Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8].[CH:20]([NH2:23])([CH3:22])[CH3:21]>CO>[OH:1][CH:2]([CH2:19][NH:23][CH:20]([CH3:22])[CH3:21])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8]
Reactant: CC(C)N
Reactant: COC(=O)CCC(=O)c1ccccc1OCC1CO1
Solvent: CO
Product: COC(=O)CCC(=O)c1ccccc1OCC(O)CNC(C)C
Yield: 101.7 %

Procedure:
A stirred mixture of methyl 3-[2-(2,3-epoxypropoxy) benzoyl]-propionate (8.3g, 0.031 mole), methanol (85 ml), and isopropylamine (16.4 ml, 0.19 mole) was heated under reflux for 90 minutes. Evaporation of the solution under reduced pressure gave methyl 3-[2-(2-hydroxy-3-isopropylaminopropoxy)benzoyl]propionate (10.2 g, 100%)as a pale brown oil.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]2[CH:12]=[N:13][C:14]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])=[C:6]2[CH2:5]1.[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34](O)=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1>>[CH3:24][C:2]([CH3:23])([CH3:1])[CH2:3][N:4]1[CH2:9][C:8]([CH3:10])([CH3:11])[N:7]2[CH:12]=[N:13][C:14]([NH:15][C:16](=[O:22])[CH:17]([NH:21][C:34](=[O:35])[CH2:33][C:28]3[CH:27]=[C:26]([F:25])[CH:31]=[C:30]([F:32])[CH:29]=3)[CH2:18][CH2:19][CH3:20])=[C:6]2[CH2:5]1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CCCC(N)C(=O)Nc1ncn2c1CN(CC(C)(C)C)CC2(C)C
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1ncn2c1CN(CC(C)(C)C)CC2(C)C

Procedure:
Following general coupling procedure A, 2-amino-pentanoic acid [7-(2,2-dimethyl-propyl)-5,5-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl]-amide is coupled with (3,5-difluoro-phenyl)-acetic acid to provide the title compound: Diagnostic C13 NMR (100 MHz, CDCl3) 13.5, 18.9, 27.4, 28.1, 28.6, 33.5, 35.4, 43.1, 52.8, 53.2, 56.2, 65.7, 69.9, 102.9, 112.3, 112.6, 117.4, 129.2, 169.9; MS m/z 490.5 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].CN>>[C:11]([C:10]1[C:9](=[O:14])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:19][N:18]([CH3:20])[CH:17]=1)(=[O:13])[CH3:12]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(=O)Cc1cccc(F)c1
Agent: CN
Product: CC(=O)c1cn(C)cc(-c2cccc(F)c2)c1=O

Procedure:
A 1.5 g. portion of 1-(3-fluorophenyl)-2,4-pentanedione was reacted with 15 ml. of N,N-dimethylformamide dimethyl acetal, and then with 10 ml. of 40% aqueous methylamine as described in Example 4. The reaction mixture was then evaporated under vacuum to dryness, and the crude product was chromatographed on a silica gel column with ethyl acetate to obtain 1 g. of the desired product, which was identified by nmr analysis in CDCl3, showing peaks at δ8.1-8.2 (m, 1H, pyridine); 6.9-7.6 (m, 5H, phenyl and 1 pyridine); 3.80 (s, 3H, N--CH3); 2.83 (s, 3H, COCH3).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:25])=[C:9]([CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[N:10]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:35])=O>C(OCC)(=O)C>[Cl:35][CH2:23][C:20]1[CH:21]=[CH:22][C:13]([O:12][CH2:11][C:9]2[N:10]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:7][C:8]=2[CH3:25])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 84.7 %

Procedure:
To a mixture of methyl 2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-5-hydroxymethylbenzoate (2.50 g) and toluene (100 mL) was added thionyl chloride (0.95 g), and the mixture was heated under reflux for 1 hr. After concentration of the reaction mixture, ethyl acetate was added to the residue, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give methyl 5-chloromethyl-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate as colorless crystals (2.23 g, yield 84%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 107-108° C.
Reaction SMILES: OO.[C:3]([O:7][C:8](=[O:36])[N:9]([CH2:16][CH:17]1[C:26]2[C:21](=[C:22]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][N:29]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:6])([CH3:5])[CH3:4].C([O-])([O-])=[O:38].[K+].[K+].CS(C)=O>O>[C:3]([O:7][C:8](=[O:36])[N:9]([CH2:16][CH:17]1[C:26]2[C:21](=[C:22]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:38])[NH2:35])=[CH:30][N:29]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:5])([CH3:6])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC(C)CCCN(CC1CCCc2c(Oc3ccc(C#N)cn3)cccc21)C(=O)OC(C)(C)C
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)CCCN(CC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21)C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 197.2 %

Procedure:
Add 30% aq. H2O2 (239 uL) to a suspension of [5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4-methyl-pentyl)-carbamic acid tert-butyl ester (111 mg, 0.239 mmol), K2CO3 (16 mg, 0.120 mmol) and DMSO (3 ml) stirring in an ice/water bath. After 1.5 hours, pour the reaction mixture into water and extract with EtOAc. Wash the extract with water and brine before drying (MgSO4) and concentrating to give [5-(5-Carbamoyl-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4 methyl-pentyl)-carbamic acid tert-butyl ester (114 mg) as a white foam. Use this material without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[C:4]2[CH:10]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[C:7]([N+:17]([O-])=O)[C:5]=2[N:6]=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][C:2]1[N:3]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[C:4]2[CH:10]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[C:7]([NH2:17])[C:5]=2[N:6]=1
Reactant: Cc1nc2c([N+](=O)[O-])cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c(N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 90.2 %

Procedure:
TiCl3 (19.7 mL) was added to a solution of 4-(2-methyl-3-(naphthalen-1-ylmethyl)-7-nitro-3H-benzo[d]imidazol-5-yl)morpholine (1.82 g), prepared following the same procedure as in Example 4, and NH4OAc (4.85 g) in MeOH (150 mL). After stirring for 7 min at room temperature, TLC showed no starting material remaining. The pH of the mixture was made basic by adding aqueous Na2CO3 solution. The solvent was removed under reduced pressure and the residue was extracted with DCM (250 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in-vacuo to afford the desired product as a white solid (1.52 g, 91%). 1H NMR (300 MHz, CDCl3) δ ppm 2.47 (s, 3H), 3.02 (t, 4H, J=4.8 Hz), 3.78 (t, 4H, J=4.8 Hz), 4.30 (s, 2H), 5.68 (s, 2H), 6.05 (d, 1H, J=1.8 Hz), 6.25 (d, 1H, J=1.8 Hz), 6.56 (d, 1H, J=7.5 Hz), 7.27 (t, 1H, J=7.5 Hz), 7.55-7.66 (m, 2H), 7.77 (d, 1H, J=8.1 Hz), 7.93 (d, 1H, J=8.1 Hz), 8.05 (d, 1H, J=8.1 Hz); LC-MS: m/e=373 [M+1]+.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](/[CH:19]=[CH:20]/[N+:21]([O-:23])=[O:22])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+]>CS(C)=O>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][N+:21]([O-:23])=[O:22])[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])/C=C/c1cccc(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.8 %

Procedure:
To an acetic acid (5.5 mL) and dimethyl sulfoxide (94 mL) solution of 1-benzyloxy-3-((E)-2-nitro-vinyl)-benzene (5.5 g, 21.5 mmol) described in Manufacturing Example 61-1-2 was added sodium borohydride (1.3 g, 34.4 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1-4:1) to obtain the title compound (3.14 g, 57%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:15])[NH:9][N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([CH3:6])([CH3:5])[CH3:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:3]([O:7][C:8](=[O:15])[N:9]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)n1cccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Sodium hydride (313 mg, 7.83 mmol, 60% purity in mineral oil) was added in one portion to a stirred, ice/water-cooled solution of pyrrol-1-yl-carbamic acid tert-butyl ester (951 mg, 5.22 mmol) and benzyl bromide (745 μL, 6.26 mmol) in DMF (20 mL); the mixture was stirred in the cold bath for 30 min, at which time TLC showed complete disappearance of starting material; then poured into diluted, cold ammonium chloride solution to quench the reaction, followed by extraction with EtOAc, then washed with water, and brine; then the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was silica gel column purified to give desired product (1.376 g) as a clear oil. ESI (m/z): 273 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[C:5]#[N:6].Cl[CH2:13][CH2:14][CH2:15][C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[O:10][CH2:17][CH2:16][CH2:15][C:14]#[CH:13])[C:5]#[N:6]
Reactant: C#CCCCCl
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C#CCCCOc1c(C)cc(C#N)cc1C
Temperature: 100 °C
Reaction time: 4 h
Yield: 59.8 %

Procedure:
A mixture of 40 g 3,5-dimethyl-4-hydroxybenzonitrile, 30.77 g 1-chloro-4-pentyne, 74.63 g potassium carbonate and 130 ml N-methylpyrrolidinone was heated with stirring to 100° C. and stirring was continued at 100° C. for 4 hrs. The mixture was cooled to room temperature and 800 ml of water was added. This mixture was extracted with 400 ml ethyl acetate and the extract was washed with 2N sodium hydroxide and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting black oil, dissolved in ethyl acetate, was passed through a pad of florisil to remove the color and the filtrate was concentrated in vacuo. The residue was recrystallized from methyl alcohol to yield 34.64 g (60.2%) of 3,5-dimethyl-4-(3-ethynylpropoxy)benzonitrile, m.p. 48°-49° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[C:23](O)=[O:24])([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH3:33][C:30]([C:27]1[CH:26]=[C:22]([C:23]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)=[O:24])[CH:21]=[C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:28]=1[OH:29])([CH3:31])[CH3:32]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
2.07 g (10 mmoles) of 1-(4-nitrophenyl)piperazine, 2.5 g (10 mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide are introduced into a 100 ml flask containing 25 ml of DMF. The reaction medium is agitated for 15 hours at ambient temperature, the precipitate which appears is filtered out and rinsed with ethyl acetate. After concentration of the filtrate under reduced pressure, the residue is diluted in 20 ml of ethyl acetate and a new insoluble is eliminated by filtration. The solvent is evaporated off under vacuum and the residue is precipitated from diethyl ether. The solid is filtered, rinsed with 2×20 ml of ethyl acetate in order to obtain a yellow powder with a yield of 89%. Melting point: 159.5-160.5° C.
Reaction SMILES: C[O-].[Na+].[CH2:4]([O:8][C:9]([C:11]1[N:12]=[CH:13][C:14]2[C:19]([C:20]=1[S:21]C(=O)N(C)C)=[CH:18][CH:17]=[C:16]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:15]=2)=[O:10])CCC>CO.O.Cl>[CH3:4][O:8][C:9]([C:11]1[N:12]=[CH:13][C:14]2[C:19]([C:20]=1[SH:21])=[CH:18][CH:17]=[C:16]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:15]=2)=[O:10]
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1SC(=O)N(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1S
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of 6.5 ml of 0.5 N sodium methoxide in methanol was added 460 mg of 4-Dimethylcarbamoylsulfanyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester. The resultant solution was heated to 50-60° C. for 8 hours, cooled to room temperature, and diluted with 10 ml water and 7.0 ml 1 N HCl. The resulting yellow precipitate was collected by filtering the solution through a (medium) porous buchner filter funnel to give 307 mg of product; MS (+) m/z 312.08 (M+1)
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH3:17][C:18]1([CH3:25])[O:22][CH:21]([CH2:23][OH:24])[CH2:20][O:19]1.[H-].[Na+].[Cl-].[Na+]>C(OC)(C)(C)C.CN(C)C=O>[CH3:17][C:18]1([CH3:25])[O:22][CH:21]([CH2:23][O:24][C:2]2[S:6][N:5]=[C:4]([S:7][CH2:8][O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:3]=2)[CH2:20][O:19]1
Reactant: Clc1nc(SCOCc2ccccc2)ns1
Reactant: CC1(C)OCC(CO)O1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC1(C)OCC(COc2nc(SCOCc3ccccc3)ns2)O1
Reaction time: 2 h
Yield: 70 %

Procedure:
To 3 g of N,N-dimethylformamide, 350 mg of 5-chloro-3-benzyloxymethylthio-1,2,4-thiadiazole and 169 mg of 2,2-dimethyl-1,3-dioxolane-4-methanol were dissolved, and added 56 mg of sodium hydride (60% in oil) at about 0° C., followed by stirring at same tempareture for 2 hours. Then, to the reaction mixture, t-butylmethylether and saturated sodium chloride aqueous solution were added, and separeted to two layers. The organic layer was dried by anhydrous sodium salfate, and concentrated. The residue obtaind was subjected to column chromatography to obtain 330 mg of 5-(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy-3-benzyloxymethylthio-1,2,4-thiadiazole.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[CH:16][CH:15]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:33][CH:32]=2)[CH2:9]1)=O)(C)(C)C.Cl.CO>>[CH:26]1([CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]2[CH:16]=[CH:15][C:14]([C@H:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]3[O:29][CH2:30][C:31]3[CH:40]=[C:39]4[C:34]([CH2:35][CH2:36][CH2:37][N:38]4[CH2:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:33][CH:32]=3)=[CH:19][CH:18]=2)[CH2:28][CH2:27]1
Reactant: COCCCN1CCCc2ccc(CO[C@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3c3ccc(OCCCOCC4CC4)cc3)cc21
Agent: Cl
Solvent: CO
Product: COCCCN1CCCc2ccc(CO[C@H]3CNCC[C@@H]3c3ccc(OCCCOCC4CC4)cc3)cc21

Procedure:
In analogy to the procedure described in example 4(b), the (3R,4R)-4-[4-(3-cyclopropylmethoxy-propoxy)-phenyl]-3-[1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl/methanol to yield the (3R,4R)-7-[4-[4-(3-cyclopropylmethoxy-propoxy)-phenyl]-piperidin-3-yloxymethyl]-1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinoline as light yellow oil; MS: 523 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2.[CH3:16][C:17](=O)[C:18](=O)[CH3:19]>O>[Cl:13][C:10]1[CH:9]=[C:8]2[N:7]=[C:6]([OH:14])[C:5]([OH:15])=[N:4][C:3]2=[C:2]2[C:11]=1[N:12]=[C:18]([CH3:19])[C:17]([CH3:16])=[N:1]2
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Reactant: CC(=O)C(C)=O
Solvent: O
Product: Cc1nc2c(Cl)cc3nc(O)c(O)nc3c2nc1C
Temperature: 50 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
A mixture of 0,5 g (2,24 mmol) 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline in 10 ml water was at 50° C. added a solution of 0,4 g (4,6 mmol) 2,3-butanedione in 5 ml water. The reaction mixture was stirred at 50° C. for 24 h. After cooling to 25° C., the precipitate was filtered off and washed with water and ethanol to give 0,3 g (50%) 6-chloro-2,3-dihydroxy-8,9-dimethylpyrazino(2,3-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6): 8.47 (1H,s), 2.60 (3H,s), 2.53 (3H,s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[CH3:12])[CH3:2].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][C:6]=1[CH3:12])[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)cc1C
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Oc2ccccc2)cc1C

Procedure:
27.5 g of 4-bromo-2-methyl-benzoic acid ethyl ester was dissolved in 120 mL of anhydrous toluene. To the solution was added 21.3 g of phenol, 73.6 g of Cs2CO3, 551 μL of ethyl acetate, 22 g of activated 4 A molecular sieves, and 5.68 g of 90% copper(I) trifluoromethanesulfonate benzene complex. The reaction was placed under a nitrogen atmosphere and heated at reflux temperature for 48 h. The resultant mixture was partitioned between water and ethyl acetate, and the mixture filtered through a fine sintered glass filter to remove insoluble material. The organic fraction was washed three times with 1.0 N NaOH, once with brine, dried over anhydrous sodium sulfate, and concentrated to 18.2 g of a pale tan liquid: 1H NMR (200 MHz, CDCl3) δ 7.93-7.88 (dd, J=1.3, 7.8 Hz, 1H) 7.39-7.30 (m, 2H), 7.19-7.10 (tt, J=1.2, 7.4 Hz, 1H), 7.06-7.7.0 (m, 2H), 6.80-6.75 (m, 2H), 4.37-4.26 (q, J=7.0 Hz, 2H), 2.56 (s, 3H), 1.40-1.33 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([C:8]1[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][C:11]([CH2:12]O)=[CH:10][C:9]=1[S:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BrH:26]>O>[CH2:1]([C:8]1[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][C:11]([CH2:12][Br:26])=[CH:10][C:9]=1[S:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: CSc1cc(CO)cc(S(N)(=O)=O)c1Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CSc1cc(CBr)cc(S(N)(=O)=O)c1Cc1ccccc1

Procedure:
4-Benzyl-3-methylthio-5-sulfamylbenzyl alcohol (10 g; prepared as described in Example 1) is while stirring added in portions to acetic acid saturated with dry hydrogen bromide (50 ml), and the mixture is stirred for 24 hours. The resulting solution is diluted with water (100 ml) and cooled to precipitate crude 4-benzyl-3-methylthio-5-sulfamylbenzyl bromide. After recrystallization from methanol it is obtained with a melting point of 149°-150° C.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCO>[CH2:10]([NH:17][C:2]([CH3:9])([CH3:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C=C(C)C
Reactant: NCc1ccccc1
Solvent: CCO
Product: CCOC(=O)CC(C)(C)NCc1ccccc1
Yield: 21.1 %

Procedure:
A solution of ethyl 3,3-dimethylacrylate (19.3 g, 0.151 mol) in EtOH (150 mL) was added benzylamine (16.2 g, 0.151 mol) and refluxed for 24 h. The reaction mixture was concentrated in vacuo. The distillation of the residue gave ethyl 3-benzylamino-3-methylbutyrate as a colorless oil (7.48 g, 21%).
Reaction SMILES: [C:1]([C@:3]1([OH:10])[CH2:7][CH2:6][N:5]([CH3:8])[C:4]1=[O:9])#[CH:2].Br[C:12]1[CH:13]=[CH:14][C:15]2[O:21][CH2:20][CH2:19][N:18]3[C:22]([CH2:28][N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=[C:30]4[CH3:38])=[C:23]([C:25]([NH2:27])=[O:26])[N:24]=[C:17]3[C:16]=2[CH:39]=1>CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:10][C@@:3]1([C:1]#[C:2][C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]4[C:22]([CH2:28][N:29]5[C:33]6[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=6[N:31]=[C:30]5[CH3:38])=[C:23]([C:25]([NH2:27])=[O:26])[N:24]=[C:17]4[C:16]=3[CH:39]=2)[CH2:7][CH2:6][N:5]([CH3:8])[C:4]1=[O:9]
Reactant: Cc1nc2ccccc2n1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: Cc1nc2ccccc2n1Cc1c(C(N)=O)nc2n1CCOc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2
Yield: 19 %

Procedure:
Similar to as described in General Procedure E with the exceptions of using Pd(PPh3)4 in DMSO, 10-bromo-3-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to yield the titled compound as a yellow solid (21 mg, 19%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O[C@@H:12]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][C@H:12]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=C(Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1)C1CC1
Product: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure B and Scheme B1 using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)cyclopropanecarboxamide: ESMS m/e: 497.1 (M+H)+.
Reaction SMILES: [NH:1]=[C:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([NH2:20])[C:14]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[CH:13]2.[BH4-].[Na+].CC(C)=O>CO>[NH2:1][CH:2]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([NH2:20])[C:14]([N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[CH:13]2
Reactant: Cc1cccc(C(=N)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: Cc1cccc(C(N)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (ice bath) solution of 6-(2-(imino(phenyl)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine (0.058 g, 0.137 mmol) in MeOH (5.0 mL) was added sodium borohydride, 99% (0.033 mL, 0.925 mmol). The mixture was then warmed to RT and stirred for 1 h. The excess NaBH4 was then treated with acetone. The resulted solution was concentrated and purified on HPLC (10-100% MeCN/H2O with 0.1% TFA modifier) to afford 6-(2-(amino(phenyl)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine as white solid. MS (ESI, pos. ion) m/z: 425 (M+1).