Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][NH2:14])[N:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH:23]([C:27](=O)[CH3:28])[C:24](=O)[CH3:25])=[CH:18][CH:17]=1>C(O)CC>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([S:22][C:23]2[C:24]([CH3:25])=[N:14][N:13]([C:9]3[N:8]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[N:12]=[CH:11][N:10]=3)[C:27]=2[CH3:28])=[CH:20][CH:21]=1
Reactant: NNc1ncnc(-c2ccccn2)n1
Reactant: CC(=O)C(Sc1ccc(Cl)cc1)C(C)=O
Solvent: CCCO
Product: Cc1nn(-c2ncnc(-c3ccccn3)n2)c(C)c1Sc1ccc(Cl)cc1
Temperature: 95 °C
Yield: 8 %

Procedure:
A stirred suspension of the product of step 3 (0.333 g, 1.77 mmol) and 3-(4-chloro-phenylsulfanyl)-pentane-2,4-dione (0.473 g, 1.95 mmol) in n-propanol was heated at 95° C. overnight. The reaction solution was concentrated directly onto silica and flash chromatographed (methylene chloride/methanol) to afford a dirty yellow solid. This material was further purified by trituration with diethyl ether to afford 0.056 g (8%) of product as a white solid: 1H NMR (DMSO-d6) δ 9.44 (s, 1H), 8.94-8.77 (m, 1H), 8.68-8.43 (m, 1H), 8.18-7.96 (m, 1H), 7.77-7.57 (m, 1H), 7.45-7.24 (m, 2H), 7.20-6.98 (m, 2H), 2.83 (s, 3H), 2.20 (s, 3H) ppm.
Reaction SMILES: [CH3:1][N:2]([C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=1)=[O:5])[NH2:3].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[BH3-]C#N.[Na+].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:3][N:2]([CH3:1])[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=2)=[O:5])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CSc1nccc(C(=O)N(C)N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCO
Product: CSc1nccc(C(=O)N(C)NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a stirred solution of 2-Methylsulfanyl-pyrimidine-4-carboxylic acid N-methyl-hydrazide, 15, (15 g, 75.8 mmol) in ethanol (60 mL) is added 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (15.1 g, 75.8 mmol). The reaction mixture is refluxed for 1.5 hour, cooled to room temperature and NaCNBH3 (7.14 g, 113.7 mmol) added. The pH of the reaction mixture is adjusted to 3 with concentrated HCl and the reaction mixture stirred for 3 hours at room temperature. The mixture is neutralized with saturated sodium bicarbonate and extracted three times with CH2Cl2 and the combined organic layers are dried (MgSO4), filtered and concentrated in vacuo. Purification over silica (EtOAc) affords 19.7 g (68% yield) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.70 (q, J=2.9 Hz, 1H), 7.36-7.27 (m, 2H), 2.61 (s, 1H), 4.16 (q, J=6.9 Hz, 1H), 3.97-3.78 (m, 2H), 3.37 (d, J=16 Hz, 3H), 2.91-2.79 (m, 2H), 2.61 (s, 3H), 1.93-1.89 (m, 2H), 1.70-1.65 (m, 2H), 1.48 (d, J=8 Hz), 9H); ESI/MS: 382.3 (M+H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5](=[O:26])[NH:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21])=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[CH:9][CH:8]=2.[CH3:27]OCCl.S(OC)(OC)(=O)=O.B(Br)(Br)Br>[Cl-].[NH4+].CN(C=O)C>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([OH:21])=[C:14]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:22]([F:23])([F:25])[F:24])[CH:11]=3)[NH:6][C:5](=[O:26])[C:4]=2[NH:3][CH3:27])[CH:19]=1
Reactant: Nc1c(-c2cc(Cl)ccc2O)c2cc(C(F)(F)F)ccc2[nH]c1=O
Reactant: COCCl
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CNc1c(-c2cc(Cl)ccc2O)c2cc(C(F)(F)F)ccc2[nH]c1=O
Reaction time: 8 h
Yield: 21 %

Procedure:
Sodium hydride (1.3 g, 27.9 mmol) was added to a solution of 3-amino-4-(5-chloro-2-hydroxyphenyl)-6-(trifluoromethyl)quinolin-2(1H)-one (4.7 g, 13.3 mmol) and dry DMF at ambient temperature under nitrogen. Neat chloromethyl methyl ether was added and the reaction was stirred overnight. The reaction was then diluted with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. Chromatography on silica gel was used to isolated a mixture of O,N- and O,O-bis methoxymethyl quinolones (3.24 g) from remaining starting material. The bis methoxymethyl mixture was dissolved in dry DMF and sodium hydride(375.4 mg, 8 mmol) was added at ambient temperature under nitrogen. Dimethyl sulfate(0.76 ml, 8.0 mmol) was added and the reaction was stirred for 1 hour. The reaction mixture was then diluted with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The crude material was taken up in dry methylene chloride and boron tribromide(1 M in methylene chloride, 2.1 eq) was added at ambient temperature under nitrogen. After 6 hours, the reaction mixture was quenched with saturated sodium bicarbonate and extracted with methylene chloride. The organic layer was combined, dried over magnesium sulfate, and concentrated. Chromatography on silica gel afforded 4-(5-chloro-2-hydroxyphenyl)-3-(methylamino)-6-(trifluoromethyl)quinolin-2(1H)-one (1.03 g, 21%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:39]>C(O)C>[ClH:39].[F:1][C:2]1[C:3]([CH2:23][NH:24][CH3:25])=[CH:4][N:5]([S:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)N2CCOCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cn(S(=O)(=O)N2CCOCC2)c(-c2cccnc2F)c1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
tert-Butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(morpholin-4-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (370 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 50° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from a mixed solvent of ethyl acetate-ethanol (9:1) to give the title compound as colorless crystals (yield 105 mg, 33%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([NH2:16])[CH:5]=1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([NH:16][S:26]([CH3:25])(=[O:28])=[O:27])[CH:5]=1
Reactant: COC(=O)c1cc(N)cc(N2CCCC2=O)c1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(NS(C)(=O)=O)cc(N2CCCC2=O)c1
Yield: 37.7 %

Procedure:
To a solution of 3-amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D4a) (200 mg, 0.85 mmol, 1 equiv) in CH2Cl2 (5 ml) and DMF (5 ml) was added NEt3 (0.181 ml, 1.3 mmol, 1.5 equiv) and methanesulphonyl chloride (0.071 ml, 1 mmol, 1.2 equiv). The resultant mixture was stirred at room temperature for 1 h, diluted with AcOEt (30 ml), washed with 2N aqueous HCl solution (30 ml), dried over MgSO4 and concentrated in vacuo. The residue was triturated with Et2O and then filtered to give 3-methanesulfonylamino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B53) as a pale yellow solid (100 mg, 38%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][C:14]#[N:15])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N:26]2[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]2)[CH:25]=1)[C:20](O)=[O:21].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[C:14]([CH2:13][O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[C:24]([N:26]3[CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH2:31]3)[CH:25]=[C:17]([F:16])[CH:18]=2)=[CH:3][CH:4]=1)#[N:15]
Reactant: CC1CCN(c2cc(F)cc(C(=O)O)c2)CC1
Reactant: N#CCOc1ccc(N)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(OCC#N)c4ccccc34)c2)CC1
Yield: 18.1 %

Procedure:
(4-Aminonaphthalen-1-yloxy)-acetonitrile (1.068 g, 5.4 mmol), 3-fluoro-5-(4-methylpiperidin-1-yl)-benzoic acid (1.27 g, 5 4 mmol), diisopropylethylamine (3 ml) and HBTU (2.45 g, 6.5 mmol) are stirred at room temperature in anhydrous dimethylformamide (20 ml) for 1 day. The mixture is then poured into ethyl acetate (200 ml) and washed with water (2×200 ml). The organic layer is then dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with 25-30% ethyl acetate in hexanes to give a pale purple solid. This is then recrystalized from ethyl acetate/methanol to give N-(4-cyanomethoxynaphthalen-1-yl)-3-fluoro-5-(4-methylpiperidin-1-yl)-benzamide as a pale purple solid (303 mg). 1H NMR 300 MHz (CDCl3) 8.27(d, 1H, J=7.5 Hz), 7.94(s, 1H), 7.86(t, 2H, J=9.6 Hz), 7.6(m, 2H), 7.3(s, 1H), 6.97(m, 2H), 6.77(d, 1H, J=11.4 Hz), 5.0(s, 1H), 3.77(m, 2H), 2.83(m, 2H), 1.75(m, 2H), 1.25-1.4(m, 3H), 1.0(d, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:7]=2)[CH:3]=1.CC(C)([O-])C.[Na+].C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.[NH:72]1[CH2:77][CH2:76][O:75][CH2:74][CH2:73]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:15]2([CH2:14][O:13][CH:11]([C:9]3[C:8]4[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:7]=4)[CH:3]=[C:2]([N:72]4[CH2:77][CH2:76][O:75][CH2:74][CH2:73]4)[CH:10]=3)[CH3:12])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:29][CH:30]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(N2CCOCC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 100 °C

Procedure:
(±)-tert-Butyl 4-((1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (75 mg, 0.113 mmol), sodium tert-butoxide (16.3 mg, 0.17 mmol), and palladium(II)acetate (1.02 mg, 4.53 μmol) were combined in toluene (2 mL) and treated with 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (3.1 mg, 9.05 μmol) and morpholine (0.012 mL, 0.136 mmol) in a microwave tube and sealed. After flushing the mixture with nitrogen, the mixture was heated at 100° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated, dissolved in ethyl acetate, washed with water and brine, concentrated, and purified by flash chromatography on silica gel (30% EtOAc/Hex) to afford 44 mg (58%) as an oil. LC/MS (HPLC method 2): tR=3.185 min, 669.25(MH)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:16]3[C:11](=[CH:12][C:13]([CH3:25])=[CH:14][CH:15]=3)[N:10]=2)=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH:26][C@H:27]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:28](O)=[O:29].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:28](=[O:29])[C@H:27]([OH:26])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:21][CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:25])=[CH:14][CH:15]=2)[N:10]=1
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3c(O)cccc3F)nc2c1
Reactant: CC(C)(C)C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)(C)C)CC3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 49.5 %

Procedure:
3-Fluoro-2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.74 mmol) was suspended in anhydrous DMF (5 mL) and cooled to 0° C. (internal temperature). Under an N2 atmosphere, (R)-2-hydroxy-4,4-dimethylpentanoic acid (118.4 mg, 0.81 mmol) was added followed by triethylamine (0.207 mL, 1.48 mmol). To this stirring solution was added HATU (337 mg, 0.888 mmol). After the complete addition of HATU, the mixture was allowed to warm to 10° C. After 45 min the reaction was complete, and it was quenched with an equal portion of ice water. A yellow precipitate formed which was collected by vacuum filtration, dissolved in CH2Cl2, and the CH2Cl2 solution was desiccated with Na2SO4, filtered, and concentrated to a viscous yellow-orange oil. The crude material was purified via silica gel chromatography using 70% CH2Cl2/hexanes (1:1) and 30% EtOAc to afford (R)-1-(4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-one as a yellow solid (171 mg, 50%). LC/MS: m/z 467.1 (M+H)+ at 2.63 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J=8.6 Hz, 1H), 7.69 (s, 1H), 7.43 (dd, J=8.6, 1.5 Hz, 1H), 7.37-7.32 (m, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.76-6.71 (m, 1H), 4.87 (d, J=7.2 Hz, 1H), 4.47-4.43 (m, 1H), 4.01-3.75 (m, 8H), 2.52 (s, 3H), 1.55 (dd, J=14.3, 3.0 Hz, 1H), 1.40 (dd, J=14.3, 8.8 Hz, 1H), 0.96 (s, 9H)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][P:5]([CH2:13][C:14](O)=[O:15])([O:7][CH2:8][C:9]([F:12])([F:11])[F:10])=[O:6].[N:19]1[CH:24]=CC=C[CH:20]=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.CNC>C(OCC)(=O)C>[CH3:20][N:19]([CH3:24])[C:14](=[O:15])[CH2:13][P:5](=[O:6])([O:7][CH2:8][C:9]([F:12])([F:11])[F:10])[O:4][CH2:3][C:2]([F:18])([F:17])[F:1]
Reactant: c1ccncc1
Reactant: O=C(O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CNC
Solvent: CCOC(C)=O
Product: CN(C)C(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Bis-(2,2,2-trifluoroethyl)phosphonoacetic acid (0.07 mol) was dissolved in 100 ml of ethyl acetate. To this solution 5.6 g of pyridine (0.07 mol) were added, followed by 20.4 g (0.093 mol) of Boc anhydride. The mixture was stirred for 15 min and anhydrous dimethylamine (0.07 mol) was added. The mixture was stirred overnight. The mixture was stirred for 1 h at 5° C., and worked-up. Following distillation bis(2,2,2-trifluoroethyl) 2-(dimethylamino)-2-oxoethylphosphonate was obtained in 80% yield.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]4)[CH2:15]2)[CH2:21]3)=[N:11][CH:12]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:33]=1[C:34](Cl)=[O:35]>O>[C:14]12([O:13][C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:34](=[O:35])[C:33]4[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:32]=4[Cl:31])=[CH:12][N:11]=3)[CH2:15][CH:16]3[CH2:22][CH:20]([CH2:19][CH:18]([CH2:17]3)[CH2:23]1)[CH2:21]2
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)nc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(OC23CC4CC(CC(C4)C2)C3)nc1)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To 5 mL of a tetrahydrofuran solution comprising 290 mg of 5-amino-2-(1-adamantyloxy)pyridine) and 150 mg of triethylamine, 5 mL of a tetrahydrofuran solution comprising 260 mg of 2-chloro-5-nitrobenzoylchloride was dropwise added, followed by stirring for about 30 minutes, and then water was added, and the precipitated crystals were collected by filtration. The collected crystals were washed with water and then dried to obtain 330 mg of N-(2-(1-adamantyloxy)-5-pyridyl)-2-chloro-5-nitrobenzamide (Compound No. 123) having a melting point of from 98 to 105° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[CH:28]([Sn](CCCC)(CCCC)CCCC)=[CH:29][C:30](=C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>CN(C=O)C.[Pd].ClCCl.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:29]([C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])([CH3:30])[CH3:28]
Reactant: C=C(C)C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(C(C)C)c3)nc12

Procedure:
From 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide with isoprenyltri-n-butyltin, bis(triphenylphosphine)palladium(II) chloride, triphenylphosphine, lithium chloride and 2,6-di-tert-butyl-para-cresol in DMF, then hydrogenation with palladium on charcoal in dichloromethane and methanol. ES-MS m/e (%): 412 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][C:11]([CH3:16])=[CH:12][C:13](O)=[O:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:10])[O:9]2)=[CH:7][CH:8]=1
Reactant: CC(C)=CC(=O)O
Reactant: COc1cccc(O)c1
Product: COc1ccc2c(c1)OC(C)(C)CC2=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
The title compound was synthesized by referring to Chem. Pharm. Bull., 1977, 25, 2788. To 3-methoxyphenol (8.5 g) and 3,3-dimethylacrylic acid (7.5 g) was added polyphosphoric acid (80 ml), and the solution was stirred for 2 hours at 100° C. The reaction mixture was poured into an ice water, the solution was stirred, and then extracted with diethyl ether, then sequentially washed with an aqueous solution of 2N sodium hydroxide, water and brine, dried over anhydrous magnesium sulfate, then filtered through NH silica gel, and the solvent was evaporated in vacuo. The residue was washed with a hexane-diethyl ether system to provide the title compound (10.6 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][CH2:11][NH:10][C:9]1=[O:14].Br[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C:9]1=[O:14]
Reactant: Cc1ccncc1N1CCCNC1=O
Reactant: Brc1ccc2ccccc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCCN(c2ccc3ccccc3c2)C1=O
Yield: 26.1 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-tetrahydro-pyrimidin-2-one (I-130b: 150 mg, 0.785 mmol) was reacted with 2-bromo-naphthalene (195 mg, 0.942 mmol), 1,4-dioxane (20 mL), copper iodide (15 mg, 0.078 mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.235 mmol) and potassium phosphate (415 mg, 1.96 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in CHCl3), followed by recrystallization using DCM and hexane afforded 65 mg of the product (26.2% yield).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=2)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9](COCC[Si](C)(C)C)[N:8]=1.[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:32]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O.C(O)(C(F)(F)F)=O>O1CCOCC1.C(Cl)Cl.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].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>[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:32]=1[C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=2)[S:5][C:6]=1[C:7]1[NH:11][CH:10]=[N:9][N:8]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: CC(=O)Nc1cc(-c2nc(Br)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(-c2nc(-c3c(C)cccc3C)c(-c3nnc[nH]3)s2)ccn1
Temperature: 140 °C
Yield: 7.5 %

Procedure:
The mixture of N-{4-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.0340 g, 0.0686 mmol), 2,6-dimethylphenylboronic acid (20.6 mg, 0.137 mmol), tetrakis(triphenylphosphine)palladium (0) (9.1 mg, 0.0073 mmol), and 2 M sodium carbonate in water (0.0850 mL, 0.170 mmol) in 1,4-dioxane (2.0 mL) in capped vial was heated to 140° C. for 19 hours. Additional tetrakis(triphenylphosphine)palladium(0) (7.1 mg, 0.0057 mmol) was added and the mixture was heated to 140° C. for 1 additional day. The mixture was filtered through celite/Na2SO4, washed with EtOAc, and evaporated under reduced pressure to give a crude intermediate. The material was treated with TFA (2.0 mL, 26 mmol) in dry DCM (2.0 mL) for 5 hours. The solvent was evaporated under reduced pressure and azeotroped with toluene to give a crude product. HPLC purification gave 0.002 g of pure product as a white powder (7.5%). LCMS: (FA) ES+ 391 and ES− 389. 1H NMR (400 MHz, d4-Methanol) δ 8.73 (s, 1H), 8.40 (d, J=5.84 Hz, 1H), 8.35 (s, 1H), 7.68 (d, J=5.84 Hz, 1H), 7.20 (m, 1H), 7.11 (s, 1H), 7.09 (d, J=7.35 Hz, 1H), 2.21 (s, 3H), 2.03 (s, 6H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[N:11]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:57]#[N:58])[C:12]2[C:17]([C:18]=1[CH2:19][N:20]1[C:31](=[O:32])[C@@H:30]([NH:33][C:34](=[O:46])[C@@H:35]([N:37](C)[C:38](=O)OC(C)(C)C)[CH3:36])[C:24]3([CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[O:23][C:22]3[CH:47]=[CH:48][CH:49]=[CH:50][C:21]1=3)=[CH:16][CH:15]=[CH:14][CH:13]=2)#[N:9].C([O-])(O)=O.[Na+].O>C(Cl)Cl>[C:8]([C:10]1[N:11]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:57]#[N:58])[C:12]2[C:17]([C:18]=1[CH2:19][N:20]1[C:31](=[O:32])[C@@H:30]([NH:33][C:34](=[O:46])[C@@H:35]([NH:37][CH3:38])[CH3:36])[C:24]3([CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[O:23][C:22]3[CH:47]=[CH:48][CH:49]=[CH:50][C:21]1=3)=[CH:16][CH:15]=[CH:14][CH:13]=2)#[N:9]
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2c(C#N)n(-c3ccccc3C#N)c3ccccc23)c2ccccc2OC12CCOCC2)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C#N)n(-c3ccccc3C#N)c3ccccc23)c2ccccc2OC12CCOCC2
Yield: 99.4 %

Procedure:
TFA (37.0 g, 25 mL, 324 mmol, Eq: 55.9) was added dropwise over 2 h to a solution of tert-butyl (S)-1-((S)-5-((2-cyano-1-(2-cyanophenyl)-1H-indol-3-yl)methyl)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (4 g, 5.81 mmol) in DCM (50 mL) at 0° C. After 30 min. the mixture was added to sat. NaHCO3/H2O 1:1, the organic phase was separated, dried over Na2SO4, filtered and concentration to give the title compound (3.4 g, 97%) as a light yellow solid. MS m/z 589 (MH+)