Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH:15]12[O:20][CH:19]1[CH2:18][CH2:17][CH2:16]2>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C@@H:18]3[CH2:17][CH2:16][CH2:15][C@H:19]3[OH:20])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: Clc1ccc(CC2CCNCC2)cc1
Reactant: C1CC2OC2C1
Solvent: CCO
Product: O[C@@H]1CCC[C@H]1N1CCC(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
Following General Procedure A, a solution of 4-(4-chlorobenzyl)-piperidine (17.86 g, 85.05 mmol) and 6-oxa-bicyclo[3.1.0]hexane (50 g, 0.6 mol) in EtOH (170 mL) was stirred at 95° C. for 40 hours, allowed to cool to room temperature, and concentrated. The residue was crystallized in hot CH2Cl2 (80 mL), the crystallization mixture was concentrated to half the volume, and kept at 0° C. overnight and filtered, and the precipitate was rinsed with cold hexanes to give the product (18.2 g, 73%) as a tan solid. The mother liquors were concentrated to half the volume, diluted with CH2Cl2 and kept at −10° C. for 1 hour, and the precipitate was rinsed with cold CH2Cl2 and hexanes to give additional product (1.8 g, 7%) as a tan solid: mp 104.1–105.5° C.; IR 3436, 2928 cm−1; 1H NMR δ 1.19–1.75 (m, 8H), 1.81–1.99 (m, 4H), 2.06 (dt, J=2.5, 11.7 Hz, 1H), 2.47 (m, 1H), 2.50 (d, J=7.0 Hz, 2H), 2.90 (m, 1H), 3.07 (m, 1H), 4.10 (m, 1H), 7.06 (m, 2H), 7.23 (m, 2H); 13C NMR δ 21.63, 27.35, 32.01, 32.15, 34.31, 37.87, 42.47, 50.47, 52.97, 75.15, 75.22, 128.27, 130.43, 131.55, 139.04; MS m/z 294 (M+H)+. Anal. (C17H24ClNO.0.1H2O) C, H, N.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[CH3:24][C:25]1([NH2:28])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>>[CH3:22][C:3]1[C:2]([NH:28][C:25]2([CH3:24])[CH2:27][CH2:26]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: CC1(N)CC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1(C)CC1
Temperature: 100 °C
Yield: 25 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48 mg, 0.162 mmol), 1-methylcyclopropanamine hydrochloride (34.9 mg, 0.324 mmol, ChemBridge, San Diego, Calif.), and DIPEA (141 μl, 0.810 mmol), heating at 100° C. for 2 h. Purification by silica gel (100% DCM to 6% MeOH/DCM) provided 2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (25% yield). 1H NMR (400 MHz, MeOH-d4) δ ppm 0.93-1.00 (m, 2H) 1.01-1.07 (m, 2H) 1.66 (s, 3H) 2.53 (s, 3H) 3.03 (t, J=7.04 Hz, 2H) 3.64 (t, J=7.04 Hz, 2H) 7.11 (s, 1H) 7.39 (t, J=7.92 Hz, 1H) 7.61 (d, J=8.02 Hz, 1H) 8.00 (d, J=7.63 Hz, 1H). MS (ESI, pos. ion) m/z: 348.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([S:13]([NH2:16])(=[O:15])=[O:14])[S:10][N:9]=1.[C:17](OCC)(OCC)([O:19][CH2:20][CH3:21])[CH3:18]>>[CH2:17]([O:19][C:20](=[N:16][S:13]([C:11]1[S:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:12]=1)(=[O:14])=[O:15])[CH3:21])[CH3:18]
Reactant: CCOC(C)(OCC)OCC
Reactant: NS(=O)(=O)c1nc(-c2ccccc2Cl)ns1
Product: CCOC(C)=NS(=O)(=O)c1nc(-c2ccccc2Cl)ns1

Procedure:
A mixture of 3 g of 3-(2-chlorophenyl)-1,2,4-thiadiazole-5-sulfonamide and 11 ml of triethyl orthoacetate was warmed to reflux for 3.5 hours. The mixture was cooled, triturated with hexane (25 ml) and filtered to give 3.13 g of solid, m.p. 70°-72° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH2:18]([O:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=2)=[CH:23][CH:22]=1)[CH3:19]>C1(C)C=CC=CC=1>[CH2:18]([O:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:3]3[C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=[C:2]3[CH3:1])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1)[CH3:19]
Reactant: CCOc1ccc(Oc2ccc(CCl)cc2)cc1
Reactant: Cc1nc2ccccc2[nH]1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOc1ccc(Oc2ccc(Cn3c(C)nc4ccccc43)cc2)cc1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A mixture of toluene (20 ml), 2-methylbenzimidazole (0.55 g, 4.2 mmole), triethylamine (0.42 g, 4.2 mmole) and 4-(4-ethoxyphenoxy)benzyl chloride (1.00 g, 3.8 mmole) was heated under reflux for 5 hours and then cooled to room temperature. The resultant mixture was washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The residue was purified by silica gel column chromatography to give 1-[4-(4-ethoxyphenoxy)benzyl]-2-methylbenzimidazole (1.20 g) as colorless liquid. nD26.0 1.5984.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]([CH2:19]Br)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:21]#[N:22].[Na+].[OH-].[NH4+]>CN(C=O)C.O>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]([CH2:19][C:21]#[N:22])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: BrCc1cc(-c2ccccc2)n(Cc2ccccc2)n1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cc(-c2ccccc2)n(Cc2ccccc2)n1
Yield: 79.3 %

Procedure:
1-Benzyl-3-(bromomethyl)-5-phenyl-1H-pyrazole (200 mg, 0.6 mmol) and sodium cyanide (30 mg, 0.6 mmol) were stirred in DMF (6 mL). After several h, more sodium cyanide (60 mg, 1.2 mmol) was added to the reaction. A 25% ammonium hydroxide solution in water was added to the reaction and the reaction mixture was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to yield 2-(1-benzyl-5-phenyl-1H-pyrazol-3-yl)acetonitrile (130 mg, yield 80%) MS (ESI) m/z: Calculated for C18H15N3: 273.13. found: 274.1 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:21]Cl)=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.C([O-])([O-])=O.[K+].[K+].[NH:31]([CH3:33])[CH3:32]>C(Cl)(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:21][N:31]([CH3:33])[CH3:32])=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(C)c(CCl)c(C)c(NC(=O)C(C)(C)C)c21
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2c(C)c(CN(C)C)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(1-Acetyl-5-chloromethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (2.0 g) was dissolved in CHCl3 (40 ml) and (CH3)2NH. HCl (3.5 g) and K2CO3 (11.8 g) were added, which was followed by stirring at room temperature for 4 hr. CHCl3 (300 ml) was added, and the mixture was washed successively with 2N-hydrochloric acid, 2N aqueous NaOH and saturated brine, and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=10/1−1/1) to give 700 mg of N-(1-acetyl-5-dimethylaminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: [F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2cnc(F)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cnc(F)cc2c1
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A slurry of 88 (413 mg, 2.013 mmol) and LiOH (56 mg, 2.34 mmol) in THF (9.8 mL) and water (1.5 mL) was stirred at RT for 1.5 h. An additional 50 mg of LiOH was added (total: 106 mg, 4.43 mmol), and the reaction was stirred for an additional 2 h. The THF was removed on a rotary evaporator. The reaction mixture was suspended in water (10 mL) and treated with 10M HCl in water (0.604 mL, 6.04 mmol). A white cloudy precipitate was collected by vacuum filtration. The precipitate was washed with water (2×2 mL) and dried under house vacuum over night to afford 349 mg (100%) of 3-fluoroisoquinoline-6-carboxylic acid (90) as a white solid, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH:3]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)=[N:11]2)=[CH:6][C:5]=1[CH3:19].C1COCC1.[OH-].[Na+]>CO>[CH3:1][CH:2]([CH3:31])[CH:3]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)=[N:11]2)=[CH:6][C:5]=1[CH3:19]
Reactant: COC(=O)c1ccc(NC(c2ccc(-n3cc4c(n3)CCCC4)cc2C)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-n2cc3c(n2)CCCC3)ccc1C(Nc1ccc(C(=O)O)cc1)C(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-((2-methyl-1-(2-methyl-4-(4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)propyl)amino)benzoate (137.3 mg), THF (0.6 mL) and methanol (0.6 mL) was added 1M aqueous sodium hydroxide solution (0.658 mL), and the mixture was stirred at 50° C. overnight. The solvent was evaporated under reduced pressure, the resulting mixture was neutralized with 1M hydrochloric acid (0.658 mL), and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. This compound was used in step D without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:22]2[CH2:24][CH2:23]2)=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([NH:20][CH3:21])=[O:19].[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+]>CO>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([N:7]2[C:6]([C:18]([NH:20][CH3:21])=[O:19])=[C:5]3[C:9]([CH:10]=[C:2]([NH:1][CH2:25][CH3:26])[C:3]([CH:22]4[CH2:24][CH2:23]4)=[CH:4]3)=[N:8]2)=[CH:16][CH:15]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N)cc2nn1-c1ccc(Br)cc1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1cc2nn(-c3ccc(Br)cc3)c(C(=O)NC)c2cc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
To a suspension of 6-amino-2-(4-bromophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide (i) (20 mg, 0.052 mmol) in MeOH (0.6 mL) was added acetaldehyde (15 μL 0.27 mmol) at 0° C. Sodium cyanoborohydride (5 mg, 0.078 mmol) was then added and the mixture was stirred at RT for 1 h. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by reverse phase flash column chromatography eluting with ACN/water (5-100%) to give 2-(4-bromophenyl)-5-cyclopropyl-6-(ethylamino)-N-methyl-2H-indazole-3-carboxamide (ii) as a white solid (7 mg, 32%).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH2:21]([NH:23][C:24](=[O:31])[C@@H:25]1[CH2:29][CH:28]([F:30])[CH2:27][NH:26]1)[CH3:22]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:26]1[CH2:27][CH:28]([F:30])[CH2:29][C@H:25]1[C:24]([NH:23][CH2:21][CH3:22])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CCNC(=O)[C@@H]1CC(F)CN1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Product: CCNC(=O)[C@@H]1CC(F)CN1C1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.02 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 530 mg of the compound obtained in Step 11-4 as starting materials, respectively 708 mg (Isomer A: colorless amorphous) and 501 mg (Isomer B: colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1Br.[C:10]1(=[O:14])[CH2:13][CH2:12][CH2:11]1.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:10]1([OH:14])[CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CCC1
Reactant: Brc1ccc(Br)c(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2cc(Br)ccc2Br)CCC1
Temperature: -45 °C
Reaction time: 1 h

Procedure:
21.09 g (67 mmol) of 1,2,4-tribromobenzene are initially introduced in 100 ml of THF under nitrogen, cooled to −45° C., and a solution (1.3 M) of 51.54 ml (67 mmol) of isopropylmagnesium chloride/lithium chloride complex in THF is added dropwise. After 1 hour, the batch is warmed to −10° C., and 5 ml (66.34 ml) of cyclobutanone are added dropwise at this temperature. The batch is allowed to thaw, and sat. NH4Cl solution is added, the mixture is extracted with methyl t-butyl ether, the organic phase is dried over sodium sulfate and filtered, the solvent is removed in vacuo, and the residue is filtered through silica gel with dichloromethane, giving 4, which is employed in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27]C2CCCCO2)[CH:21]=1)[O:11][CH2:12][C:13]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][CH2:14]1.[CH2:34]1COCC1.N1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=1)[O:11][CH2:12][C:13]1([CH2:16][C:17]([O:19][CH3:34])=[O:18])[CH2:14][CH2:15]1
Reactant: C1CCOC1
Reactant: O=C(O)CC1(CO[C@H](CCc2ccccc2Br)c2cccc(COC3CCCCO3)c2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)CC1(CO[C@H](CCc2ccccc2Br)c2cccc(CO)c2)CC1
Reaction time: 144 h

Procedure:
The acid of Step 7 (1.816 g, 3.51 mmol) was esterified with CH2N2 at 0° C. in ether:THF. The excess CH2N2 was quenched with AcOH and the product was concentrated and stripped with toluene twice. This ester was dissolved in 20 mL MeOH and then pyridine (7 μL) and pyridinium p-toluenesulfonate (220 mg, 0.88 mmol) were added. After 6 days of stirring, the solvent was evaporated. 25% aq. NH4OAc was then added and the product was extracted in EtOAc, dried over Na2SO4, and purified by flash chromatography on silica with EtOAc:hexane 30:70; yield: 1.53 g, (97%).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:21](Cl)[C:22]#[CH:23]>O.CN(C)C=O>[CH2:23]([O:12][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[N:4][N:3]=[N:2]2)=[N:11][CH:10]=1)[C:22]#[CH:21]
Reactant: Oc1ccc(-n2cnnn2)nc1
Reactant: C#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1ccc(-n2cnnn2)nc1
Temperature: 80 °C

Procedure:
To a flask under N2 fitted with a reflux condenser was added 6-tetrazol-1-yl-pyridin-3-ol (2.25 g, 13.7 mmol) and N,N-dimethylformamide (8.2 mL). Potassium carbonate (3.79 g, 27.4 mmol, 2 eq.), potassium iodide (0.143 g, 0.86 mmol, 0.06 eq.) and propargyl chloride (1.98 mL, 17.9 mmol, 1.3 eq.) were added and heated at 80° C. for three hours. The reaction was cooled to room temperature and 10 mL of water was added to affect precipitation. The solid was filtered off, washed with water and dried overnight. The expected product was used in the next step without further purification. 1H NMR (DMSO-d6): δ 10.08 (1H, s), 8.36 (1H, d, J=3.0 Hz), 8.01 (1H, d, J=9 Hz), 7.79 (1H, dd, J=3.0, 9.0 Hz), 5.01 (2H, s), 3.71 (1H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:12]=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[CH2:15]([O:14][N:13]=[CH:12][C:5]1([C:3]([OH:4])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C1(C=NOCc2ccccc2)CCCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(C=NOCc2ccccc2)CCCCCC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 89.6 %

Procedure:
A mixture of 1-(benzyloxyimino-methyl)-cycloheptanecarboxylic acid methyl ester (5.2 g, 18 mmol) and lithium hydroxide monohydrate (7.56 g, 180 mmol) in THF (80 mL) and water (40 mL) was stirred at 60° C., for 24 h. The THF was removed in vacuo and the reaction mixture was acidified to pH 4 with 6N aqueous HCl and was extracted with dichloromethane (50 μL×5). The combined organic layers were dried (MgSO4) and were evaporated in vacuo to yield the title compound (4.44 g, 90%). MH+276.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:18][OH:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[CH:10]=1.[H-].[Na+].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]([F:17])[C:12]([F:16])=[C:13]([F:15])[CH:14]=1)[CH2:18][O:19][C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2cc(F)c(F)c(F)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3cc(F)c(F)c(F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (3-fluoro-4-(3,4,5-trifluorophenoxy)phenyl)methanol in THF (6 mL), sodium hydride (0.013 g, 0.323 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (0.040 g, 0.216 mmol) in DMF (1 mL).
Reaction SMILES: [C:1](Cl)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[OH:29][CH2:28][CH2:27][N:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:22][CH2:23]1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: NCCCN1CCN(CCO)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCC(=O)NCCCN1CCN(CCO)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 50 mL chloroform solution of 6.21 g. (0.025 1 mol) of myristoyl chloride was added dropwise under argon to an ice cold 75 mL chloroform solution of 4.79 g. (0.0256 mol) of N-(3-aminopropyl)-N'-(2-hydroxyethyl)piperazine. After stirring for two hours, 100 mL of aqueous sodium carbonate was added and stirred for 30 minutes. The layers were separated and the chloroform layer was washed with aqueous sodium carbonate (2×125 mL) followed by water (2×75 mL). The chloroform layer was concentrated in vacuo and the remaining amber liquid was crystallized successively from ethyl acetate to yield 4.56 g. (45.6%) of the subject compound.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH:7]1[CH2:12][CH2:11][CH2:10]/[C:9](=[CH:13]\N(C)C)/[C:8]1=O)([CH3:4])([CH3:3])[CH3:2].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:42][C:43]([NH2:45])=[NH:44])[CH:33]=[CH:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1>>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH:7]1[C:8]2[N:45]=[C:43]([NH:42][C:32]3[CH:33]=[CH:34][C:35]([N:36]4[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]4)=[C:30]([O:29][CH3:28])[CH:31]=3)[N:44]=[CH:13][C:9]=2[CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)/C=C1\CCCC(O[Si](C)(C)C(C)(C)C)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(O[Si](C)(C)C(C)(C)C)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 2-(tert-butyl-dimethyl-silanyloxy)-6-[1-dimethylamino-meth-(E)-ylidene]-cyclohexanone (80 mg, 0.28 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (74 mg, 0.20 mmol) using in analogous manner the procedure described in example 45b). Obtained as an orange gum (27 mg, 29%). MS ISP (m/e): 466.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.49 (s, 1H), 8.32 (s, 1H), 7.72 (d, 1H), 7.65 (s, 1H), 7.54 (s, 1H), 7.18 (d, 1H), 7.02 (s, 1H), 4.60 (m, 1H), 3.78 (s, 3H), 2.60-2.70 (m, 1H), 2.14 (s, 3H), 1.86 (m, 3H), 1.72 (m, 1H), 0.85 (s, 9H), 0.20 (s, 3H), 0.05 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:13](OCC)(=[O:19])[C:14](OCC)=[O:15]>>[NH:1]1[C:2]2[CH:3]=[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]3=[CH:10][C:11]=2[NH:12][C:14](=[O:15])[C:13]1=[O:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc2ccccc2cc1N
Product: O=c1[nH]c2cc3ccccc3cc2[nH]c1=O
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A mixture of 2,3-diaminonaphthalene (2.87 g, 18.14 mmol) and diethyl oxalate (30 mL, 223 mmol) was heated to reflux for 14 hours, cooled to RT and filtered. The residue was washed with EtOH and dried in vacuo to give the title compound as a brown solid (3.15 g, 82%); mp>350° C.; IR (KBr, cm−1) 3045, 2942, 2869,1716, 1642,1406, 877; 1H NMR (DMSO) δ 12.11 (s, 2H), 7.84-7.81 (m, 2H), 7.54 (s, 2H) 7.39 (dd, J=6.3, 3.0, 2H); LC/MS 92.5% (220 nm), m/z (M+H+) 213.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][C:14]1([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]1.O.NN>C(O)C>[NH2:3][CH2:12][CH2:13][C:14]1([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1(CCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(CCN)CC1
Yield: 312.1 %

Procedure:
To a solution of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]cyclopropylcarbamate (3.3 g, 2.4 mmol) in ethanol (100 mL) was added hydrazine hydrate (5 mL) and the resulting mixture was heated under reflux for 16 hours. The mixture was filtered and washed with diethyl ether. The filtrate was concentrated in vacuo to afford 1.5 g of the pure compound as an orange oil (yield was 75%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([CH3:22])([OH:21])[CH3:20])[CH:15]=3)[CH:10]=[N:9]2)[C:5](Br)=[CH:4][N:3]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([CH3:22])([OH:21])[CH3:20])[CH:15]=3)[CH:10]=[N:9]2)[C:5]([C:28]2[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=2)=[CH:4][N:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(O)C#Cc1ccc2cnn(-c3nc(N)ncc3Br)c2c1
Product: Cn1cc(-c2cnc(N)nc2-n2ncc3ccc(C#CC(C)(C)O)cc32)cn1

Procedure:
5-bromo-4-(6-bromoindazol-1-yl)pyrimidin-2-amine (3 g) was reacted with 2-methyl-3-butyn-2-ol (1 eq) via Sonagashira Coupling to afford 0.7 g of 4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol following flash column chromatography. 4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol (0.1 g) was reacted with 1-methyl-4-pyrazoleboronic acid pinacol ester via Suzuki Coupling to afford 12.2 mg of 4-[1-[2-amino-5-(1-methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-ol following reverse phase hplc purification. MS (Q1) 374. 1H NMR (400 MHz, DMSO) delta 8.57 (s, 1H), 8.30 (s, 1H), 7.88-7.81 (m, 2H), 7.48 (s, 1H), 7.24 (dd, J=8.3, 1.1 Hz, 1H), 7.05 (s, 2H), 6.98 (s, 1H), 5.47 (s, 1H), 3.73 (s, 3H), 1.48 (s, 6H).