Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[Na].O.Cl.[C:7]([NH2:15])(=[NH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:16]/[C:17](/[CH:22]=O)=[CH:18]\N(C)C>CO>[CH3:22][C:17]1[CH:16]=[N:14][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:15][CH:18]=1
Reactant: N=C(N)c1ccccc1
Reactant: C/C(C=O)=C\N(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cnc(-c2ccccc2)nc1
Temperature: 25 °C

Procedure:
A solution of sodium methoxide in methanol is generated by dissolving sodium metal (0.89 g, 30.0 mmol) in dry methanol (25 mL). This solution is added via an addition funnel to a solution of benzamidine hydrochloride hydrate (2.35 g, 15.0 mmol) and 3-dimethyl-amino-2-methylpropenal (1.16 g, 10.2 mmol) in dry methanol (50 mL) at room temperature. The reaction mixture is refluxed for 4 hours, then cooled at room temperature. The mixture is concentrated in vacuo and the residue partitioned between dichloromethane (50 mL) and water (50 mL). The aqueous layer is extracted with dichloromethane (50 mL) and the combined organic layers are dried over magnesium sulfate. Filtration and concentration in vacuo gives 5-methyl-2-phenyl-pyrimidine as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:6])[CH2:3][OH:4].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([CH3:20])[N:14]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:8]([O:7][C@H:5]([CH3:6])[C@H:2]([NH:1][C:17]1[CH:16]=[C:15]([CH3:20])[N:14]=[C:13]([Cl:12])[N:18]=1)[CH2:3][OH:4])([CH3:10])([CH3:9])[CH3:11]
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: C[C@@H](OC(C)(C)C)[C@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cc(N[C@H](CO)[C@@H](C)OC(C)(C)C)nc(Cl)n1
Temperature: 25 °C
Yield: 24.3 %

Procedure:
A solution of (2R,3R)-2-amino-3-(tert-butoxy)butan-1-ol (267 mg, 1.35 mmol, 1.1 equiv), 2,4-dichloro-6-methylpyrimidine (200 mg, 1.23 mmol, 1.0 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.54 mL, 3.1 mmol, 2.5 equiv) in 1,4-dioxane (6 mL) was heated at 75° C. for 4 h. The reaction was cooled to room temperature and concentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane) provided (2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol (86 mg, white solid) in 24% yield. 1H NMR (400 MHz, CDCl3) δ 6.17 (s, 1H), 4.02 (m, 2H), 3.79-3.64 (m, 2H), 2.30 (s, 3H), 1.22 (s, 9H), 1.18 (d, J=6.2 Hz, 3H); MS m/z 288.1 (M+H)+; Rt-0.59 min.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:33])[CH2:19][CH2:18][N:17]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][N:28]=4)[N:25]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:33][C:14]1([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=2)[CH2:15][CH2:16][N:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:24]([C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][N:28]=3)[N:25]=2)[CH2:18][CH2:19]1
Reactant: Oc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
Methyl 2-bromoacetate (0.121 mL, 1.28 mmol) was added to 4-(4-hydroxyphenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (323 mg, 0.85 mmol) and potassium carbonate (235 mg, 1.70 mmol) in DMF (5 mL). The resulting suspension was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated to dryness, then water (50 mL) was added and the mixture was stirred for 20 minutes. The resulting precipitate was collected by filtration, washed with water then ether and dried to afford methyl 2-[4-[4-hydroxy-1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetate (384 mg, 100%) as a beige solid.
Reaction SMILES: [NH2:1][C:2]1([C:10]#[N:11])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4][CH2:3]1.ClC(Cl)C.Cl.[F:17][C:18]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:19]=1[CH2:20][O:21][C:22]1[C:23]2[N:24]([C:28]([C:32](Cl)=[O:33])=[C:29]([CH3:31])[N:30]=2)[CH:25]=[CH:26][CH:27]=1>C(N(CC)CC)C>[C:10]([C:2]1([NH:1][C:32]([C:28]2[N:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH2:20][C:19]4[C:18]([F:17])=[CH:38][CH:37]=[CH:36][C:35]=4[F:39])[C:23]3=[N:30][C:29]=2[CH3:31])=[O:33])[CH2:7][O:6][C:5]([CH3:8])([CH3:9])[O:4][CH2:3]1)#[N:11]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)Cl
Reactant: CC1(C)OCC(N)(C#N)CO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1(C#N)COC(C)(C)OC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
Under an argon gas flow, to a mixture of 10.4 g of 5-amino-2,2-dimethyl-1,3-dioxane-5-carbonitrile, 27.8 ml of triethylamine, and 280 ml of dichloroethane were added 27.2 g of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carbonyl chloride hydrochloride and 12 ml of dichloroethane at room temperature, followed by stirring at 70° C. for 2 hours. After leaving to be cooled to room temperature, the insoluble materials were separated by filtration and washed with dichloroethane. The filtrate was washed with a 10% aqueous citric acid solution three times, and the aqueous layer was extracted with chloroform. The organic layer was combined, washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was azeotropic distilled with ethyl acetate twice. To the obtained residue was added THF, and the insoluble materials were separated by filtration and washed with THF. The filtrate was concentrated and the residue was purified by silica gel column chromatography to obtain 27.7 g of N-(5-cyano-2,2-dimethyl-1,3-dioxan-5-yl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:31])[CH:15]([CH2:27][C:28](O)=[O:29])[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9][CH:8]=1.[CH3:32][NH:33][CH3:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:31])[CH:15]([CH2:27][C:28]([N:33]([CH3:34])[CH3:32])=[O:29])[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:11][CH:12]=1
Reactant: CN1CCN=C1c1ccc(NC(=O)C(CC(=O)O)NC(=O)Nc2ccc(Cl)cc2)cc1
Reactant: CNC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN(C)C(=O)CC(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(C2=NCCN2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a solution of 1:1 mixture of the R and S isomers of N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-carboxymethyl-2-(4-chlorophenylaminocarbonylamino)-acetamide (from EXAMPLEs 60 and 62, 45 mg, 0.10 mmol) and dimethylamine (2N in THF, 0.25 mL, 0.50 mmol) in DMF (2 mL), BOP (100 mg, 0.22 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (25 mg). MS 471.1 and 473.1 (M+H, Cl pattern).
Reaction SMILES: [Br-].[C:2](=[S:4])=[S:3].Br[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:7]#[N:8].O>C1COCC1>[CH3:6][C:9]1[CH:14]=[CH:13][C:12]([C:2]([S:4][CH:6]([C:7]#[N:8])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[S:3])=[CH:11][CH:10]=1
Reactant: N#CC(Br)c1ccccc1
Reactant: S=C=S
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=S)SC(C#N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100 ml round bottom flask was added 10 ml 4-tolylmagiesium bromide (1.0M solution in ethyl ether) and diluted to 20 ml with anhydrous THF. 0.76 g carbon disulfide was added dropwise to this mixture and stirred for ½ h at room temperature. Then to the dark red solution was added 2 g α-bromobenzeneacetonitrile dropwise and the mixture stirred for another 2 h. Water was added to the mixture and the organic product was extracted with diethyl ether (3×50 ml), dried with magnesium sulfate overnight and filtered. After removal of solvent and column chromatography (5:2 mixture of hexane and ethyl ether), pure α-cyanobenzyl 4-methyldithiobenzoate was obtained as a red odorless solid (48% yield). Proton and carbon NMR spectra were consistent with the expected structure, CTA-CP-6.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Cl)[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrC1C(OC)=C(C(CSC2C=CC=CC=2OC)=CC=1)[C:29](OC)=[O:30]>>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:30][CH3:29])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1OC
Reactant: COC(=O)c1c(CSc2ccccc2OC)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2OC)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 68, starting from methyl 3-bromo-2-methoxy-6-(2-methoxyphenylthiomethyl)benzoate (Intermediate 76).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([OH:14])=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([OH:14])=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(O)ncnc2c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc2c(O)ncnc2c1
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A solution of 7-nitroquinazolin-4-ol (3.62 g, 18.9 mmol) with 10% Pd/C (0.25 g) in DMF (15 mL) was stirred under H2 (1 atm) for 18 h, then partially concentrated at elevated temperature, filtered warm through Celite® to remove catalyst and then concentrated to a brown solid. The solid was triturated with EtOAc (50 mL), filtered, dried, redissolved in DMF (25 mL), treated with 10% Pd/C (0.25 g) and stirred overnight under an H2 atmosphere. The mixture was filtered free of catalyst and the filtrate evaporated at reduced pressure to yield a brown solid which was triturated with EtOAc (50 mL) and filtered to yield 7-aminoquinazolin-4-ol (2.27 g, 74% yield). MS (ESI) m/e (M+H+) 162.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[CH2:9]([O:11][CH2:12]Cl)[CH3:10].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:12][O:11][CH2:9][CH3:10])=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCOc1cnc(Cl)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
A stirred mixture of 2-chloro-5-pyrimidinol (107) (1.00 g, 7.66 mmol) and chloromethyl ethyl ether (1.75 mL, 18.9 mmol) in anhydrous DMF (2.5 mL) was treated with K2CO3 (2.15 g, 15.6 mmol). After stirring at room temperature for 16 h, the mixture was added to ice/aqueous NaHCO3 (100 mL) and extracted with 50% Et2O/petroleum ether (5×100 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-1% Et2O/petroleum ether firstly gave foreruns, and then further elution with 1-10% Et2O/petroleum ether gave 2-chloro-5-(ethoxymethoxy)pyrimidine (108) (1.27 g, 88%) as an oil; 1H NMR (CDCl3) δ 8.43 (s, 2H), 5.27 (s, 2H), 3.74 (q, J=7.1 Hz, 2H), 1.23 (t, J=7.1 Hz, 3 H); HRESIMS calcd for C7H10ClN2O2 m/z [M+H]+ 191.0396, 189.0425. found 191.0397, 189.0426.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([CH:11]=[CH2:12])[O:9][CH:8]=[N:7]1)=[O:5])[CH3:2].[OH2:13].C(N(CC)CC)C>O1CCCC1.ClCCl>[CH2:1]([O:3][C:4](=[O:5])[CH:6]([NH:7][CH:8]=[O:13])[CH:10]([OH:9])[CH:11]=[CH2:12])[CH3:2]
Reactant: C=CC1OC=NC1C(=O)OCC
Reactant: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CC(O)C(NC=O)C(=O)OCC
Reaction time: 62 h

Procedure:
128 g of the 5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester are dissolved in 70 ml of tetrahydrofuran, and 27.4 g of water and 3.5 g of triethylamine are added. The reaction mixture is stirred for 62 hours at 65°-70° and, having been cooled, is taken up in 200 ml of dichloromethane. The solution is dried over 200 g of magnesium sulphate, filtered and concentrated by evaporation in vacuo. Purification by column chromatography (silica gel;hexane/ethyl acetate 3:2) of the viscous oil that remains yields 2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester in the form of a diastereoisomeric mixture, m.p. 50°-51°.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][N:32]=2)[CH:28]=O)[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[CH:26]=[C:27]([CH2:28][N:1]3[CH:2]([C:11]4[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=4[F:19])[CH2:3][CH:4]([CH3:10])[C:5]3=[O:7])[CH:30]=[CH:31][N:32]=2)[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: O=Cc1ccnc(-n2cccn2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccnc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with 2-(1H-pyrazol-1-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 381.04 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][NH:17][C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([O:33]CCC)=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([N:17]([CH3:16])[C@H:18]3[CH2:37][N:22]4[C:23]5[C:28]([C:29]([CH2:30][C:31]([OH:33])=[O:32])=[C:21]4[CH2:20][CH2:19]3)=[CH:27][CH:26]=[CH:25][CH:24]=5)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C1(c2ccc(F)cc2)CCCC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 449.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][O:14][CH:15]1[CH2:31][CH:30]2[C:18]([CH3:43])([CH:19]3[CH:27]([CH:28]([OH:32])[CH2:29]2)[CH:26]2[C:22]([CH3:41])([CH:23]([CH:33]([CH3:40])[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:24][CH2:25]2)[CH:21]([OH:42])[CH2:20]3)[CH2:17][CH2:16]1.O.NN.Cl>CO>[NH2:3][CH2:12][CH2:13][O:14][CH:15]1[CH2:31][CH:30]2[C:18]([CH3:43])([CH:19]3[CH:27]([CH:28]([OH:32])[CH2:29]2)[CH:26]2[C:22]([CH3:41])([CH:23]([CH:33]([CH3:40])[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:24][CH2:25]2)[CH:21]([OH:42])[CH2:20]3)[CH2:17][CH2:16]1
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(OCCN5C(=O)c6ccccc6C5=O)CCC4(C)C3CC(O)C12C
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(OCCN)CCC4(C)C3CC(O)C12C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
1.7 g of methyl 4-{3-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethoxy]-7,12-dihydroxy-10,13-dimethylhexadecahydrocyclopenta[a]phenanthren-17-yl}pentanoate and 0.52 ml of hydrazine hydrate (80%) are dissolved in 14 ml of methanol and the solution is refluxed for 3 hours. It is then cooled to 40° C. and the reaction mixture is treated with 8.7 ml of a 2N aqueous HCl solution. It is stirred at 40° C. for 30 minutes, then the volatile constituents are removed in vacuo. Chromatography on silica gel using acetone/water 10:1 yields 540 mg of resinous solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30](O)=[O:31])[CH2:19][C:20]3[CH:28]=[C:27]([CH3:29])[C:23]4[NH:24][CH:25]=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH2:66]([N:73]1[CH2:78][CH2:77][N:76]([CH:79]2[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]2)[CH2:75][CH2:74]1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1.C([O-])(O)=O.[Na+]>C1COCC1.CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:28]=[C:27]([CH3:29])[C:23]4[NH:24][CH:25]=[N:26][C:22]=4[CH:21]=3)[C:30]([N:82]3[CH2:83][CH2:84][CH:79]([N:76]4[CH2:75][CH2:74][N:73]([CH2:66][C:67]5[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=5)[CH2:78][CH2:77]4)[CH2:80][CH2:81]3)=[O:31])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:36]2[CH:35]=[CH:34][CH:33]=[CH:5][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2nc[nH]c12
Reactant: c1ccc(CN2CCN(C3CCNCC3)CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(Cc4ccccc4)CC3)CC2)cc2nc[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 120 mg (0.22 mmol) (R)-1-carboxy-2-(7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 85 mg (0.27 mmol) TBTU and 120 μL (0.86 mmol) triethylamine in 10 mL THF and 1 mL DMF was stirred for 1 h at RT, then combined with 90 mg (0.27 mmol) 1-benzyl-4-piperidin-4-yl-piperazine (used as the bishydrochloride salt) and stirred overnight at RT. The reaction solution was combined with 1 mL semisaturated NaHCO3 solution and extracted with 100 mL EtOAc. The organic phase was dried over Na2SO4, filtered and evaporated down i.vac.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18](I)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[CH:2]=1.[OH:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:22])[CH:28]=4)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[CH:2]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: O=C(Nc1cccnc1)N1CC(Oc2ccc(I)cn2)C1
Product: O=C(Nc1cccnc1)N1CC(Oc2ccc(-c3cccc(O)c3)cn2)C1
Yield: 47.2 %

Procedure:
This compound was prepared by the method outlined for example 5 step 6. Thus 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridin-3-ylamide (300 mg, 0.76 mmol) was reacted with 3-hydroxyphenylboronic acid (156 mg, 1.14 mmol) to afford a crude product purified by flash chromatography on silica gel eluting with solvent gradient of 1:19 to 1:9 7N ammonia in methanol solution: dichloromethane. This affords the title compound (130 mg, 47%) as a colourless powder.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([CH:46]2[CH2:48][CH2:47]2)[C:36]([N:38]([CH3:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:37])[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH:46]1([N:35]([CH2:34][C@@H:10]2[CH2:9][NH:8][CH2:12][C@H:11]2[CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C:36]([N:38]([CH3:45])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:37])[CH2:48][CH2:47]1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)N(C)c2ccccc2)C2CC2)C(C)C)ccc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CN(C(=O)N(C)c2ccccc2)C2CC2)C(C)C)ccc1OC

Procedure:
A solution of (3R*,4R*)-3-(1-cyclopropyl-3-methyl-3-phenyl-ureidomethyl)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (195 mg, 0.29 mmol) in 4N HCl/dioxane (8 mL) is stirred at RT until the reaction is complete. Lyophilization affords the title compound as a colorless foam. MS (LC-MS): 567.1 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 4.57 min.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10]([N+:13]([O-])=O)=[C:9]([CH3:16])[N:8]2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C1COCC1.CC(OC)(C)C.[Pd]>[NH2:13][C:10]1[C:11](=[O:12])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:8]([CH3:17])[C:9]=1[CH3:16]
Reactant: Cc1c([N+](=O)[O-])c(=O)n(C2CCCCC2)n1C
Agent: [Pd]
Solvent: COC(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Temperature: 25 °C
Reaction time: 57.5 h

Procedure:
To 2-cyclohexyl-1,5-dimethyl-4-nitro-1H-pyrazol-3(2H)-one (415 g, 1.73 mol) in MeOH (4500 ml) and THF (4500 ml) was added 10% Pd/C (70 g) and the reaction mixture was hydrogenated at 0.1 bar and RT for 57.5 h. The resulting mixture was filtered through a pressure strainer and washed with methanol (1×1 L) and THF (2×1 L). The filtrate was concentrated under reduced pressure to give a dark red oil. The oil was dissolved immediately in TBME (4 L), concentrated under reduced pressure to ca. 2 L and seeded (100 mg). The suspension was stirred for 2 h at RT and cooled in an ice bath for 1 hr. The solid was collected by filtration and washed with ice cold TBME in portionwise until the filtrate was colourless and dried under vacuum to give the title compound;
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C[O:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][N:14]=1)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:5]([O:4][C:1](=[O:3])[CH2:2][C:11]([C:13]1[CH:18]=[N:17][C:16]([NH:19][C:20](=[O:25])[C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:15][N:14]=1)=[O:10])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Temperature: -20 °C
Reaction time: 0.67 h

Procedure:
A 3-necked 1-L round bottomed flask equipped with a magnetic stirrer, addition funnel, thermocouple probe and nitrogen inlet/outlet was charged with 25.00 mL (185.5 mmol) of tert-butyl acetate, 20.00 g (84.30 mmol) of the compound prepared in step 2 and 20 mL of THF. After cooling to −20° C., a solution of 261.4 mL (261.4 mmol) of 10M lithium bis(trimethylsilyl)amide (LHMDS) in THF was added dropwise, while maintaining the temperature of the reaction mixture between −20° C. and 0° C. The resulting red solution was stirred at −20° C. for 40 min. HPLC analysis indicated complete reaction. The mixture was allowed to warm to 0° C., then quenched by the addition of pre-cooled 200 mL (260.3 mmol) of 25 wt % citric acid solution. The organic layer was separated, washed with 2×200 mL of saturated sodium chloride solution and concentrated at 30° C./60 mmHg to a volume of ca. 50 mL. The concentrated solution was diluted with 200 mL of butanone and again concentrated at 30° C./60 mmHg to ca. 50 mL. The concentrate was again diluted with 200 mL of butanone and concentrated at 30° C./60 mmHg to a volume of ca. 100 mL. NMR analysis indicated the absence of THF. The resulting butanone solution of the title compound was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[N:4][CH:3]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1cncc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of 6-chloro-pyrazin-2-ylamine (50 mg, 0.38 mmol) in acetic acid (1.9 mL) was treated with acetic anhydride (0.04 mL, 0.42 mmol). The mixture was heated to reflux for 1 h, cooled to room temperature, then poured into saturated NaHCO3 (30 mL) and extracted with ethyl acetate (2×30 mL). The organic layers were combined, washed with brine, dried (Na2SO4), filtered, and concentrated to dryness to give the title compound I-5a (58.6 mg).