Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](=S)[NH2:23])C1C=CC=CC=1.CI.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:37][NH2:38])=O)=[CH:30][CH:29]=1.CO>C(#N)C>[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]2[NH:23][C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[OH:8])[CH2:16][CH2:15][O:14][C:13]4([CH3:21])[CH3:20])=[N:38][N:37]=2)=[CH:30][CH:29]=1
Reactant: NNC(=O)Cc1ccc(F)cc1
Reactant: CC1(C)OCCn2c1nc(C(N)=S)c(OCc1ccccc1)c2=O
Solvent: CI
Solvent: CC#N
Solvent: CO
Product: CC1(C)OCCn2c1nc(-c1nnc(Cc3ccc(F)cc3)[nH]1)c(O)c2=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a slurry of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide (0.04 g, 0.116 mmol, 1.0 equiv) in acetonitrile (1.2 mL) under a nitrogen atmosphere, was added MeI (0.011 mL, 0.174 mmol, 1.5 equiv). The reaction was heated at 50° C. (oil bath) for 1 h. The reaction was then cooled to ambient temperature and concentrated in vacuo. 2-(4-Fluorophenyl)acetohydrazide (0.058 g, 0.35 mmol, 3 equiv) was then added to the residue followed by methanol (1 mL) and the slurry was heated at 70° C. (oil bath). After stirring 1 h, the reaction was cooled to ambient temperature and concentrated in vacuo. DMF (1 mL) was added to the residue and the solution was heated at 150° C. (oil bath) for 3.5 h. The reaction was then cooled to ambient temperature and stirred 3 d. The reaction was heated at 140° C. (oil bath) for 2 h. The reaction was cooled to ambient temperature and concentrated in vacuo. The residue was added to a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×2). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was purified by reverse phase preparatory HPLC to provide the title compound (0.021 g, 49% yield) as a gray solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (s, 2H), 7.21-7.39 (m, 2H), 7.00 (t, J=8.69 Hz, 2H), 4.17 (s, 2H), 4.05 (s, 4H), 1.62 (s, 6H); LCMS (ES+, (M+H)+) m/z 372.16.
Reaction SMILES: Cl[CH:2]([CH2:12][C:13]([Cl:16])([Cl:15])Cl)[C:3]([CH3:11])([CH3:10])[CH:4]([C:8]#[N:9])C(O)=O.N>CN(C)C=O.O>[Cl:16][C:13]([Cl:15])=[CH:12][CH:2]1[C:3]([CH3:10])([CH3:11])[CH:4]1[C:8]#[N:9]
Reactant: CC(C)(C(Cl)CC(Cl)(Cl)Cl)C(C#N)C(=O)O
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(C#N)C1C=C(Cl)Cl
Temperature: 140 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
4-Chloro-2-cyano-3,3-dimethyl-6,6,6-trichlorohexanoic acid (40 g) was dissolved in dimethyl formamide (66 ml) and the solution, at room temperature, was saturated with gaseous ammonia with no external cooling. The solution was stirred at 140° C. for 5 hours, then diluted with water and extracted with ether (3×100 ml). The ether solution was washed with saturated NaCl, dried over MgSO4 and evaporated to afford Compound A as a yellow oil (purity 85%) which partly crystallized on standing. Yield 79%.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:26])([CH3:25])[NH:3]1.[BH4-].[Na+]>CO>[CH3:26][C:4]1([CH3:25])[CH2:5][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([OH:24])[CH3:23])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:7][C:2]([CH3:27])([CH3:1])[NH:3]1
Reactant: CC(=O)Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1

Procedure:
The title compound was prepared by reduction of {4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propan-2-one with sodium borohydride in MeOH. Yield: 32 mg (100%).
Reaction SMILES: C[Si](C)(C)Cl.[CH3:6][C:7]([N+:13]([O-:15])=[O:14])([CH3:12])[CH2:8][CH2:9][CH2:10]O.[I-:16].[Na+]>C(#N)C>[I:16][CH2:10][CH2:9][CH2:8][C:7]([CH3:12])([N+:13]([O-:15])=[O:14])[CH3:6]
Reactant: CC(C)(CCCO)[N+](=O)[O-]
Reactant: [I-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(CCCI)[N+](=O)[O-]

Procedure:
70 mL (0.544 mol) trimethylchlorosilane are added dropwise at ambient temperature to 40 g (0.272 mol) 4-methyl-4-nitro-pentan-1-ol and 81.5 g (0.544 mol) sodium iodide in 350 mL acetonitrile. The reaction mixture is filtered, evaporated down and combined with diethyl ether. The organic phase is washed with sodium bisulphite solution and water, dried and freed from the solvent. Yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[OH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O.[F-].[K+]>C1(C)C=CC=CC=1.C(O)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:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:30][CH2:31]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Reactant: OB(O)c1ccccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccccc2O)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 58.4 %

Procedure:
To 400.0 mg (0.66 mmol) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate in 16 ml toluene were added 15.17 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium(0), 108.6 mg (0.79 mmol) (2-hydroxyphenyl)boronic acid in 4.0 ml ethanol and 118.3 mg (2.04 mmol) potassium fluoride in 4.0 ml water. The mixture was stirred at 100° C. for 20 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 240 mg (59%) tert-butyl 4-{3-[(3R)-3-({1-[5-(2-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH:5]=[C:6]1[CH2:10][N:9]([C:11]([OH:13])=[O:12])[CH:8]([C:14]([OH:16])=[O:15])[CH2:7]1.O.[OH-].[Li+]>O1CCCC1.O>[C:4]([O:12][C:11]([N:9]1[CH2:10][C:6](=[CH:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=2)[CH2:7][CH:8]1[C:14]([OH:16])=[O:15])=[O:13])([CH3:17])([CH3:5])[CH3:3]
Reactant: O=C(O)C1CC(=Cc2cccc(F)c2)CN1C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=Cc2cccc(F)c2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 153.2 %

Procedure:
To a stirred solution of 4-(3-Fluoro-benzylidene)-pyrrolidine-1,2-dicarboxylic acid 1-terf butyl ester 2-methyl ester (3.23 g, 9.63 mmol) in tetrahydrofuran (150 ml), was added 1M lithium hydroxide monohydrate (1.21 g, 28.9 mmol) in water (50 ml). The mixture was stirred at room temperature for 3 days. Tetrahydrofuran was removed by evaporation under reduced pressure, the residue diluted with water (30 ml) and acidified to pH 2.0-3.0 using 1M hydrochloric acid. The aqueous was extracted with diethyl ether (3×100 ml) and the combined organics dried over magnesium sulfate. The solvent was removed by evaporation under reduced pressure to give the title compound (2.37 g, 77%) as a white foam.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[F:13][CH:14]([CH2:19][CH2:20][CH2:21][CH3:22])[C:15](OC)=[O:16]>C1COCC1>[F:13][CH:14]([CH2:19][CH2:20][CH2:21][CH3:22])[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCC(F)C(=O)OC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(F)C(=O)CP(=O)(OC)OC
Reaction time: 0.17 h

Procedure:
Dimethyl methylphosphonate (8.38 g) was dissolved in dry THF (250 ml) and cooled to -78° C. n-Butyllithium (1.6-M, 42 ml) was added dropwise, and the reaction was stirred for 10 minutes. The above methyl fluorocaproate (200 g) in THF (10 ml) was added dropwise. After addition, the mixture was stirred at -78° C. for 45 minutes, and then at room temperature for additional 45 minutes. The crude product obtained after the conventional work-up was chromatographed (hexane/ethyl acetate=1/1). Yield; 5.04 g (62 g)
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12](I)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:32]([N:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1)[C:33]#[CH:34]>CN(C)C=O.CO.CS(C)=O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:19][C:17]1[C:18]2[N:10]([CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:11]=[C:12]([C:34]#[C:33][CH2:32][N:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]3)[C:13]=2[N:14]=[C:15]([CH2:20][CH2:21][CH2:22][CH3:23])[N:16]=1
Reactant: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCCCc1nc(N)c2c(n1)c(I)cn2COCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCc1nc(N)c2c(n1)c(C#CCN1CCN(C(=O)OC(C)(C)C)CC1)cn2COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
To a degassed solution of 5-((benzyloxy)methyl)-2-butyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine (150 mg, 0.344 mmol) in anhydrous N,N-dimethylformamide (3 mL) under nitrogen atmosphere at room temperature was added copper(I) iodide (13 mg, 0.068 mmol), bis(triphenylphosphine)palladium(II)dichloride (27 mg, 0.038 mmol) and, finally, triethylamine (0.086 mL, 0.619 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 10 minutes and then tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate (139 mg, 0.619 mmol) was added in one portion. The reaction mixture was heated to 55° C. in a pre-heated oil bath and stirred at 55° C. for 40 minutes. The reaction was evaporated in vacuo to yield a dark brown oil. The oil was partitioned between water and dichloromethane. The organic layer was separated and the aqueous back extracted with dichloromethane. The combined organic extracts were passed through a hydrophobic frit and evaporated in vacuo to yield a dark brown oil. The oil was dissolved in MeOH:DMSO (1:1) (2×1 mL) and purified by MDAP (Method B). Appropriate fractions were combined and evaporated in vacuo to yield the title compound as a brown oil (180 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:22]1[N:23]([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[N:24]=[N:25][CH:26]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][CH2:31][CH:27]([N:23]5[N:24]=[N:25][CH:26]=[N:22]5)[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: c1nnn(C2CCNC2)n1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(n4ncnn4)C3)c(F)cc2c1=O

Procedure:
A solution of 1-cyclopropyl-6,7,8-trifluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid (28.3 mg, 0.1 mmol), 3-(1,2,3,4-tetrazol-2-yl) pyrrolidine hydrochloride (35.1 mg, 0.2 mmol) and DBU (45.6 mg, 0.3 mmol) in acetonitrile (2 ml) was refluxed under nitrogen for 23 hrs. The solvent was then evaporated to dryness. The residue was diluted with water and extracted with chloroform. The organic extract was dried over Na2SO4, concentrated and the residue was crystallized from methanol-water. Yield: 12 mg, m.p. 192°-199° C. 1H NMR (CDCl3) δ: 8.7 (s, 1H), 8.5 (s, 1H), 7.8 (dd, 1H), 5.6-5.4 (m, 1H), 4.46-3.76 (m, 5H), 2.9-2.45 (m, 2H), 1.35-1.02 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)([CH3:25])=[O:24].Cl.C(=O)(O)[O-].[Na+]>COCCO.CCO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([P:23]([CH3:25])([CH3:22])=[O:24])=[CH:32][CH:31]=2)=[N:3][CH:4]=1
Reactant: CP(C)(=O)c1ccc(N)cc1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: COCCO
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(P(C)(C)=O)cc2)ncc1Cl
Temperature: 140 °C
Yield: 149.1 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (prepared as in Example 17: 50 mg, 0.14 mmol) in 1 mL of 2-methoxyethanol was added 4-(dimethylphosphoryl)-aniline (0.025 g, 0.14 mmol) and 0.12 ml of 2.5M HCl in EtOH. The mixture was heated in a sealed tube at 140° C. for 1 h. The mixture was basified with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was purified by prep-HPLC to give the final product (0.100 g, 15% yield). MS/ES+: m/z=478.
Reaction SMILES: Cl.N1C=CC=CC=1.[CH2:8]([N:15]1[C:21](=[O:22])[CH:20]2[N:23](C)[CH:17]([CH2:18][CH2:19]2)[C:16]1=[O:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:8]([N:15]1[C:16](=[O:25])[CH:17]2[NH:23][CH:20]([CH2:19][CH2:18]2)[C:21]1=[O:22])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN1C2CCC1C(=O)N(Cc1ccccc1)C2=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C1C2CCC(N2)C(=O)N1Cc1ccccc1
Yield: 5 %

Procedure:
In a dry flask were mixed 15 g of dry pyridine hydrochloride and 3.15 g (130 mmol) of 3-benzyl-2,4-dioxo-8-methyl-3,8-diazabicyclo [3.2.1] octane prepared according to U.S. Pat. No. 3,328,398 in 1967, Jun. 27. The mixture was heated in an oil bath preheated at 220° C. for 20 mn, cooled in an ice-bath, dissolved in 90 ml water, extracted four times with 100 ml ethyl ether. The organic layers were collected and dried over magnesium sulfate. After removing the solvent, the residue was chromatographied over silica-gel using dichloromethane/ethylacetate (80:20) to afford 1.5 g of the title compound (50%). M.P. 72° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1>C(OCC)C.C(OCC)(=O)C.[Cl-].[NH4+]>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:5]2([OH:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:12][CH:11]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CN1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN1CCC(O)(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of N-methyl-piperidin-4-one (1.50 g, 13.3 mmol) in diethyl ether (10 mL) was degassed under a nitrogen stream. The solution was cooled to 0° C. in an salt ice bath. To the stirring solution was added 4-fluorophenylmagnesium bromide (1.74 g, 14.6 mmol) dropwise over 5 min. A solid formed partway through the addition, and additional diethyl ether was added (2 mL). The reaction was then stirred at 0° C. for 2 h. To the suspension was added aqueous ammonium chloride (15 mL). The biphasic solution was diluted with ethyl acetate (40 mL) and additional saturated aqueous ammonium chloride (20 mL). The layer was separated, and the organic extract washed with brine (50 mL), dried over sodium sulfate, filtered, and the solvent removed under vacuum to give I-293 (965 mg, 32% yield) as a brown powder. The product was taken on without further purification. 1H NMR (400 MHz, DMSO-d6): 7.51-7.48 (m, 2H), 7.13-7.09 (m, 2H), 4.80 (s, 1H), 2.52-2.53 (m, 3H), 2.36-2.30 (m, 2H), 2.19 (s, 3H), 1.94-1.87 (m, 2H), 1.57-1.54 (m, 2H) ppm.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:21]1[C:34]2[C:35]3=[C:36]4[C:31](=[CH:32][CH:33]=2)[CH:30]=[CH:29][CH:28]=[C:27]4[CH:26]=[CH:25][C:24]3=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[C:1]1([C:11]2[CH:16]=[CH:15][C:14]([C:28]3[C:27]4[C:36]5=[C:35]6[C:24](=[CH:25][CH:26]=4)[CH:23]=[CH:22][CH:21]=[C:34]6[CH:33]=[CH:32][C:31]5=[CH:30][CH:29]=3)=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc(-c2cccc3ccccc23)cc1
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc2c(-c3ccc(-c4ccc5ccc6cccc7ccc4c5c67)cc3)cccc2c1
Yield: 99.3 %

Procedure:
7.4 g of 4-(naphthalene-1-yl)phenyl boronic acid prepared by a well known method and 7.0 g of conventional 1-bromopyrene were dissolved in 80 ml of dimethoxyethane (DME). Subsequently, 0.58 g of tetrakistriphenylphosphine palladium and 40 ml of 2M-sodium carbonate aqueous solution were added therein, followed by argon displacement. After heating and refluxing over 8 hours, it was stood to cool and then an organic layer was extracted therefrom by toluene. The organic layer was washed by saturated salt water, followed by drying through anhydrous sodium sulfate, and then the organic solvent was removed by an evaporator. The residue was refined through a silica gel chromatography (a developing solvent: toluene) and then 10.0 g of 1-(4-naphthalene-1-yl-phenyl) pyrene was obtained. (yield: 99%)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=O)[CH:8]([O:17][C:18]([O:20]C2C=CC=CC=2)=O)[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:32].C(O)(=O)C>O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:32][C:18](=[O:20])[O:17][C:8]=2[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(Cl)s1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CCCc1oc(=O)[nH]c1-c1ccc(Cl)s1
Yield: 58 %

Procedure:
A mixture of ethyl 6-(5-chloro-2-thienyl)-6-oxo-5-phenoxycarbonyloxyhexanoate (30.5 g), ammonium acetate (28.6 g) and acetic acid (100 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was poured into 500 ml of water, and the resulting solid precipitate was collected, washed with water and isopropyl ether and air-dried to give crystals of ethyl 4-[4-(5-chloro-2-thienyl)-2-oxo-4-oxazolin-5-yl]butanoate (13.6 g, 58%). Recrystallization from acetone-isopropyl ether gave pale yellow prisms. Melting point 95-96° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[N:18]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[C:17]3[CH:24]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=[CH:27][C:16]=3[N:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:23][O:22][CH2:21][CH2:20][CH2:19][N:18]1[C:17]2[CH:24]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=[CH:27][C:16]=2[N:15]=[C:14]1[CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COCCCn1c(C2CCCN(C(=O)OC(C)(C)C)C2)nc2ccc(C(=O)OC)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCn1c(C2CCCNC2)nc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
Methyl 2-(1-(tert-bu toxycarbonyl)piperidin-3-yl)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylate (43B) (3.10 mmol, 1.25 g) in DCM (10 mL) was added TFA (2 mL). The reaction solution was stirred at rt for 1 hr and then concentrated in vacuo. The residue was purified by preparative LC/MS (15-40% CH3CN in H2O) to afford methyl 1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole-6-carboxylate (43C) (1.48 mmol, 490 mg, yield: 47.7%). ESI-MS: m/z 332.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[Sn](CCCC)(CCCC)CCCC)([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33]([N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2Br)[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C1(PC2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:28]([O:32][C:33]([N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:27])[CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccc1NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2c(Br)cccc2C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(-c2ccccc2PC2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccncc1-c1cccc2c1CCN(C(=O)OC(C)(C)C)C2
Temperature: 100 °C
Reaction time: 24 h
Yield: 29.4 %

Procedure:
A mixture of (3-tributylstannyl-pyridin-4-yl)-carbamic acid tert-butyl ester (0.7 g, 1.44 mmol), 5-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.45 g, 1.44 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.066 g, 0.072 mmol) and 2-(cyclohexylphosphino)biphenyl (0.075 g, 0.216 mmol), in toluene was heated with stirring to 100° C. for 24 h. The solvent was evaporated and the residue purified by flash chromatography eluting with 50% ethyl acetate in hexanes to yield 0.18 g 5-(4-tert-butoxycarbonylamino-pyridin-3-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester).
Reaction SMILES: [Cl:1][C:2]1(Cl)[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]([CH3:14])[CH2:3]1.C([O-])(=O)C.[Na+].[H][H]>[Pd].C(O)(=O)C>[Cl:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]([CH3:14])[CH2:3]1
Reactant: CN1CC(Cl)(Cl)C(=O)Nc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CC(Cl)C(=O)Nc2ccccc21

Procedure:
A mixture of 3.06 g of 3,3-dichloro-5-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one, 30 ml of glacial acetic acid, 2.2 g of anhydrous sodium acetate and 86 mg of 5% palladium on charcoal is hydrogenated at atmospheric pressure until the theoretical amount of hydrogen has been absorbed. The suspension is filtered through celite and the solids are washed with 5 ml of acetic acid. Concentration of the filtrate and treatment of the residue with 17 ml of water for 30 min. affords 3-chloro-5-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[CH3:15][S:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)c1ccc2nc(S)oc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc2nc(SC)oc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
To a stirred mixture of methyl 2-mercaptobenzo[d]oxazole-6-carboxylate (5 g, 23.92 mmol) and solid K2CO3 (9.9 g, 71.76 mmol) in anhydrous DMF (50 mL) at rt was added methyl iodide (10.2 g, 71.76 mmol). The mixture was stirred at rt for 15 h. The reaction mixture was diluted with water then extracted with DCM (×3). The combined organic layers were washed with water and 2 M aq HCl. The organic layer was separated and dried over MgSO4, filtered, and concentrated under reduced pressure to afford methyl 2-(methylthio)benzo[d]oxazole-6-carboxylate (4.24 g, 80%) as a light pink solid that did not require further purification. 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=1.1 Hz, 1H), 8.04 (dd, J=1.1, 8.3 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 3.95 (s, 3H), 2.79 (s, 3H). LCMS (ESI) m/z 224 (M+H)+.