Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].I[CH2:19][CH3:20]>C1COCC1>[C:4]([O:3][C:1](=[O:2])[N:8]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)[CH2:19][CH3:20])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)c1ccc(Br)cn1
Reaction time: 0.33 h

Procedure:
To a solution of 2-(BOC-amino)-5-bromopyridine (500 mg) in THF (20 mL) at 0° C. was added sodium hydride (88 mg) and the reaction stirred for 20 min. Then, iodoethane (0.18 mL) was added and the reaction stirred at room temperature for 16 h. The reaction was quenched with water (20 mL) and extracted into ethylacetate (3×20 mL). The organic layers were dried (MgSO4) and reduced in vacuo to give (5-bromo-pyridin-2-yl)-ethyl-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.Br.C(O)(=O)C.CS(C)=O>C(O)(=O)C>[O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=[CH:3]1
Reactant: O=C1CCC(C(=O)O)=NN1
Agent: Br
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(=O)[nH]n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.5 %

Procedure:
To a solution of 6-oxo-1,4,5,6-tetrahydropyridazine-3-carboxylic acid (20 g) in acetic acid (50 mL) is added 25% hydrobromic acid/acetic acid (200 mL) and thereto is added dropwise dimethylsulfoxide (22.0 g) at room temperature. The mixture is stirred at room temperature for 3 days. The resultant precipitates are collected by filtration, washed successively with acetic acid and water and dried at 40° C. overnight to give 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (10.55 g, yield; 54%) as colorless crystals. MS (ESI) m/z: 139 [M−H]−
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]([NH2:22])=[O:21])[CH:16]=[CH:17][CH:18]=1)(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]([NH2:22])=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1cccc(NC(N)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: NC(=O)Nc1cccc(CCCCO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-[3-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)phenyl]urea (5.67 g) in THF (50 ml) was treated with TFA (13.56 ml) and stirred at room temperature for 1 h. Further TFA (5 ml) was added and the reaction mixture stirred for a further 16 hours. The reaction mixture was concentrated in vacuo. The residue was co-evaporated with methanol and then suspended in methanol and heated at reflux for 20 h prior to concentration in vacuo. The residue was purified by chromatography (SPE, DCM-MeOH 9:1) to give the title compound. LCMS RT=2.14 min.
Reaction SMILES: CC(OC([NH:8][C@@H:9]([C:16]([OH:18])=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.C(O)CCCCCCC/C=C\CCCCCCCC>C(#N)C>[NH2:8][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]([OH:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCCCCCCC/C=C\CCCCCCCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: NC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To a solution of N-Boc L-phenylglycine (2.51 g, 10 mmol) in acetonitrile (50 ml), was added portionwise 1,1′-carbonyldiimidazole (3.24 g, 20 mmol). The solution was stirred at room temperature for 1 h, oleyl alcohol (3.15 ml, 2.68 g, 10 mmol) was added, and the reaction mixture further stirred for 2 h at room temperature. The solvent was evaporated, the residue was dissolved in ethyl acetate (150 ml), washed successively with 5% NaHCO3, 5% citric acid and water, dried on MgSO4 and evaporated to dryness. The residue was dissolved in 1% HCl in ethyl acetate (100 ml), and the solution set aside for 6 h at room temperature, and evaporated to dryness. The residue thus obtained was crystallized from ether/n-hexane to give 1.6 g 3.65 mmol, 36.5% yield) of an off-white solid, mp 101-103° C. Racemic mixture was attained.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18]Cl.O>ClCCl.C(NC(C)C)(C)C>[CH3:16][O:17][CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: COCCl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Solvent: O
Product: COCOc1ccc(C(=O)c2ccccc2)cc1

Procedure:
2 g of 4-hydroxybenzophenone was dissolved in 20 ml dichloromethane and 2.12 ml diisopropylamine, and then stirred with 0.9 ml chloromethyl methyl ether at room temperature for 16 hours. Dichloromethane and water were added to the reaction mixture, which was then extracted with dichloromethane three times, washed with saturated aqueous sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was evaporated to give 4-(methoxymethoxy)benzophenone as an oil quantitatively. Yield: 2.44 g.
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15](/[C:16](=[N:28]/[O:29][CH3:30])/[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C=C1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[CH3:30][O:29]/[N:28]=[C:16]1/[C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]([CH2:17]/1)[CH2:19][C:20](=[O:50])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:12]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: CO/N=C1\CC2CCCC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@H]12
Product: CO/N=C1\CC2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Yield: 55 %

Procedure:
The title compound II-au was prepared in 55% yield from 3,3:17,17-bis(ethylendioxy)-7-(E)-methoxyiminoandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The crude product was purified by flash chromatography (SiO2, n-hexane/EtOAc 6/4). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 3.72 (3H, s), 2.89 (1H, m), 2.63-0.93 (19H, m), 1.12 (3H, s), 0.82 (3H, s).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8].C1CCC([N:27]=[C:28]=[N:29]C2CCCCC2)CC1.ON1C(=O)CCC1=O.N#CN.[Na].Cl.[Cl-].[Na+]>C1COCC1.O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:18]([NH:29][C:28]#[N:27])=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CC[C@@H](C(=O)N[C@@H](Cc2ccccc2)C(=O)O)N1
Agent: Cl
Agent: N#CN
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: C1CCOC1
Product: N#CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCC(=O)N1
Reaction time: 6 h
Yield: 42.5 %

Procedure:
L-Pyroglutamyl-L-phenylalanine (4.10 g, 0.0148 mol) was allowed to react with DCC (3.37 g, 0.0163 mol) and N-hydroxysuccinimide (1.88 g, 0.0163 mol) in 60 ml of THF at ice bath temperature for 3 hours, and then at room temperature overnight. The reaction mixture was filtered and the filtrate was added drop-wise to a solution of sodium cyanamide (1.90 g, 0.0297 mol) in 60 ml of distilled water at ice bath temperature. The reaction was allowed to proceed at this temperature for 6 hours. The reaction mixture (pH 8) was then neutralized to pH 7 with 10% HCl, saturated with sodium chloride, and extracted with ethyl acetate (2×50 ml). The aqueous portion (pH 6.2) was acidified to pH 1.5 with 10% HCl and extracted with EtOAc/THF (3:1) (100 ml) and ethyl acetate (2×50 ml). The combined organic extract was dried over anhydrous sodium sulfate and evaporated in vacuo to give 4.20 g (94.5% yield) of crude product as an off-white solid residue. This was crystallized from abs. EtOH/diethyl ether to give 1.36 g (crop 1) of 15. The filtrate was concentrated and crystallized in the same manner to give 9.53 g (crop 2), giving a total yield of 42.5%. Mp 163°-165° C.; [α]D23 +7.81° (c 1.0, MeOH); TLC: Rf =0.29 in CHCl3 /MeOH/AcOH (80:20:5), detected by UV quenching and orange color with ferricyanide spray reagent; IR (Nujol, cm-1) 3350 (NH), 3020 (C6H5), 2160 (C≡N), 1650-1690 (C=O); NMR (methanol-d4, δ from TMS) 7.22 (s, --C6H5), 4.5-4.7 (q, --NH--CH--C=O), 4.0-4.2 (m, --NH--CH--C=O), 2.8-3.2 (m, --CH2 --C6H5), 1.7-2.6 (m, cycl. O=C--CH2 --CH2 --). Anai. Calcd for C15H16N4O3 : C, 59.99; H, 5.37; N, 18.66. Found: C, 59.61; H, 5.61; N, 18.40.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[CH3:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[O:8])=[CH:26][C:25]=1[CH3:32]
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Reactant: Cc1cc(C=O)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(F)c(C)c3)CC2)cc1
Temperature: 110 °C
Yield: 59.8 %

Procedure:
A mixture of (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D13) (40 mg, 0.13 mmol) and 4-fluoro-3-methyl benzaldehyde (0.02 ml, 0.16 mmol), NaBH(OAc)3 (84 mg, 0.4 mmol) and CH3COOH (0.076 ml, 1.3 mmol) in DCM (10 ml) was heated at 110° C. (2 cycles of 5 min each) under microwave irradiation. The resulting mixture was purified by SPE-Si (2 g) eluting with a mixture DCM/AcOEt from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D29) (33 mg).
Reaction SMILES: [CH2:1]([S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1C=O>>[CH2:1]([S:8](/[CH:11]=[CH:12]/[C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccccc1
Reactant: O=Cc1ccccc1Cl
Product: O=S(=O)(/C=C/c1ccccc1Cl)Cc1ccccc1
Yield: 72 %

Procedure:
A solution of benzyl sulfonylacetic acid (0.01 mol) and 2-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 72% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16](=[CH:21][CH:22]=1)[C:17]([O:19]C)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16](=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(NCc1ccc(C(=O)O)c(OCc2ccccc2)c1)OCc1ccccc1
Temperature: 75 °C
Yield: 90 %

Procedure:
Methyl N-(benzyloxycarbonyl)-4-aminomethyl-2-O-benzylsalicylate (6.81 g, 16.8 mmoles) was dissolved in tetrahydrofaran (50 mL). A solution of lithium hydroxide monohydrate (0.78 g, 18.5 mmoles) in water (25 mL) was added, and the reaction mixture was stirred and heated at 75° C. for 24 hours. The solution was cooled, and 1N aqueous hydrochloric acid (50 mL) was added. The reaction mixture was extracted twice with ethyl acetate (150 mL then 50 mL). The combined ethyl acetate extracts were washed with water (75 mL) and saturated aqueous sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to 150 mL. The ethyl acetate solution was heated to boiling, and hexanes (150 mL) was added. The solution was cooled in ice, and crystals formed. The crystals were collected by filtration, washed with hexanes, and dried in vacuo to afford 5.92 g (90% yield) of N-(benzyloxy-carbonyl)-4-aminomethyl-2-O-benzylsalicylic acid (m.p. 139°-140° C., open capillary, uncorrected).
Reaction SMILES: [C:1]([NH:9][C:10](=[NH:18])[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCl)(C)(C)C.[OH-].[Na+].O>C(O)C>[O:11]([C:10]1[N:9]=[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:8][N:18]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N=C(NC(=O)c1ccccc1)Oc1ccccc1
Agent: CC(C)(C)OCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(Oc2noc(-c3ccccc3)n2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
N-benzoyl-O-phenylisourea (0.8 g) was dissolved in ethanol (40 ml), and t-butylhypochlorite (0.36 g) was added at 0° to 5° C. After one hour, 2 molar aqueous sodium hydroxide (2 ml) was added and the mixture was stirred for 2 hours at ambient temperature (20° C.). The reaction mixture was poured into an equal volume of water and extracted with dichloromethane (100 ml). The separated organic layer was evaporated under reduced pressure and the residue was purified by chromatography over silica gel using dichloromethane as eluant to give 3-phenoxy-5-phenyl-1,2,4-oxadiazole (0.4 g, 57%), m.p. 62° C.
Reaction SMILES: [CH:1]([CH:4]1[NH:9][C:8](=O)[CH2:7][NH:6][C:5]1=O)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:1]([CH:4]1[CH2:5][NH:6][CH2:7][CH2:8][NH:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1NC(=O)CNC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C1CNCCN1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2 g of 3-isopropyl-piperazine-2,5-dione could be suspended in anhydrous THF under nitrogen and cooled in an ice-bath. 4 equiv. of lithium aluminium hydride could be added. The reaction could be stirred at 0° C. for 0.5 h, then heated to reflux overnight. The reaction could be quenched by the subsequent addition of 1 mL/gLiAlH4 of water, 1 mL/gLiAlH4 of 5% aqueous sodium hydroxide solution and 3 mL/gLiAlH4 of water. The resulting solid could be separated by filtration through Celite and rinsed with ethyl acetate. The filtrate could be concentrated in vacuo to afford 2-isopropyl-piperazine.
Reaction SMILES: Br[CH2:2][C@H:3]1[O:7][C:6](=[O:8])[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C>[N:17]([CH2:2][C@H:3]1[O:7][C:6](=[O:8])[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CBr)OC1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CN=[N+]=[N-])OC1=O
Temperature: 60 °C
Yield: 98.2 %

Procedure:
To a stirred slurry of compound 1A, (8.47 g, 28.8 mmol) in 127 mL of DMF at room temperature was added sodium azide (2.25 g, 34.6 mmol). The reaction mixture was then heated to 60° C. under argon for 9 h. The reaction mixture was then cooled, quenched with 200 mL of ice-cold water and extracted four times with 200 mL portions of ether. The combined organic extracts were washed three times with water, once with saturated NaCl and dried over Na2SO4, then MgSO4, filtered and evaporated under reduced pressure. Purification by silica gel chromatography (3:17 EtOAc/CH2Cl2) provided the title compound (7.25 g, 98%) as a colorless oil. MS [M+Na]+: found 278.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.[C:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[C:31]1[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][CH:32]=1)(O)=[O:21]>>[C:37]([C:34]1[CH:35]=[CH:36][C:31]2[C:24]3[C:23](=[CH:28][CH:27]=[C:26]([O:29][CH3:30])[CH:25]=3)[C:20](=[O:21])[C:32]=2[CH:33]=1)([OH:39])=[O:38]
Reactant: COc1ccc(C(=O)O)c(-c2ccc(C(=O)O)cc2)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc2c(c1)-c1ccc(C(=O)O)cc1C2=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A mixture of 2.5 g of phosphorous pentoxide and 25 ml of methanesulfonic acid were stirred together under a nitrogen atmosphere overnight. To this mixture were added 2.3 g of 2,4'-dicarboxy-5-methoxybiphenyl. The reaction mixture was stirred at room temperature for six hours with the addition of methanesulfonic acid to keep the mixture sufficient for stirring. The mixture was then warmed to 40° C. for one hour, cooled, and poured into ice water. The resulting yellow-green precipitate was recovered by filteration, washed with water, and dried to provide 1.6 g of the desired subtitle intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].CO.[H][H]>[C].[Pd].C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2ccccc2c(=O)n1Cc1ccc2c(c1)OCO2
Yield: 91.3 %

Procedure:
A mixture of 2-benzo[1,3]dioxol-5-ylmethyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), 10% palladium carbon (300 mg), methanol (6 ml) and THF (6 ml) was stirred at room temperature under 1 atm hydrogen pressure for 12 hrs. Palladium carbon was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized (ethyl acetate-hexane) to give the title compound (230 mg).
Reaction SMILES: CCN([CH:7]([CH3:9])[CH3:8])C(C)C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C@H:21]([C@@H:28]([NH2:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C@@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:28]([NH:35][CH2:31][CH2:30][CH2:29][CH2:28][C:21]2[CH2:9][C:7]([CH3:8])=[CH:24][CH2:23][CH:22]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1=CCC=C(CCCCN[C@@H](c2ccccc2)[C@@H](NS(=O)(=O)c2ccc(C)cc2)c2ccccc2)C1
Temperature: 135 °C
Reaction time: 14 h
Yield: 110.9 %

Procedure:
The tosylates (10.45 g, 32.61 mmol, isomer ratio: 1,4 type/1,5 type=77/23) obtained in Example 2 were dissolved in 40 ml of toluene, and DIPEA (4.79 g, 32.61 mmol) and (S,S)-TsDPEN (11.95 g, 32.61 mmol) were added thereto, followed by stirring at 135° C. for 14 hours. After that, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1). Thus, 9.31 g of the title compounds were obtained as a yellow oily substance. Yield: 55.5% (isomer ratio: 1,4 type/1,5 type=77/23). Note that the following NMR spectrum data are those of the isomer mixture.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[C:11]2[CH:12]=[N:13][C:14]([NH:16][C:17]([NH:19][C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])=[O:18])=[CH:15][C:10]=2[N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:8]=1)=[O:5].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[C:11]2[CH:12]=[N:13][C:14]([NH:16][C:17]([NH:19][C@@H:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH3:21])=[O:18])=[CH:15][C:10]=2[NH:9][N:8]=1)=[O:5]
Reactant: COCC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COCC(=O)Nc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-2-methoxy-N-(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide (0.056 mmol) was taken up in TFA (1 ml) and the reaction mixture was stirred at room temperature for 1 h. Triethylsilane (0.009 ml, 0.056 mmol) was added drop wise, and the reaction mixture stirred for an additional 5 minutes. The mixture was concentrated, re-dissolved in DMSO (1.5 mL) and submitted for purification by mass-triggered prep. HPLC to afford (R)-2-methoxy-N-(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide. TFA (15.9 mg, 0.033 mmol, 58.9% yield) as a white solid. MS ESI calc'd. For C18H21N6O3 [M+H]+ 369. found 369. 1H NMR (ppm, 600 MHz, DMSO): δ 10.62 (s, 1H); 9.28 (br s, 1H); 9.00 (s, 1H); 7.75 (s, 1H); 7.46 (s, 1H); 7.31-7.32 (m, 4H); 7.19-7.22 (m, 1H); 4.85 (t, J=7.2 Hz, 1H); 4.09 (s, 2H); 3.35 (s, 3H); 1.39 (d, J=6.9 Hz, 3H).
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]([CH:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[OH:30])=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[N:21]2)=[CH:16][CH:15]=1>C1COCC1.CS(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]([C:29]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)=[O:30])=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[N:21]2)=[CH:16][CH:15]=1
Reactant: OC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
2-Iodoxybenzoic acid (1.42 g, 2.3 mmol; 45% purity) was added to an ice cold solution of [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-methanol (520 mg, 1.5 mmol) in THF/DMSO 1/1 (28 ml). The reaction mixture was stirred for 1 h at ambient temperature, ice water/brine 1/1 was added and the mixture was extracted two times with iPrOAc. The combined extracts were washed with ice water/saturated aqueous ammonium chloride solution 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (404 mg, 1.2 μmol; 78%) as colorless solid. MS: m/e=339.1 [M+H+].
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].[F:7][CH:8]([C:14](OCC)=[O:15])[C:9](OCC)=[O:10]>C(O)C>[F:7][C:8]1[C:9]([OH:10])=[N:5][C:4]([NH2:6])=[N:3][C:14]=1[OH:15]
Reactant: CCOC(=O)C(F)C(=O)OCC
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1nc(O)c(F)c(O)n1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
Sodium (257 mg, 11 mmol) was dissolved in absolute ethanol (50 ml) with stirring under argon. When the sodium had thoroughly dissolved, guanidine hydrochloride (2) (502 mg, 5 mmol) and diethyl fluoromalonate (1) (790 mg, 4.4 mmol) were added. The solution was left to stir at room temperature overnight. A condenser was then attached to the flask and the solution was refluxed under argon for 4.5 hours. The solution was cooled to room temperature and concentrated. The residue was redissolved in 20 ml hot H2O and acidified to pH 4. The mixture was cooled on ice and the precipitate was collected, yielding (3) as a peach colored solid (618 mg, 96%): MS (70 eV, EI)m/z (relative intensity) 146(M+, 100), 18 (95), 172 (26), 17 (24), 300 (21); IR (mull, cm-1) 3363, 1695, 1601, 1420, 1208, 677, 666; UV (MeOH, nm) 206(3,840), 235(3,380), 270(11,600). Exact Mass Calcd for C4H4N3O2F: 146.0366. Found: 146.0371.