Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([CH:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[OH:10])[CH:3]=1.O[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([CH:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCc1sc(Br)cc1C(O)C1CCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCc1sc(Br)cc1C(Oc1ccc(C(=O)OC)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
To a mixture of (5-bromo-2-ethylthiophen-3-yl)(cyclohexyl)methanol (1.50 g) synthesized above, methyl 4-hydroxybenzoate (904 mg), 1,1′-(azodicarbonyl)dipiperidine (2.50 g) and tetrahydrofuran (30 mL) was added tributylphosphine (2.47 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the precipitate was removed by filtration and washed with diisopropyl ether. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9, volume ratio) to give the title compound (1.20 g, 55%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(NC(=O)c2ccc(C)cc2)cc1
Yield: 40.4 %

Procedure:
A mixture of 4-methyl-benzoyl chloride (0.74 mL, 0.0056 mol) and 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.93 g, 0.0045 mol) in toluene (22 mL) was refluxed under nitrogen for 17 hours and allowed to cool. The mixture was diluted with THF (20 mL), and washed with 0.1 M aqueous sodium hydroxide. The solids that remained undisolved were filtered, washed with water, and dried in house vacuum (40° C., air bleed) to give 0.592 g of 4-[4-(4methyl-benzoylamino)-phenyl]-4-oxo-butyric acid, methyl ester as an off-white solid; mp 192-195° C.
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]([O:13][CH2:14][C:15]2[CH:34]=[CH:33][C:18]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[OH:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].Br[CH2:46][C:47]([O:49][CH3:50])=[O:48]>O>[C:1]([C:9]1[CH:36]=[CH:35][C:12]([O:13][CH2:14][C:15]2[CH:34]=[CH:33][C:18]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[O:37][CH2:46][C:47]([O:49][CH3:50])=[O:48])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(C(=O)c3ccccc3)c(O)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a mixture of 4-[4-(4-benzoyl-3-hydroxyphenoxymethyl)phenoxymethyl]-5-methyl-2-phenyloxazole (1.52 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.14 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Methyl bromoacetate (0.57 g) was added to the mixture and the mixture was stirred at 80° C. for 2 hrs., The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give methyl 2-[2-benzoyl-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenoxy]acetate as an oil (1.65 g, 94%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]=[C:23]=[O:24].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:21][NH:22][C:23](=[O:24])[O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:9]2[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=1
Reactant: Oc1cccc(C2CCCN2CCc2ccccc2)c1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2CCc2ccccc2)c1
Reaction time: 4 h
Yield: 84 %

Procedure:
To a solution of 3-[1-(2-phenylethyl)-2-pyrrolidinyl]phenol (0.83 g) in dry tetrahydrofuran (40 ml) was added methyl isocyanate (0.20 ml) followed by milled potassium carbonate (0.51 g)) at ambient temperature, under nitrogen. The reaction mixture was stirred for 4 hrs, filtered through a pad of celite, and the solids were washed with ethyl acetate. The combined filtrates were concentrated, and the residue was purified by flash column chromatography (silica gel 30-75% ether/heptane). The appropriate fractions were collected and concentrated to afford 0.84 g (84%) of product. The analytical sample was prepared by flushing the compound through alumina with ether.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:10][C:9]2([CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[O:8][N:7]=1)=[O:5])C.O.[Li+].[OH-]>CO>[O:8]1[C:9]2([CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)C1=NOC2(CCOCC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=NOC2(CCOCC2)C1
Yield: 96 %

Procedure:
A solution of 1,8-dioxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid ethyl ester (3.00 g, 1.41 mmol, as prepared in the previous step) in MeOH (60 mL) and water (20 mL) was treated with LiOH (649 mg, 1.55 mmol) at rt for 2.5 h. MeOH was removed in vacuo. The resulting aqueous solution was acidified with 1 N aq HCl and extracted three times with EtOAc (100 mL, 100 mL, 50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to afford the title compound (2.50 g, 96%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 3.86-3.95 (m, 2H), 3.74 (dt, J=11.8, 4.7 Hz, 2H), 3.01 (s, 2H), 1.91-1.99 (m, 2H), 1.80-1.89 (m, 2H).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[N:19]1[C:27]2[N:22]3[C:23](=[N:28][CH:29]=[C:21]3[C:20]=1[SH:30])[CH:24]=[CH:25][CH:26]=2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N:19]1[C:27]2[N:22]3[C:23](=[N:28][CH:29]=[C:21]3[C:20]=1[S:30][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1)[CH:24]=[CH:25][CH:26]=2
Reactant: Sc1nc2cccc3ncc1n32
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(Sc2nc3cccc4ncc2n43)CC1
Temperature: 80 °C
Reaction time: 11 h
Yield: 56 %

Procedure:
To a solution of tert-butyl 4-[(methylsulfonyl)oxy]-1-piperidinecarboxylate (3.5 g, 12.5 mmol) in DMF (60 ml) were added 1,4,7b-triazacyclopenta[cd]inden-2-thiol (3.7 g, 21.3 mmol) and DBU (3.7 ml, 25 mmol), and the mixture was stirred at 80° C. for 11 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added water (200 ml) The mixture was extracted with a mixed solution of THF and ethyl acetate (3/2, 500 ml). The organic layer was washed with saturated aqueous solution of sodium chloride (200 ml), successively, and dried over anhydrous sodium sulfate, concentrated under reduced pressure. The concentrate was subjected to flash column chromatography (silica gel 30 g, ethyl acetate/hexane=1/2 to 1/0), and the desired fraction was concentrated under reduced pressure. To the concentrate was added disopropyl ether and the precipitates were collected by filtration to give the titled compound (2.5 g, 7 mmol) as yellowish powdery crystals.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1/[CH:10]=[C:11](\[CH3:17])/[C:12]([O:14]CC)=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH3:24][N:25]([CH3:33])[C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>CN(C=O)C>[F:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([O:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([N:25]([CH3:33])[CH3:24])[CH:27]=2)[C:3]=1/[CH:10]=[C:11](\[CH3:17])/[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)/C(C)=C/c1c(F)cc(F)cc1F
Reactant: CN(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C\c1c(F)cc(F)cc1Oc1cccc(N(C)C)c1)C(=O)O

Procedure:
11 b/12 b) The ester from 11 a/12 ma, 3 eq. of potassium carbonate and 1.1 eq. of 3-dimethylaminophenol were stirred in DMF at 150° C. for 3 hours. An isomer mixture of the ethyl esters of E-3-[2,6-difluoro-4-(3-dimethylaminophenoxy)]-2-methyl-propenoic acid and E-3-[2,4-difluoro-6-(3-dimethylaminophenoxy)-phenyl]-2-methyl-propenoic acid was isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.[NH:9]1[CH2:17][CH2:16][CH:12]([C:13]([NH2:15])=[O:14])[CH2:11][CH2:10]1.C(N(CC)CC)C>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:9]1[CH2:17][CH2:16][CH:12]([C:13]([NH2:15])=[O:14])[CH2:11][CH2:10]1
Reactant: Clc1ccncc1Br
Reactant: NC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Product: NC(=O)C1CCN(c2ccncc2Br)CC1
Yield: 33.2 %

Procedure:
General procedure C was followed using 3-bromo-4-chloro-pyridine (0.10 g, 0.52 mmol) and isonipecotamide (67 mg, 0.52 mmol) NMP (2 mL) and triethylamine (0.14 mL, 1.0 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, gradient 99:1 to 95:5) to furnish the title compound as a white solid (49 mg, 33%), LC-MS (ESI) Rt 0.80 min, m/z 284 (100%, [M+H]+); m/z (ESI) C11H15BrN3O requires 284.0393 found [M+H]+ 284.0392.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11]([CH3:13])=[CH2:12].S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:11]([CH3:13])([CH3:12])[CH2:10][Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C=C(C)CCl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(CCl)c1cc(Br)ccc1O
Reaction time: 1 h
Yield: 41.7 %

Procedure:
To a stirred, cooled (ice bath) mixture of 4-bromophenol (0.512 g, 3 mmol) and 3-chloro-2-methylpropene (0.32 mL, 3.3 mmol), concentrated sulfuric acid (0.1 mL, 1.5 mmol) was added and the dark reaction mixture was stirred for 1 h. The reaction mixture was diluted with cold water and extracted with ether. The ethereal extract was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil. Flash column chromatography of the oil over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent afforded the title compound as an oil (0.33 g, 42.6%). Some dialkylated product was also formed and some starting material was recovered.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH:16]([C:20]([NH:22][C:23]4[CH:24]=[C:25]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=4)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:21])[CH2:17]3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].[N+:48]([CH2:50]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:49]>CO>[O:2]1[C:1]([C:3]2[CH:8]=[C:7]([O:9][C:10]3[CH:19]=[C:18]4[C:13]([CH2:14][CH2:15][CH:16]([C:20]([NH:22][C:23]5[CH:24]=[C:25]([CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=5)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:21])[CH2:17]4)=[CH:12][CH:11]=3)[CH:6]=[CH:5][N:4]=2)=[CH:50][N:48]=[CH:49]1
Reactant: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(C=O)c4)cc3C2)cc(C(F)(F)F)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(-c5cnco5)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 74.3 %

Procedure:
To a solution of tert-butyl [3-[({7-[(2-formylpyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}carbonyl)amino]-5-(trifluoromethyl)benzyl]carbamate (120 mg, 0.21 mmol) in MeOH (2 mL), was added potassium carbonate (116 mg, 0.84 mmol) and 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene (45.2 mg, 0.23 mmol). The reaction mixture was heated at 70° C. for 30 min. and then allowed to cool to rt and the solvents were evaporated. The residue was dissolved in DCM, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl [3-{[(7-{[2-(1,3-oxazol-5-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalen-2-yl)carbonyl]amino}-5-(trifluoromethyl)benzyl]carbamate (95.0 mg, 74.1%). LCMS: (FA) ES+ 609.3, ES− 607.4.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)[CH2:13]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][CH2:33][CH2:34][OH:35]>CC#N>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[O:24][CH2:32][CH2:33][CH2:34][OH:35])[CH2:13]1
Reactant: Oc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCOc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Reaction time: 2 h
Yield: 32 %

Procedure:
(R*)-3-{1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol (208 mg, 0.64 mmol), K2CO3 (103 mg, 0.74 mmol), 3-bromo-1-propanol (86 mg, 0.62 mmol) and MeCN (5 ml) were heated under microwaves at 105° C. for 6 h. More K2CO3 (103 mg) and 3-bromo-1-propanol (86 mg) were added and the heating was continued for 2 h. The solvent was removed and the residue was taken up in DCM. This solution was washed with water and 1 M NaOH and evaporated to dryness. Flash chromatography (heptane/EtOAc) gave 76 mg of the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13]Br.O.[OH-].[K+]>C(O)(=O)C>[Br:13][C:4]1[CH:3]=[CH:2][C:1]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])=[CH:6][CH:5]=1
Reactant: O=C1CCCN1c1ccccc1
Reactant: BrBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCN1c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
8.06 g of N-phenylpyrrolidinone were dissolved in 33 ml glacial acetic acid; the mixture was cooled to 0°-5° C. and then a solution of 2.65 ml bromine in 12 ml of glacial acetic acid was added dropwise. Stirring was continued for 30 minutes at room temperature. Work-up was accomplished by pouring the mixture into 1 l of water and neutralizing the mixture with KOH. The solid was filtered and dissolved in ethylacetate and washed with a sodium thiosulphate solution until the brown colour disappeared; washing with brine and drying with MgSO4 provided 8.5 g of a white crystalline mass that could be recrystallized from ether; m.p. 102° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH2:14]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26](Cl)=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[N:29]2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:9]([O:8][C:7](=[O:13])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26]1[C:25]2[C:30](=[CH:31][C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:24]=2)[N:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])([CH3:10])([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Reaction time: 18 h
Yield: 79.8 %

Procedure:
tert-Butyl N-(4-aminobutyl)carbamate (28.6 g, 152.0 mmol) was added dropwise to a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (40.7 g, 138 mmol), prepared in Parts A-D of Example 1, and triethylamine (38.5 mL, 276 mmol) in dichloromethane over a period of 1.5 hours. After the reaction was stirred for 18 hours, the reaction mixture was washed twice with water and once with saturated aqueous sodium chloride. The organic was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from 2-propanol to afford 51.4 g of tert-butyl[4-(7-benzyloxy-3-nitroquinolin-4-ylamino)butyl]carbamate as a golden brown powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[CH3:10])[C:5]([C:36](O)=[O:37])=[CH:4][N:3]=1.[CH2:39]([N:41]=[C:42]=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.CNC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[CH3:10])[C:5]([C:36]([N:41]([CH3:42])[CH3:39])=[O:37])=[CH:4][N:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4C(=O)O)n(-c4ccccc4)c(=O)c23)ccn1
Agent: CNC
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4C(=O)N(C)C)n(-c4ccccc4)c(=O)c23)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-amino-4-((1-(8-(2-methoxypyridin-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)-pyrimidine-5-carboxylic acid (44 mg, 0.087 mmol) in anhydrous N,N-dimethylmethanamide (3 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (25 mg, 0.13 mmol) and hydroxybenzotriazole (18 mg, 0.13 mmol) were added and the resulting mixture was stirred at RT for 30 min. To this mixture, dimethylamine (2M in THF, 0.065 mL, 0.13 mmol) and N,N-diisopropylethylamine (0.040 mL, 0.19 mmol) were added and the reaction mixture was stirred at RT for 3 h. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product 112, (S)-2-amino-4-((1-(8-(2-methoxypyridin-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)-N,N-dimethylpyrimidine-5-carboxamide. ESI-MS m/z: 533.8 [M−H]
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N=C=NCCCN(C)C)C.[NH2:22][CH2:23][C:24]1[N:29]=[C:28]2[S:30][C:31]3[CH2:32][N:33]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:34][CH2:35][C:36]=3[C:27]2=[C:26]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[CH:45]=2)[C:25]=1[Cl:54].[N:55]1([CH2:60][C:61](O)=[O:62])[CH:59]=[N:58][CH:57]=[N:56]1>O.CN(C)C=O>[CH2:37]([N:33]1[CH2:34][CH2:35][C:36]2[C:27]3[C:28]([S:30][C:31]=2[CH2:32]1)=[N:29][C:24]([CH2:23][NH:22][C:61](=[O:62])[CH2:60][N:55]1[CH:59]=[N:58][CH:57]=[N:56]1)=[C:25]([Cl:54])[C:26]=3[C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[CH:45]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(O)Cn1cncn1
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(Cl)c(CNC(=O)Cn3cncn3)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
N-hydroxybenotriazole (HOBt) (0.427 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) (0.535 g) were added to an ice-cooled mixture of the compound (1.0 g) obtained in Example 18B, (1,2,4-triazol-1-yl)acetic acid (0.325 g) and N,N-dimethylformamide (DMF) (20 ml), the mixture was stirred at room temperature for 8 hours, poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (20:1, v/v) to yield 7-benzyl-3-chloro-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-2-(1,2,4-triazol-1-ylacetylaminomethyl)thieno[2,3-b:5,4-c']dipyridine (0.55 g, 50%), which was then recrystallized from ethyl acetate-hexane to yield a colorless powder having a melting point of 101 to 102° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([CH2:25][CH3:26])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>CO.O1CCOCC1>[ClH:27].[ClH:27].[N:11]1([C:15]2[CH:16]=[C:17]([CH2:25][CH3:26])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCc1cc(N2CCCNCC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(6-Ethylquinolin-8-yl)[1,4]-diazepan-1-carboxylic acid tert-butyl ester (1.0 g, 1.0 equiv) was dissolved in MeOH (5 mL) and 1.0 M HCl in 1,4-dioxane (10 mL) was added to the mixture. After stirring at room temperature for 1 hour, the mixture was concentrated to dryness to afford the title compound (1.0 g). MS (ES) m/z 256.1 (M+H+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10]1)=O.C(OCC)(=O)C>O1CCCC1>[F:19][C:16]([F:17])([F:18])[CH2:15][N:12]1[CH2:13][CH2:14][N:9]([NH2:7])[CH2:10][CH2:11]1
Reactant: O=NN1CCN(CC(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NN1CCN(CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a suspension of lithium aluminum hydride (2.22 g, 58.5 mmol) in tetrahydrofuran (100 mL) that cooled with ice bath, a solution of 1-nitroso-4-(2,2,2-trifluoroethyl)piperazine (5.43 g, 27.5 mmol) in tetrahydrofuran (10 mL) was added dropwise and the reaction mixture was allowed to warm to ambient temperature, then stirred for 5 days. The reaction mixture was cooled with ice bath, ethyl acetate was added until cease bubbling up, and water (2.1 mL) was added then the mixture was stirred for 20 min. To this mixture, 15% w/v sodium hydroxide solution (2.1 mL) and water (6.3 mL) were added, then the suspension mixture was allowed to warm to ambient temperature and then the mixture was stirred vigorously for 1 h. Magnesium sulfate was added to the mixture and stirred for a while, then the suspension was filtered. The filtrate was concentrated to afford 4-(2,2,2-trifluoroethyl)piperazine-1-amine as oil (4.72 g, y. 94%).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3][CH2:2]1.[IH:12].CS[C:15]1[NH:16][CH2:17][CH2:18][N:19]=1>CO>[IH:12].[NH:19]1[CH2:18][CH2:17][N:16]=[C:15]1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:1][CH2:2]1
Reactant: C1CCC2(CC1)CCNCC2
Reactant: CSC1=NCCN1
Agent: I
Solvent: CO
Product: C1CCC2(CC1)CCN(C1=NCCN1)CC2
Yield: 41.4 %

Procedure:
3-Azaspiro[5,5]undecane (0.38 g, 2 mmol) and 2-methylthio-2-imidazoline hydroiodide (0.44 g, 1.8 mmol) was refluxing in CH3OH overnight, concentrated in vacuo and purified by flash chromatography to give yellow oil (0.26 g, 65% yield). 1H NMR (360 MHz, CDCl3) δ 8.27 (br s, 2H), 3.72 (s, 4H), 3.39 (t, J=5.83 Hz, 4H), 1.50 (t, J=5.94 Hz, 4H), 1.47-1.44 (m, 10H); 13C NMR (90 MHz, CDCl3) δ 159.48, 43.39, 42.73, 36.02, 35.26, 30.83, 26.65, 21.61. 21.49; ESI-MS: Calculated for C13H24IN3 (M−I)+ 222.3, Found: 222.5.