Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[S:12][C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]=2[C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C=O)C>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:2][C:3]2[S:12][C:6]3[N:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]=3[C:4]=2[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH2:25][CH2:24]1
Reactant: Nc1ncnc2sc(CBr)c(-c3ccc([N+](=O)[O-])cc3)c12
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CN1CCN(Cc2sc3ncnc(N)c3c2-c2ccc([N+](=O)[O-])cc2)CC1
Yield: 33.1 %

Procedure:
A mixture of Example 57A (330 mg) and N-methylpiperazine (0.3 mL, 2.71 mmol) in DMF (6 mL) was stirred at room temperature overnight and concentrated. The concentrate was absorbed on silica gel and purified by flash column chromatography with ethyl acetate followed by 12% methanol/dichloromethane to provide 115 mg the desired product. Rf=0.38 (12% methanol/dichloromethane).
Reaction SMILES: N[C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[N+]([O-])(OCCC(C)C)=O.[CH:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:11]1([C:9]2[O:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:7]=3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccccc1
Reactant: Nc1ccc2nc(-c3ccccc3)oc2n1
Agent: CC(C)CCO[N+](=O)[O-]
Product: c1ccc(-c2ccc3nc(-c4ccccc4)oc3n2)cc1

Procedure:
A mixture of 180 mg. of 5-amino-2-phenyloxazolo[ 5,4-b]pyridine, 10 ml. of benzene and 0.2 ml. of isoamyl nitrate was refluxed for 11/2 hours. The hot solution was filtered and concentrated to dryness. The residue was extracted with ether and the extract was filtered through aluminum oxide and concentrated to dryness. The crystalline residue was recrystallized from ethyl acetate to give 2,5-diphenyloxazolo[ 5,4-b]pyridine, m.p. 151°-152° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][N:21]([CH3:36])[C:22](=[O:35])[CH2:23][N:24]1[C:28]2[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=2[S:26][C:25]1=[O:34])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]2[S:26][C:25](=[O:34])[N:24]([CH2:23][C:22]([N:21]([CH2:20][C:12]3[N:11]([CH2:10][CH2:9][OH:8])[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=3)[CH3:36])=[O:35])[C:28]=2[CH:29]=1
Reactant: CN(Cc1nc2ccccc2n1CCO[Si](C)(C)C(C)(C)C)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(Cc1nc2ccccc2n1CCO)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a mixture of N-{[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-benzimidazol-2-yl]methyl}-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide (520 mg) and THF (15 mL) was added tetrabutylammonium fluoride (1.0 M THF solution, 1.43 mL), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/MeOH=99/1-90/10). The obtained solid was washed with EtOAc to obtain 2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-{[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]methyl}-N-methylacetamide (340 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[CH3:1][N:2]([CH3:17])[C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:16])[CH2:14][CH2:13][CH:12]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CN(C)c1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(6-dimethylamino-pyridin-3-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: C([Li])CCC.BrN1C=CC=NC1.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>O1CCCC1.C(OCC)C>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:26]([C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[OH:27])[CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Brc1cccnc1
Agent: BrN1C=CC=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C(O)c2cccnc2)cc1
Temperature: -120 °C
Reaction time: 5 h

Procedure:
To a 500-ml 3-neck round bottom flask equipped with an addition funnel, septum, thermometer and an argon inlet is added 150 ml of anhydrous diethylether and 94 ml of 1.6 molar butyllithium solution (in hexane). The system is cooled to -120° C. and 23.8 gm of 3-bromopyrimidine in 75 ml of anhydrous tetrahydrofuran is added over 2 hours. After addition of the 3-bromopyridine, the system is stirred for an additional 45 minutes at this time, 18.3 ml of 4-methoxybenzaldehyde in 75 ml of tetrahydrofuran is added to the system while maintaining a temperature of -120° C. The system is kept at -120° C. for an additional 5 hours after addition of the 4-methoxy-benzaldehyde and afterwards the system is allowed to come to room temperature. After 10 hours at room temperature, the system is quenched with saturated ammonium chloride (in water). The system is adjusted to pH 2 with concentrated HCl solution. The solution is extracted with ether. The aqueous solution is then made basic with a 50% NaOH solution. The product is extracted with methylene chloride which then dried over sodium sulfate. The methylene chloride is removed by stripping and the residue triturated with hexane to give the 3-pyridyl-4-methoxyphenylcarbinol, which is converted to the compounds of this invention as described in Examples 1-7.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:2]=1.C(O)(=O)C>CO.[Pd]>[NH:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:6]1
Reactant: COC(=O)C(=Cc1ccncc1)C(=O)OC
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(CC1CCNCC1)C(=O)OC

Procedure:
A solution of dimethyl (4-pyridylmethylene)malonate [XXVIIIa] (925 g) in methanol (9 L) was hydrogenated in the presence of glacial acetic acid (360 mL) and 10% palladium on activated carbon catalyst (92.5 g) at 60° C. and 200 psi. The catalyst was filtered off and the resulting solution of the title compound in the form of acetic acid salt was used directly in the next step.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1>C1COCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:18][CH:16]2[CH2:15][N:14]([C:12]([N:8]3[CH2:9][CH2:10][CH2:11][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:13])[CH2:17]2)=[CH:24][CH:25]=1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(OCc2ccc(Cl)cc2)C1
Temperature: 80 °C
Yield: 51.9 %

Procedure:
To a stirred solution of 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (40 mg, 0.158 mmol) in THF (3 mL) was added NaH (13 mg, 0.316 mmol, 60% in mineral oil). The suspension was stirred at RT for 1 h before 1-(bromomethyl)-4-chlorobenzene (65 mg, 0.316 mmol) was added in one portion. The resulting mixture was heated at 80° C. for 1 H, cooled to RT and concentrated at reduced pressure. The crude residue was dissolved in MeOH and filtered through a short pad of silica before purification by preparative HPLC to provide the title compound (31 mg, 40%) as colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:4][C:3]=1[CH3:18].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Li+].[Cl-].[CH2:35]([C@@H:42]1[CH2:46][O:45][C:44](=[O:47])[NH:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:43]2[C@H:42]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:46][O:45][C:44]2=[O:47])=[O:17])=[CH:4][C:3]=1[CH3:18]
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: Cc1cc(CCCCCCCC(=O)O)ccc1F
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(CCCCCCCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)ccc1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a cooled (−10° C.) solution of 8-(4-fluoro-3-methylphenyl)octanoic acid (0.452 g, 1.791 mmol) in 15 mL of THF, were added stepwise triethylamine (0.67 mL, 4.836 mmol) and pivaloyl chloride (0.24 mL, 1.971 mmol). The reaction mixture was stirred at −10° C. for 1 h and then LiCl (0.084 g, 1.971 mmol) and (R)-4-benzyloxazolidin-2-one (0.349 g, 1.971 mmol) were added stepwise. After warming slowly to room temperature and stirring overnight, the reaction mixture was diluted with ethyl acetate (80 mL) and washed with saturated NaHCO3 solution and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (0.666 g, 90% yield). GC-MS: tR=9.6 min; m/z 411 (M+).
Reaction SMILES: [O:1]1[C@@H:3]2[C@H:4](O)[C@@H:5]3[C@@H:14]([C@@:15]4([CH3:27])[CH2:16][CH2:17][C@H:18]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:19][C@@:2]124)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]3[C@@H:7]2[CH2:29][C@@H:8]2[C:9]1=[O:28].[Cl:31]C(Cl)(Cl)C(C(Cl)(Cl)Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:31][C@@H:4]1[C@H:3]2[O:1][C@:2]32[C@:15]([CH3:27])([CH2:16][CH2:17][C@H:18]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:19]3)[C@@H:14]2[C@@H:5]1[C@H:6]1[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:28])[C@H:8]2[CH2:29][C@@H:7]12
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@@H](O)[C@H]3O[C@]32C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@H](Cl)[C@H]3O[C@]32C1
Temperature: 12.5 °C

Procedure:
reaction of compound 2 with hexachloroacetone in dichloromethane added with triphenylphosphine at a temperature of 0-5° C. followed by heating to 10-15° C., to yield 7α-chloro-5,6β-epoxy-15β,16β-methylen-3β-pivaloyloxy-5β-androstan-17-one 3:
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C@@H:7]([CH:11]1[CH2:13][CH2:12]1)[C:8]([OH:10])=[O:9].[CH2:14](O)[CH3:15]>>[NH2:6][C@@H:7]([CH:11]1[CH2:13][CH2:12]1)[C:8]([O:10][CH2:14][CH3:15])=[O:9]
Reactant: CCO
Reactant: N[C@H](C(=O)O)C1CC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H](N)C1CC1
Temperature: 25 °C

Procedure:
Sulfuric acid (conc., 1.704 g, 0.926 mL, 17.37 mmol) was added to a solution of (S)-2-amino-2-cyclopropylacetic acid (1 g, 8.69 mmol) in ethanol (12 mL) and heated to reflux for 5 h, then cooled to rt. The reaction mixture was concentrated under vacuum to remove solvent and water (10 mL) was added. The pH of the mixture was adjusted to 10 using 2M aq. sodium hydroxide and was then extracted with DCM (3×15 mL). The organic phase was dried with sodium sulfate and concentrated under vacuum to provide (S)-ethyl 2-amino-2-cyclopropylacetate (862 mg) which was used as is.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12](F)[N:11]=[CH:10][C:9]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.Cl.[O:30]1CCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:10][NH:11][C:12](=[O:30])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)cc2-c2ccc(Cl)cc2)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCN(Cc2c[nH]c(=O)cc2-c2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 307C (1.6 g) and 5% HCl (20 mL) in tetrahydrofuran (20 mL) was heated at 80° C. overnight. The solvent was removed to dryness. This solid was re-dissolved and added to tetrahydrofuran (50 mL). To this mixture were added BOC2O (di-t-butyl-dicarbonate) (1.118 g), triethylamine (0.72 mL), and 4-dimethylamionpyridine (1.4 g). The solvent was removed, and the residue was partitioned between water and ethyl acetate. The reaction mixture was stirred overnight. The organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by Prep HPLC eluting with 20-100% acetonitrile/water with 0.1% trifluoroacetic acid to give the title compound.
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:29])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][OH:28])[O:24][CH2:23]2)[CH:17]([CH:30]([OH:32])[CH3:31])[C:16]3=[O:33])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:38].O>[Pd].O1CCOCC1>[Na+:38].[OH:32][CH:30]([CH:17]1[C:16](=[O:33])[N:15]2[CH:18]1[CH:19]([CH3:29])[C:20]([S:21][CH:22]1[CH2:26][CH:25]([CH2:27][OH:28])[O:24][CH2:23]1)=[C:14]2[C:12]([O-:13])=[O:11])[CH3:31]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CO)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(CO)C3)C(C)C12
Yield: 46.2 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.170 g of product from Example 78, 0.0328 g of sodium bicarbonate, 2 ml of water, 11.3 ml of dioxane, and 0.070 g of 10% palladium/carbon to give 0.060 g of the desired compound.
Reaction SMILES: [CH2:1]([NH2:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:7](Cl)(=[O:9])[CH3:8].C(N(CC)CC)C.C(Cl)Cl>O>[CH2:1]([NH:6][C:7](=[O:9])[CH3:8])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)CN
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NCC(C)(C)C
Yield: 97.6 %

Procedure:
A solution of neopentylamine (2.0 g, 23.0 mmol), acetyl chloride (1.96 mL, 27.6 mmol), triethylamine (3.84 mL, 27.5 mmol), and DCM (100 mL) were stirred at room temp for 2 h. The mixture was poured into water and extracted with DCM (3×40 mL). The organic phase was dried over Na2SO4, and the solvent was removed to afford N-neopentylacetamide as white solid (2.90 g, 98%). NMR confirmed the structure of N-neopentylacetamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].[Cl:20]N1C(=O)CCC1=O>C(#N)C>[Cl:20][C:7]1[CH:6]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:4]=[C:3]([C:1]#[N:2])[C:8]=1[OH:9]
Reactant: COC(=O)c1ccnc(-c2ccc(O)c(C#N)c2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(=O)c1ccnc(-c2cc(Cl)c(O)c(C#N)c2)c1

Procedure:
Methyl 2-(3-cyano-4-hydroxyphenyl)isonicotinate and N-chlorosuccinimide were stirred at room temperature in acetonitrile to obtain methyl 2-(3-chloro-5-cyano-4-hydroxyphenyl)isonicotinate. ES: 289.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>CO>[C:20]1([C:18]2[CH:19]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]=[N:16][C:17]=2[C:26]#[N:27])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccccc3)c(C#N)nn2)CC1
Solvent: CO
Product: N#Cc1nnc(N2CCNCC2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(6-cyano-5-phenyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (D14) (0.133 g, 0.37 mmol) in methanol (10 ml) was added Amberlyst® 15 ion exchange resin, acidic form (4.1 mmol/g) (1.3 g, 5.3 mmol) and the reaction mixture was shaken at room temperature for 18 h. After this period, the mixture was filtered and then a saturated solution of ammonia in methanol was added. The mixture was shaken for 1 h, filtered and the filtrate evaporated in vacuo. The residue was purified by HPLC. The desired fractions were collected and evaporated in vacuo to yield EN (0.06989 g, 72%) as a white solid. C15H15N5 requires 265; Found 266 (MH+).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:38])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])[CH:17]=1)=[O:7])(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][NH:22][C:18]1[CH:17]=[C:16]([NH:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[C:6]([OH:7])=[O:5])=[O:38])[CH:21]=[CH:20][CH:19]=1)([OH:33])=[O:32]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)CNc1cccc(NCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)CNc1cccc(NCC(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 8 h
Yield: 63 %

Procedure:
A solution of 170 mg (0.32 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethylamino]-phenylamino]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 130 mg (63%) of the title compound as a brown foam.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.CCN(CC)CC.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CC#N>[CH3:25][O:24][C:22](=[O:23])[CH2:21][N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=2)=[N:4]1
Reactant: COC(=O)CBr
Reactant: Oc1cccc(-c2nn[nH]n2)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)Cn1nnc(-c2cccc(O)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(2H-tetrazol-5-yl)phenol (250.8 mg, 1.547 mmol) in MeCN (10 mL) at rt was added Et3N (0.237 mL, 1.701 mmol) followed by methyl bromoacetate (260 mg, 1.701 mmol). The reaction was stirred at rt for 16 h. Volatiles were removed. Chromatography over silica eluting with 30-60% EtOAc/hexanes afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.75 (d, 1H, J=7.5 Hz), 7.69 (s, 1H), 7.39 (t, 1H, J=8.0 Hz), 7.01 (dd, 1H, J=8.0, 2.3 Hz), 5.53 (bs, 1H), 5.50 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: C(OC([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:15])=[CH:12][CH:13]=2)[C:8]([O:16][CH3:17])=[N:7]1)=O)C.BrC1C=CC=C2C=1C(OC)=NN2>>[Br:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[NH:6][N:7]=[C:8]2[O:16][CH3:17]
Reactant: CCOC(=O)n1nc(OC)c2cc(Br)ccc21
Agent: COc1n[nH]c2cccc(Br)c12
Product: COc1n[nH]c2ccc(Br)cc12

Procedure:
5-Bromo-3-methoxy-1H-indazole CCX was prepared from 5-Bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester using the procedure described for preparation of 4-Bromo-3-methoxy-1H-indazole CLXXXVI (Example 37).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:13]O.C([O-])=O.[Na+]>C(O)=O>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:13]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: COc1ccc(C#N)c(O)c1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
2-Hydroxy-4-methoxybenzaldehyde (55 g; 0.36 mol), hydroxylamine hydrochloride (30 g; 0.43 mol) and sodium formate (34 g; 0.5 mol) were refluxed in formic acid (200 ml; 98-100%) for 1.25 h. The solution was then rapidly chilled in an ice bath, with stirring over 30 min. The resulting precipitate was separated by filtration and washed well with water. Following drying, in a desicator under vacuum, the title compound was obtained (45 g; 0.3 mol; 84% yield) as a brick-red solid, mp 169-171° C., rf (EtOAc) 0.43.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[S:6][C:7]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[C:11]([O:18][CH3:19])=[CH:10][C:8]=2[N:9]=1.[NH:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:11]1[C:12]([O:16][CH3:17])=[C:13]([O:14][CH3:15])[C:7]2[S:6][C:5]([CH2:4][CH2:3][CH2:2][N:20]3[CH2:26][CH2:25][CH2:24][N:23]([CH2:2][CH2:3][CH2:4][C:5]4[S:6][C:7]5[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[C:11]([O:18][CH3:19])=[CH:10][C:8]=5[N:9]=4)[CH2:22][CH2:21]3)=[N:9][C:8]=2[CH:10]=1
Reactant: C1CNCCNC1
Reactant: COc1cc2nc(CCCBr)sc2c(OC)c1OC
Product: COc1cc2nc(CCCN3CCCN(CCCc4nc5cc(OC)c(OC)c(OC)c5s4)CC3)sc2c(OC)c1OC

Procedure:
2-(3-Bromopropyl)-5,6,7-trimethoxybenzothiazole (444 mg) and homopiperazine (64 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [BH4-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[C:18]4=[N:19][C:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[CH:26]=[O:27])=[CH:21][CH:22]=[C:17]4[N:16]=[N:15]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1>CO>[N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[C:18]4=[N:19][C:20]([C:23]5[CH:24]=[C:25]([CH2:26][OH:27])[CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:22]=[C:17]4[N:16]=[N:15]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1cccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
Sodium borohydride (0.018 g, 0.493 mmol) was added to a solution of example 3 (0.180 g, 0.493 mmol) in methanol (4 ml), cooled to 0° C., and stirred for 1 h. Ice-cold water was added to the mixture, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as a yellow solid (0.044 g, 24%). M.P. 191-193° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.63 (d, J=8.7 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.21 (d, J=8.3 Hz, 2H), 8.12 (d, J=8.8 Hz, 1H), 8.02 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.83 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (m, 3H), 6.20 (s, 2H), 5.30 (t, J=5.7 Hz, 1H), 4.58 (d, J=5.4 Hz, 2H). MS (m/z): 368.37 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:23](Cl)([O:25][CH2:26][CH:27]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24].Cl>O.O1CCOCC1>[C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)=[CH:6][CH:7]=1)([O:25][CH2:26][CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:24]
Reactant: Nc1ccc(-c2cccc(C(=O)O)c2)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2cccc(C(=O)O)c2)cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Cool a mixture of 4′-aminobiphenyl-3-carboxylic acid (Preparation C, Step 4) (7.46 g, (35 mmol) and Na2CO3 (9.3 g, 87.7 mmol) in H2O /dioxane (2:1, 300 mL) to ˜5° C. Add Fmoc-Cl (9.05 g, 35 mmol), and stir the mixture at ice bath temperature for 4 hours. Allow reaction mixture to warm to room temperature and stir for 24 hours. Pour into ice water, and acidify with aqueous HCl. Collect the precipitate, wash with water, and dry in vacuo. Recrystallize from EtOAc to give the title compound, m.p. 270.5-272° C. HPLC; FAB MS m/z 436 [M+H]+.