 (dd, J=8.7, 2.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.04 (br s, 2H), 3.96 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[N:16]=[C:17]=[S:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[C:10]=1[N:16]1[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:17]1=[S:18]
Reactant: Cc1cccc(C)c1N=C=S
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(=O)N(c2c(C)cccc2C)C1=S
Yield: 18.4 %

Procedure:
The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 8.2 g of 2,6-dimethylphenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethanol. Title compound (2.3 g) was obtained as a white solid (2.3 g). m.p. 128°-131° C. Anal. Calcd. for. C13H16N2O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.83; H, 6.50; N, 11.25. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[N:8][C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=3)=[CH:10][N:6]2[N:7]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Yield: 727.3 %

Procedure:
A stirred solution of 6-chloropyridazin-3-amine (0.842 g, 0.0065 mol) and 2-bromo-1-[3-nitro-4-(trifluoromethyl)phenyl]ethanone (2.03 g, 0.65 mmol) in acetonitrile (37.34 mL) is heated at 90° C. for 48 hr. The reaction mixture is concentrated and purified by silica gel chromatography (CH2Cl2 to EtOAc) to give the title compound (1.62 g, 73% yield). LCMS m/z=343.3 [M+H]+, tR=3.15 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.CN([CH:17]=[O:18])C.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([CH:17]=[O:18])=[CH:5][CH:4]=1
Reactant: COc1cccc2c(C)cccc12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C=O)c2c(C)cccc12
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a well stirred solution of 1-methoxy-5-methylnaphthalene (above Step-3 intermediate) (7.0 g, 40.7 mmol) in toluene (8 mL) and DMF (4.7 mL, 61 mmol) at 0° C. was added, POCl3 (4.6 mL, 49.6 mmol) drop wise and the reaction mixture was stirred for 45 min at 0° C. and then refluxed for 2 h. The dark red solution was cooled to RT and poured into a mixture of ice (50 mL) and 10% aq. NaOH (100 mL) with stirring. The crude product was extracted with EtOAc (4×75 mL) and the combined organic layer was washed with 1 N HCl (3×50 mL), water (3×50 mL), brine, dried (Na2SO4) and filtered. The solvent was evaporated and the residue was washed with hexanes (2×15 mL) to afford the desired compound (6.4 g, 79%) as reddish brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](O)([CH3:23])([CH3:22])[CH3:21].O.NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH2:13][CH:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Agent: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 5 L flange flask was charged 1-benzyloxycarbonylpiperidine-4-carboxylic acid 20 (200 g, 759.6 mmol) in DCM (500.0 mL) followed by additional DCM (2.000 L), t-butanol (140.8 g, 181.7 mL, 1.899 mol) and DMAP (46.40 g, 379.8 mmol). The mixture was cooled on ice/salt/water bath (internal −3.4° C.). 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine (Hydrochloric Acid (1)) (145.6 g, 759.6 mmol) was added portionwise over 15 mins, with addition funnel rinsed with DCM (500.0 mL). Mixture was stirred on ice bath for approx. 2 h. Ice bath was then removed (internal 3° C.) and allowed to warm to room temperature overnight. Mixture was washed with 5% citric acid (2×500 mL), then saturated NaHCO3 (500 mL), water (500 mL), and organics dried over MgSO4, which was then filtered and concentrated in vacuo to leave product 21 as a viscous light yellow oil which turned to a white solid on standing. (246.1 g, 101%). 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.31 (m, 5H), 5.08 (s, 2H), 3.90 (dt, 2H), 2.93 (br s, 2H), 2.43 (tt, 1H), 1.80-1.76 (m, 2H) and 1.45-1.37 (m, 11H).
Reaction SMILES: [H-].[Na+].C1([C@H]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[NH:13][C:12]2=[O:20])C)C=CC=CC=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(COC)OC>[CH2:21]([N:13]1[CH:14]2[C:18](=[O:19])[O:17][CH2:16][CH:15]2[NH:11][C:12]1=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1OCC2NC(=O)N(Cc3ccccc3)C12
Reaction time: 0.5 h

Procedure:
48 ml of dimethoxyethane and 0.39 g (16.2 mmol) of sodium hydride were placed in a 100-ml three-neck flask equipped with a magnetic stirrer under argon and with complete exclusion of moisture. Then 3.24 g (13.2 mmol) of (3aS,6aR)-1-[(R)-(1-phenylethyl)]-dihydro-1H-furo[3,4-d]-imidazol-2,4(3H,3aH)-dione was added. After a stirring time of 10 min., 2.76 g (16.2 mmol) of benzyl bromide was added and the suspension was stirred for 30 min. Then the reaction mixture was evaporated. The residue was dissolved with 25 ml of dichloromethane and 25 ml of water. The phases were separated and the aqueous phase was washed three times, each time with 15 ml of water. The organic phases were combined, dried with 5 g of magnesium sulfate and evaporated. (3aS,6aR)-1-[R)-(1-phenylethyl)]-3-benzyl-dihydro-1H-furo-[3,4-d]-imidazol-2,4(3H,3aH)-dione was obtained as a beige product in a yield of 3.56 g (80.5 percent). Concerning the product:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[N:3]=1.[K].[S-:19][C:20]#[N:21].[S-]C#N.[K+]>C(O)(=O)C>[S:19]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[N:3]=1)[C:20]#[N:21]
Reactant: N#C[S-]
Reactant: FC(F)C(F)(F)c1nc(Cl)c2ccccc2n1
Agent: [K+]
Agent: [K]
Solvent: CC(=O)O
Product: N#CSc1nc(C(F)(F)C(F)F)nc2ccccc12
Reaction time: 2 h

Procedure:
7.9 g of 4-chloro-2-(1,1,2,2-tetrafluoroethyl)-quinazoline are dissolved in 10 ml of glacial acetic acid and subsequently 4.9 g of potassium-thiocyanate are added to this solution. Whilst stirring at room temperature the potassium thiocyanate dissolves in approximately 1 hour. The solution is stirred for another 2 hours, a precipitation being obtained. This precipitation is drawn off, washed with water and dried in vacuo. After recrystallization from isoporpanol the resulting 4-thiocyano-2-(1,1,2,2-tetrafluoro-ethyl)-quinazoline has a melting point of 112°-114.5°C.
Reaction SMILES: [CH2:1]1[CH:9]([CH2:10][C:11]([OH:13])=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C(N(CC)CC)C.Cl.Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(OP(C#N)(=O)OCC)C>C(Cl)Cl>[CH:9]1([CH2:10][C:11]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)[CH2:36][CH2:35]2)=[O:13])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1]1
Reactant: O=C(O)CC1CCc2ccccc21
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2CCN(C(=O)CC3CCc4ccccc43)CC2)cc1
Reaction time: 3 h

Procedure:
A mixture of 1-indanylacetic acid (CIX, EXAMPLE 66, 7.4 g, 42 mmol) and triethylamine (29.3 ml, 210 mmol), and 1-(4-methoxyphenyl)piperazine dihydrochloride (LXV, 13.3 g, 50.4 mmol) in methylene chloride (420 ml) is stirred at 20°-25° under a nitrogen atmosphere. Diethylcyanophosphonate (12.7 ml, 84 mmol) is added over a period of 10 min at 20°-25°. After the stirring for 3 hr, the reaction is quenched with sodium hydroxide (20%) and extracted with methylene chloride (2×500 ml). The organic phase is washed with saline, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude product is purified by crystallization from ethyl acetate/methanol. The mother liquor is purified by liquid chromatography on silica gel 60 (230-400 mesh, 400 g), eluting with hexane/ethyl acetate (1/2). The appropriate fractions homogeneous by TLC are combined and concentrated under reduced pressure to give a solid. Both solids are combined to give the title compound, mp=111°-112°; NMR (CDCl3, TMS) 7.26-6.83, 3.77 and 3.85-1.54 δ.
Reaction SMILES: ClC1C(C2C=CC=CC=2)=N[N:5]=[C:4]2N(C)N=C(C3C=CC(C#N)=CC=3)C=12.[Cl:26][C:27]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:31][N:30]=[C:29]2[N:39]([CH3:49])[N:40]=[C:41]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44](I)[CH:43]=3)[C:28]=12.ClC1C(C2C=CC=CC=2)=NN=C2N(C)N=C(C3C=CC(I)=CC=3)C=12>>[Cl:26][C:27]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:31][N:30]=[C:29]2[N:39]([CH3:49])[N:40]=[C:41]([C:42]3[CH:43]=[C:44]([CH:45]=[CH:46][CH:47]=3)[C:4]#[N:5])[C:28]=12
Reactant: Cn1nc(-c2cccc(I)c2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: Cn1nc(-c2ccc(C#N)cc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: Cn1nc(-c2ccc(I)cc2)c2c(Cl)c(-c3ccccc3)nnc21
Product: Cn1nc(-c2cccc(C#N)c2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 34 was synthesised following similar procedures outlined in Example 35 (Compound 24), using 4-chloro-3-(3-iodophenyl)-1-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (Compound 3, Example 30) as the starting material instead of 4-chloro-3-(4-iodophenyl)-1-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (Compound 43, Example 23).
Reaction SMILES: [C:1]1([CH:7]([O:24][C:25]2[CH:49]=[CH:48][C:28]([C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])[CH:32]=3)=[O:30])=[CH:27][CH:26]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(O)(=O)C>C(O)C>[C:1]1([CH:7]([O:24][C:25]2[CH:49]=[CH:48][C:28]([C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])[CH:32]=3)=[O:30])=[CH:27][CH:26]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(CCN3CCN(c4ccccc4OC)CC3)c3ccccc3)cc2)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccccc1N1CCN(CCC(Oc2ccc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)cc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
Ethyl 4-{3-{4-{1-phenyl-3-[4-(2-methoxyphenyl) piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate (1.89 g) obtained in Step 3 was dissolved in ethanol (20 ml). Potassium hydroxide (0.80 g) was added to the resultant solution and stirred for 3 hours at room temperature. After adding acetic acid (2 ml) to the reaction mixture, the solvent was distilled off. Water was added thereto, followed by extraction with ethyl acetate. The resultant extract was washed with brine and dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (methylene chloride: methanol=40:1), obtaining 1.68 g of 4-{3-{4-{1-phenyl-3-[4-(2-methoxyphenyl)piperazin-1-yl] propoxy}benzoyl}indol-1-yl}butanoic acid as amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:34]=[CH:33][C:14]3[CH2:15][CH2:16][C:17]4[C:18]([C:30]([NH2:32])=[O:31])=[N:19][N:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][CH:23]=5)[C:21]=4[C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[OH:36]S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([N:20]2[C:21]3[C:13]4[CH:12]=[C:11]([NH:10][C:8]([C:7]5[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=5)=[O:9])[CH:34]=[CH:33][C:14]=4[CH2:15][CH2:16][C:17]=3[C:18]([C:30]([NH2:32])=[O:31])=[N:19]2)=[CH:23][CH:24]=1)(=[O:36])[CH3:29]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: C#Cc1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Temperature: 100 °C

Procedure:
A mixture of 8-{[(2-chloropyridin-3-yl)carbonyl]amino}-1-(4-ethynylphenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (442 mg, 1.2 mmol), water (65 mg, 3.6 mmol), and triflic acid (270 mg, 1.8 mmol) in dioxane (10 mL) was heated to 100° C. for 18 h. The mixture was cooled to RT, aqueous NaHCO3 was added, and filtered. The product was washed with water and ether, and dried. This gave product (293 mg, 67%). 1H NMR was consistent with its structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=O)[CH:5]=[CH:4][C:3]1=2.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:43]2)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=[S:43])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(NC(=S)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 110.0 mg (0.25 mmol) ethyl 4-[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoate (Compound 35) and 121.0 mg (0.30 mmol) of [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (Lawesson's Reagent) in 12.0 ml of benzene was refluxed overnight. Upon cooling to room temperature, the mixture was filtered and the filtrate concentrated under reduced pressure. The title compound was isolated by column chromatography (10 to 25% EtOAc/hexanes) as a yellow solid. 1H NMR (CDCl3): δ 8.92 (1H, s), 8.06 (2H, t, J=8.5 Hz), 7.88-7.70 (3H, m), 7.42 (2H, d, J=8.1 Hz), 7.18 (4H, m), 6.03 (1H, t, J=4.7 Hz), 4.37 (2H, q, J=7.1 Hz), 2.38 (3H, s), 2.36 (2H, d, J=4.7 Hz), 1.56 (3H, t, J=7.1 Hz), 1.35 (6H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.COC1C2C=NC([NH:45][C:46]([NH:48][C@@H:49]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH3:50])=[O:47])=CC=2N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)N=1>>[CH:8]([C:6]1[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:4]=2[CH:3]=[C:2]([NH:45][C:46]([NH:48][C@@H:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH3:50])=[O:47])[N:7]=1)=[O:9]
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C=O)c12

Procedure:
(R)-1-(4-Formyl-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea was prepared from Intermediate 11B using the same procedure described for (R)-1-(3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Example 40, Step 2).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][C:14]([OH:16])=O)[C:8]=2[Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=O.[O:22]([CH2:26][CH2:27][NH2:28])[N+:23]([O-:25])=[O:24]>C(O)C>[O:22]([CH2:26][CH2:27][NH:28][C:14](=[O:16])[CH2:13][O:12][C:9]1[C:8]([Br:17])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1)[N+:23]([O-:25])=[O:24]
Reactant: O=C(O)COc1noc(-c2ccccc2)c1Br
Reactant: NCCO[N+](=O)[O-]
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: O=C(COc1noc(-c2ccccc2)c1Br)NCCO[N+](=O)[O-]
Yield: 64.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.53 g of 5-phenyl-4-bromo-3-isoxazolyloxyacetic acid and 0.30 g of nitroxyethylamine nitrate, 0.44 g of the title compound was obtained as colorless needles (solvent for recrystallization; ethanol).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=3[O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=[O:18])[C:11]([CH3:13])=[CH:12][C:7]=2[O:6][C:5]([CH3:28])([CH3:27])[C:4]1=[O:29])[CH3:2].[CH3:30][Mg]Br.C(OCC)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1>[C:17]([C:16]1[CH:19]=[CH:20][C:21]([O:22][C:23]([F:25])([F:24])[F:26])=[C:14]([C:10]2[C:11]([CH3:13])=[CH:12][C:7]3[O:6][C:5]([CH3:28])([CH3:27])[C:4](=[O:29])[N:3]([CH2:1][CH3:2])[C:8]=3[CH:9]=2)[CH:15]=1)(=[O:18])[CH3:30]
Reactant: C[Mg]Br
Reactant: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=O)ccc3OC(F)(F)F)cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C(C)=O)ccc3OC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A solution of Compound 1D (200 mg, 0.49 mmol) in dry 3 mL of dry THF is cooled to −78° C. and treated with a 3M solution of methyl magnesium bromide in diethyl ether (0.17 mL, 0.54 mmol). The reaction was allowed to warm to room temperature, the reaction turned blue when it was complete. The mixture was quenched with 5 mL of a saturated aqueous solution of NH4Cl and passed through a SPE. The crude product was eluted with EtOAc. After removing excess solvent the crude alcohol was then dissolved in 2 mL of dichloromethane and treated with Dess-Martin reagent (250 mg, 0.59 mmol) and stirred at room temperature overnight. The reaction was quenched with 4 mL of saturated sodium thiosulfate solution and 4 mL of saturated sodium bicarbonate solution, the reaction mixture was stirred until clear. The reaction mixture was passed through another SPE and eluted with dichloromethane, removal of solvent yielded crude ketone which was purified with flash chromatography (25% EtOAc/hexane) to yield 95 mg (46%) of the desired product and a white solid. MS (electrospray): mass calculated for C22H22F3NO4, 421.15; m/z found 422.1 [M+H]+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[N:12]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]3[CH2:37]CCCO3)=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:11]=1)[CH3:8])(C)(C)C.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]1[N:50]([S:51]([C:54]2[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=2)(=[O:53])=[O:52])[CH:49]=[C:48]([CH2:61][N:62]([CH3:70])[C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])[CH:47]=1.C1(C)C=CC(S(O)(=O)=[O:78])=CC=1>CO>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]1[N:12]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:37]([NH:50][CH3:49])=[O:78])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:11]=[C:10]([CH2:9][NH:7][CH3:8])[CH:14]=1.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]1[N:50]([S:51]([C:54]2[CH:55]=[CH:56][C:57]([OH:60])=[CH:58][CH:59]=2)(=[O:52])=[O:53])[CH:49]=[C:48]([CH2:61][N:62]([CH3:70])[C:63](=[O:69])[O:64][C:65]([CH3:66])([CH3:67])[CH3:68])[CH:47]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(OC3CCCCO3)cc2)c1)C(=O)OC(C)(C)C
Agent: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(O)cc2)c1)C(=O)OC(C)(C)C
Solvent: CO
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(OCC(=O)NC)cc2)c1
Reaction time: 3 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((4-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate tert-Butyl ((5-(2-fluorophenyl)-1-((4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 4c (2.3 g, 4.28 mmol) was dissolved in 30 mL of methanol, followed by addition of p-toluenesulfonic acid (148 mg, 0.86 mmol), and then the reaction solution was stirred for 3 h. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with elution system B to obtain the title product tert-butyl ((5-(2-fluorophenyl)-1-((4-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 4d (2.0 g, a colorless oil) in 80% yield.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16]([OH:18])=O)[CH2:6]1)(=[O:3])[CH3:2].[NH2:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[O:23][CH2:24][C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16](=[O:18])[NH:19][C:20]2[CH:33]=[CH:32][CH:31]=[C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH:21]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)O
Reactant: C=CCOC(=O)COc1cccc(N)c1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)COc1cccc(NC(=O)[C@@H]2C[C@H](SC(C)=O)CN2C(=O)OCC=C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.5 %

Procedure:
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-carboxypyrrolidine (1.59 g, 5.82 mM), allyl 3-aminophenoxyacetate (2.5 g, 0.012M), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (3.88 g, 0.016M) were dissolved in toluene (50 ml) and stirred 18 h at ambient temperature. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with 2M hydrochloric acid (2×30 ml), water, saturated NaHCO3, and brine. Crude product was purified by chromatography on silica, using a gradient from dichloromethane to dichloromethane/diethyl ether (4:1), to give title compound (3.0 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:18]1([CH:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[C:18]1([CH:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][NH:33][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:27][CH2:26]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(C=Cc1cccnc1)NCCC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Batch size: 2.3 g (15.5 mmol) 3-(3-pyridyl)-acrylic acid, 2.7 g (21.3 mmol) oxalyl chloride and 4.1 g (13.9 mmol) 2-(1-diphenylmethylpiperidine-4-yl)-ethylamine in 60 ml abs. dichlormethane.