Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].C1N2CN3CN(C2)C[N:22]1C3>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:22]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Solvent: CCO
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Temperature: 25 °C

Procedure:
To 1350 ml. of ethanol there was added 90 gm. of 2-chloroacetamido-5-chlorobenzophenone and 92.5 gm. of hexamethylenetetramine. Ammonia was bubbled through the resultant medium under a pressure. The resultant medium was heated to reflux. The resultant reaction medium was evaporated in vacuum to dryness. It was triturated then with 250 ml. of hot water twice on a steam bath. The aqueous phase was removed by decantation. The crystalline residue was heated for 30 minutes in 250 ml. of toluene on a steam bath and then cooled to room temperature. The crystals which formed were filtered, washed twice with 25 ml. of toluene and 25 ml. of petroleum ether and dried to constant weight yielding 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one melting point 213°-215° C.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=O)[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:25][CH:26]1[CH:33]2[CH2:34][C:29]3([CH2:36][OH:37])[CH2:30][CH:31]([CH2:35][CH:27]1[CH2:28]3)[CH2:32]2>>[CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([NH:25][CH:26]3[CH:27]4[CH2:35][CH:31]5[CH2:30][C:29]([CH2:36][OH:37])([CH2:34][CH:33]3[CH2:32]5)[CH2:28]4)=[O:21])[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(OCCC2CCN(S(=O)(=O)C3CC3)CC2)c1
Reactant: NC1C2CC3CC1CC(CO)(C3)C2
Product: O=C(NC1C2CC3CC1CC(CO)(C3)C2)c1cccc(OCCC2CCN(S(=O)(=O)C3CC3)CC2)c1

Procedure:
Prepared from 3-[2-(1-cyclopropanesulfonyl-piperidin-4-yl)-ethoxy]-benzoic acid and 4-amino-1-hydroxymethyladamantane to give the title compound as a mixture of two isomers.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:8]([O:21][CH3:22])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:23]N(C=NC=[N+](C)C)C.[Cl-].C(O)(=O)C.C([O-])(=O)C.[Na+]>O1CCOCC1>[CH3:22][O:21][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:1]=[CH:23][NH:6][C:4]2=[O:5]
Reactant: COc1cc(C(N)=O)c(N)cc1OCCCN1CCOCC1
Reactant: CN(C)C=NC=[N+](C)C
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
A mixture of 2-amino-5-methoxy4-(3-morpholinopropoxy)benzamide (4.57 g, 12.25 mmol) and Gold's reagent (2.6 g, 15.89 mmol) in dioxane (35 ml) was heated at reflux for 5 hours. Acetic acid (0.55 ml) and sodium acetate (1.0 g) were added to the reaction mixture which was heated for a further 3 hours. The mixture was cooled to ambient temperature and the volatiles removed by evaporation. The residue was adjusted to pH7 with 2 M sodium hydroxide and then purified on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with methanol (gradient of 0 to 60%) in water. Concentration of the fractions by evaporation gave a precipitate which was collected by filtration and dried under vacuum over phosphorus pentoxide to give 6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (3.04 g, 78%) as a white solid.
Reaction SMILES: O[CH:2]([C:18]1[CH:27]=[CH:26][C:21]2[C:22](=[O:25])[O:23][CH2:24][C:20]=2[C:19]=1[CH3:28])[CH2:3][N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C:5]1=[O:17]>CO.[OH-].[OH-].[Pd+2]>[CH3:28][C:19]1[C:20]2[CH2:24][O:23][C:22](=[O:25])[C:21]=2[CH:26]=[CH:27][C:18]=1[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][C:5]1=[O:17]
Reactant: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)CC2=O)ccc2c1COC2=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1c(CCN2CCNCC2=O)ccc2c1COC2=O

Procedure:
A solution of tert-butyl 4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-oxopiperazine-1-carboxylate (160 mg, 0.41 mmol) in 20 mL of MeOH was treated with Pd(OH)2 (120 mg, 0.21 mmol) was stirred under 40 psi atmosphere of H2 at 60 C. After 18 hrs the solution was filtered through a pad of celite which was subsequently washed with EtOAc. The filtrate was concentrated and the residue was then redissolved in 2 mL of DCM was treated with 4 mL of 4N HCl in dioxane at room temperature. After 2 hours excess solvent was removed and the residue partitioned between 3 mL of 1N NaOH and 10 mL of 10% IPA/Chloroform. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated to give the title product. The free amine was used without further purification. 1H NMR (500 MHz; CDCl3): 7.82 (m, 2H), 5.40 (dd, J=2.3, 8.0 Hz, 1H), 5.27 (s, 1H), 3.74-3.70 (m, 1H), 3.61 (s, 2H), 3.45-3.41 (m, 1H), 3.38-3.34 (m, 1H), 3.26-3.22 (m, 1H), 3.04-3.01 (m, 2H), 2.06 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=O)[NH:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:30]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[NH:30][C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[CH:15][N:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(Br)cc2)C1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Temperature: 140 °C
Yield: 56.3 %

Procedure:
A mixture of 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 3.6 mmol) and ammonium acetate (1.4 g, 18.2 mmol) in xylene (15 mL) was heated in a sealed tube at 140° C. for 2 hours. The volatile component was removed in vacuo, and the residue was dissolved in ethyl acetate (150 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (795 mg, 56%). m/z 391.8, 393.8 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([C:10]2[C:19]([CH:20]=[O:21])=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[Cl-].[NH4+].O>C(O)C>[CH:1]1([CH2:6][N:7]([C:10]2[C:19]([CH2:20][OH:21])=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC1CCCC1)c1nc2ccccc2cc1C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCN(CC1CCCC1)c1nc2ccccc2cc1CO
Reaction time: 1 h

Procedure:
To a solution of 2-[N-(cyclopentylmethyl)-N-ethylamino]quinoline-3-carbaldehyde (25 mg, 0.088 mmol) in ethanol (1 mL) is added sodium borohydride (5 mg, 0.13 mmol) and the mixture is stirred for 1 hour. After addition of sat. ammonium chloride and water, the mixture is extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated to give {2-[N-(cyclopentylmethyl)-N-ethylamino]quinolin-3-yl}methanol, which is used without further purification.
Reaction SMILES: C([Li])CCC.CC(NC(C)C)C.[CH3:13][N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15]1.[C:23]1([CH2:29][N:30]2[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32][CH2:31]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH4+].[Cl-]>C1COCC1.O>[CH3:13][N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]1[C:33]1([OH:37])[CH2:34][CH2:35][CH2:36][N:30]([CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:31][CH2:32]1
Reactant: Cn1cnc2ncccc21
Reactant: O=C1CCCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: Cn1c(C2(O)CCCN(Cc3ccccc3)CC2)nc2ncccc21
Temperature: -70 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
n-Butyllithium (1.6M in hexanes, 0.164 mol) was added dropwise at −30° C. under N2 flow to a mixture of N-(1-methylethyl)-2-propanamine (0.164 mol) in THF (70 ml). The mixture was cooled to −70° C. A mixture of 1-methyl-1H-imidazo[4,5-b]pyridine (0.0751 mol) in THF (70 ml) was added dropwise. The mixture was stirred for 1 hour. A mixture of hexahydro-1-(phenylmethyl)-4H-azepin-4-one (0.0787 mol) in THF (60 ml) was added at −70° C. The mixture was stirred at −70° C. for 2 hours, brought to 0° C., poured out into water and NH4Cl and extracted with DCM and a small amount of methanol. The organic layer was separated, dried, filtered and evaporated to dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.5). The desired fractions were collected and the solvent was evaporated, yielding 8.8 g of (±)-hexahydro-4-(1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-1-(phenylmethyl)-1H-azepin-4-ol (compound 152).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]([CH3:11])([CH3:10])[CH2:5][CH2:6][CH2:7][C:8]#[N:9].[Li+].[OH-]>O1CCCC1.CO.O>[C:8]([CH2:7][CH2:6][CH2:5][C:4]([CH3:11])([CH3:10])[C:3]([OH:12])=[O:2])#[N:9]
Reactant: COC(=O)C(C)(C)CCCC#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(CCCC#N)C(=O)O
Reaction time: 8 h
Yield: 66.1 %

Procedure:
A mixture of 5-cyano-2,2-dimethyl-pentanoic acid methyl ester (4.50 g, 27 mmol) and 2 M aq. LiOH solution (40 mL, 80 mmol) in 30 mL of a 3:2:1 tetrahydrofuran/methanol/water solution was rapidly stirred overnight, then concentrated to approximately half volume. The mixture was extracted with ethyl acetate, then acidified with conc. HCl solution and extracted three times with ethyl acetate. The final three organic layers were combined and sequentially washed with sat. aq. NaHCO3 solution and sat. aq. NaCl solution, dried over MgSO4, filtered and concentrated to afford 2.77 g (67%) of 5-cyano-2,2-dimethyl-pentanoic acid as a brown oil, which was used without further purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C(#N)C.Br[CH2:21][CH2:22][CH2:23][CH3:24]>O>[CH2:21]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCBr
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCN1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 556.3 %

Procedure:
To a mixture of 15 g (0.015 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 15.93 g (0.115 mol) of K2CO3, and 100 ml of acetonitrile is added drowpwise 11.25 ml (0.105 mol) of 1-bromobutane. The mixture is stirred overnight at room temperature and then at 65° C. for 2 hours. After cooling, the mixture is diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to yield 16.63 g (80%) of the title compound as a yellow liquid: IR (neat) 2959 and 1092 cm-1 ; NMR (CDCl3)δ3.97 (s, 4H), 2.56 (s, 4H), 2.38 (m, 2H), 1.77 (t, 4H), 1.49 (m, 2H), 1.34 (m, 2H), 0.92 (t, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][C:25]=1[CH3:37]>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=3)=[CH:26][C:25]=2[CH3:37])=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCCN
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Product: Cc1cc(C2=NNC(=O)CC2)ccc1OCCCNCC(O)COc1ccc(CCOCC(C)C)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)-phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([NH2:7])([NH2:6])=[N:2][C:3]([NH2:5])=[S:4].Br[CH:9]1[CH2:14][CH:13]([CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:11][C:10]1=O.C(OCC)(=O)C>C(O)C>[CH:15]([CH:13]1[CH2:14][CH2:9][C:10]2[N:5]=[C:3]([NH:2][C:1]([NH2:7])=[NH:6])[S:4][C:11]=2[CH2:12]1)([CH3:17])[CH3:16]
Reactant: NC(=S)N=C(N)N
Reactant: CC(C)C1CCC(=O)C(Br)C1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)C1CCc2nc(NC(=N)N)sc2C1

Procedure:
2-imino-4-thiobiuret (5 mmol) is added accompanied by stirring to a solution of 2-bromo-4-isopropyl-cyclohexanone (5 mmol) in ethanol (10 ml) and the reaction mixture is then refluxed for 16 hours. After evaporating-off of the solvent ethyl acetate is added to the residue and the precipitated-out product is isolated by filtering off: tR 2.75 min (LC-1, one peak); ESI-MS (+/−): m/z 239.25 [M+H]+/237.24 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[C:10]([CH2:16][O:17]C(=O)C)[CH:9]=3.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.Cl>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[C:10]([CH2:16][OH:17])[CH:9]=3
Reactant: CC(=O)OCc1ccc2c(ccc3ccc(Br)cc32)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccc2c(ccc3ccc(Br)cc32)c1
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A solution of 3-bromo-7-(acetoxymethyl)-phenanthrene (2.042 g, 6.20 mmol) in 50 ml of THF was cooled to 0° C. and a solution of diisobutylaluminum hydride in hexane (1.0M, 14 ml, 14 mmol) was added dropwise. After 30 minutes, the solution was cautiously hydrolyzed with 1N HCl and was then diluted with ethyl acetate and washed successively with 1N HCl, sat. NaHCO3, H2O, and brine. Drying (MgSO4) and evaporation gave 1.77 g (99%) of the title compound as a white solid which was used in the next reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(O)(=O)C>[Br:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[Br:1])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: O=C1Cc2cc(Br)c(Br)cc2N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.5 %

Procedure:
6-Bromooxindole (0.168 g, 0.8 mmol) was dissolved in acetic acid (4 mL) and stirred for 5 min at room temperature. N-Bromosuccinimide (0.14 g, 0.8 mmol) was added and the yellow reaction mixture was stirred for 3 h at ambient temperature. The mixture was poured onto ice and the resulting precipitate was collected by filtration and dried in vacuo to give 0.192 g (83% yield) of the title compound as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.61 (s, 1 H), 7.60 (s, 1 H), 7.14 (s, 1 H), 3.52 (s, 2 H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:18])[C:11](=[O:17])[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[CH2:2]2.[CH:19]1([Mg]Cl)[CH2:23][CH2:22][CH2:21][CH2:20]1>CCOCC>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:18])[C:11]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)([OH:17])[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[CH2:2]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1cccs1
Reactant: Cl[Mg]C1CCCC1
Solvent: CCOCC
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1cccs1)C1CCCC1

Procedure:
Prepared using the same method as for Intermediate I-14, but from 20.8 g (0.0784 mol) of 2-oxo-2-thien-2-ylacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester and cyclopentylmagnesium chloride, 0.08 mol (40 ml of a solution 2M in ether). The oil obtained (15.64 g) was purified by chromatography on silica gel eluting with chloroform/methanol/ammonia 97:3:0.5 to obtain 8.38 g (32%) of a pure product, mixture of diastereomers: I-15a and I-15b. Structure confirmed by 1H-NMR.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][N:17]([Si](C(C)C)(C(C)C)C(C)C)[C:14]2=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)OCc3ccccc3)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)c1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
Into a Round bottom flask was added compound 21 (250.0 mg, 0.0006118 mol) and Tetrahydrofuran (5.0 mL, 0.062 mol) and Tetra-n-butylammonium fluoride (190 mg, 0.00073 mol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage to give product 22 (55 mg).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[C:14]([NH:17][C:18]3[C:19]4[N:20]([CH:25]=[CH:26][N:27]=4)[CH:21]=[C:22]([Br:24])[N:23]=3)[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[N:10]1[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:19]4[N:20]([CH:25]=[CH:26][N:27]=4)[CH:21]=[C:22]([Br:24])[N:23]=3)=[CH:13][C:12]=2[NH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)n1cnc2ccc(Nc3nc(Br)cn4ccnc34)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1cn2ccnc2c(Nc2ccc3nc[nH]c3c2)n1

Procedure:
A quantity of 0.23 g (1 mmole) of 6-Amino-benzoimidazole-1-carboxylic acid tert-butyl ester is treated with 0.27 g (1 mmole) of 6,8-Dibromo-imidazo[1,2-a]pyrazine in acetonitrile with 3 eq. of K2CO3 at reflux for 16 hrs. The reaction mixture is cooled partitioned between ethyl acetate and water, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoimidazole-1-carboxylic acid tert-butyl ester. 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoimidazole-1-carboxylic acid tert-butyl ester is treated with an excess of TFA in dichloromethane at room temperature for 2 hrs. The reaction solution is evaporated in vacuo and partitioned between saturated Na2CO3 and ethyl acetate, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford (3H-Benzoimidazol-5-yl)-(6-bromo-imidazo[1,2-a]pyrazin-8-yl)-amine.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH2:8][C@@H:9]2[C@@H:25]([C@:26]3([CH3:33])[C:31]=1[CH2:30][C@@H:29]([OH:32])[CH2:28][CH2:27]3)[CH2:24][CH2:23][C@@:22]1([CH3:34])[C@H:10]2[CH2:11][CH2:12][C@@H:13]1[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:4][CH3:5])[CH3:2].N1C=CC=CC=1.[C:41](Cl)(=[O:44])[CH2:42][CH3:43].C(=O)(O)[O-].[K+]>O>[CH2:4]([N:3]([CH2:6][C:7]1[CH2:8][C@@H:9]2[C@@H:25]([C@:26]3([CH3:33])[C:31]=1[CH2:30][C@@H:29]([O:32][C:41](=[O:44])[CH2:42][CH3:43])[CH2:28][CH2:27]3)[CH2:24][CH2:23][C@@:22]1([CH3:34])[C@H:10]2[CH2:11][CH2:12][C@@H:13]1[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:1][CH3:2])[CH3:5]
Reactant: CCN(CC)CC1=C2C[C@@H](O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]2C1
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)O[C@H]1CC[C@@]2(C)C(=C(CN(CC)CC)C[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 2 h

Procedure:
To a solution of 10 parts of 6-(diethylaminomethyl)cholest-5-en-3β-ol in 40 parts of pyridine at 0° is added, slowly and with stirring, 5 parts of propionyl chloride. When the addition is complete, stirring is continued for 2 hours while the reaction mixture warms to room temperature, whereupon 100 parts of water and 100 parts of aqueous 5% potassium bicarbonate are consecutively mixed in. The oil which separates is extracted with hexane. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation, affording 6-(diethylaminomethyl)-3β-(propionyloxy)cholest-5-ene as the residue.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:51])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]=[CH:47][CH2:46]2)[CH:8]([CH3:52])[CH:7]([OH:53])[CH2:6][C:5]1=[O:54])[CH:2]=[CH2:3]>CO.[Pd]>[OH:39][C:20]12[O:35][CH:24]([CH:23]([O:36][CH3:37])[CH2:22][CH:21]1[CH3:38])[CH:25]([O:33][CH3:34])[CH2:26][CH:27]([CH3:32])[CH2:28][C:29]([CH3:31])=[CH:30][CH:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:54])[CH2:6][CH:7]([OH:53])[CH:8]([CH3:52])[CH:9]([C:43]([CH3:51])=[CH:44][CH:45]1[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]1)[O:10][C:11](=[O:42])[CH:12]1[N:17]([CH2:16][CH2:15][CH2:14][CH2:13]1)[C:18](=[O:41])[C:19]2=[O:40]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CC=CCC3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Pd]
Solvent: CO
Product: CCCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCCCC3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a solution of the product of Example 49 (60 mg) in dry methanol (12 ml) was added 10% Pd-on-C (100 mg) and the resulting suspension was stirred in an ice bath for one hour under an atmosphere of hydrogen. The reaction mixture was then filtered and concentrated to an oil in vacuo. Chromatography on silica eluting with hexane in an increasing acetone gradient then gave the title compound as a foam (44 mg).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[H-].[Na+].CCCCCC.CC>O1CCCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C#CC(O)(CF)CF
Agent: CC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CC(CF)(CF)OS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
An amount (1.2 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol and p-chlorobenzenesulfonyl chloride (2.1 g) were dissolved in tetrahydrofuran (10 ml); to the solution under cooling with ice, 60% oily sodium hydride (0.48 g) was added under a nitrogen atmosphere. After the end of the addition, the mixture was stirred for 4 hours while its temperature was raised to room temperature. A hexane/ethane mixed solvent (1/1) was added to the reaction mixture, which was then washed with water and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane/methylene chloride=1/1) and then recrystallized from methylene chloride/hexane to give the titled compound (2.2 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:18][CH2:17][C@@:11]3([NH:15][C:14](=[O:16])[O:13][CH2:12]3)[CH2:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:18][CH2:17][C@@:11]3([NH:15][C:14](=[O:16])[O:13][CH2:12]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2CC[C@]3(COC(=O)N3)C2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1N[C@@]2(CC[C@@H](c3ccc(O)cc3)C2)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
A solution of (5R,7R)-7-(4-methoxy-phenyl)-3-oxa-1-aza-spiro[4.4]nonan-2-one (3.95 g, 16.0 mmol) in DCM (30 mL) was cooled in an ice bath and 1M BBr3 in DCM solution (64.0 mL, 64.0 mmol) was added at a rapid dropwise rate and the reaction was allowed to continue stirring at about 0° C. for about 0.5 hour. The reaction was quenched by dropwise addition of methanol (25.0 mL). The reaction was allowed to warm to room temperature and then concentrated. The residue was triturated with water (50 mL), filtered, rinsed with water (2×5.0 mL), and dried to yield 3.14 g (84%) of (5R,7R)-7-(4-hydroxy-phenyl)-3-oxa-1-aza-spiro[4.4]nonan-2-one as a gray solid.