Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][N:11]=[C:10]([C:15]#[C:16][CH:17]([OH:19])[CH3:18])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)#[CH:21].C(N(CC)CC)C>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.CN1CCCC1=O>[CH2:1]([C:8]1[C:13]([C:21]#[C:20][C:22]2([OH:30])[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[CH:12][N:11]=[C:10]([C:15]#[C:16][CH:17]([OH:19])[CH3:18])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)C#Cc1cc(Cc2ccccc2)c(Br)cn1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(O)C#Cc1cc(Cc2ccccc2)c(C#CC2(O)CN3CCC2CC3)cn1
Reaction time: 1 h

Procedure:
110 mg of 4-benzyl-5-bromo-2-(3-hydroxy-1-butynyl)pyridine, 53 mg of 3-ethynyl-3-quinuclidinol, 50 mg of tetrakis(triphenylphosphine)palladium(0), 7 mg of cuprous iodide and 0.5 ml of triethylamine were added to 2 ml of 1-methyl-2-pyrrolidinone, followed by stirring for one hour in an oil bath kept at 100° C. After cooling as it was, it was evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 5% methanol/ethyl acetate, to synthesize 32 mg of the target compound.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH3:20])=[N:18][C:12]=2[O:11][C@@H:10]([CH2:25][O:26][CH3:27])[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:34]>CO.[OH-].[OH-].[Pd+2]>[ClH:34].[CH:21]1([N:19]([CH3:20])[C:17]2[CH:16]=[N:15][C:13]3[CH2:14][NH:8][CH2:9][C@H:10]([CH2:25][O:26][CH3:27])[O:11][C:12]=3[N:18]=2)[CH2:22][CH2:23][CH2:24]1
Reactant: COC[C@H]1CN(Cc2ccccc2)Cc2ncc(N(C)C3CCC3)nc2O1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC[C@H]1CNCc2ncc(N(C)C3CCC3)nc2O1
Temperature: 50 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a solution of (6R)-8-benzyl-N-cyclobutyl-6-(methoxymethyl)-N-methyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (390 mg) in methanol (10 mL) was added 20% Pd(OH)2/C (50 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 6 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the obtained crude product in ethyl acetate (10 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (291 μL), and the mixture was stirred for 5.5 hr. The reaction mixture was filtered, and the obtained crystals were washed with ethyl acetate to give the title compound (206 mg, 62%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:8]2[C:21]([Br:24])=[CH:22][S:23][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-]>CO.C1COCC1>[Br:24][C:21]1[C:8]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=3)[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[S:23][CH:22]=1
Reactant: COC(=O)c1cc2scc(Br)c2n1Cc1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2scc(Br)c2n1Cc1ccc(C(F)(F)F)cc1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
To a solution of the crude product of Step 3 (4 g) in 50 ml of 1:1 MeOH/THF was added 25 ml of 1N aqueous LiOH solution. The reaction mixture was stirred at 55° C. for 4 h and the concentrated under reduced pressure to move the volatile solvent. The resulting aqueous solution was treated with 5 ml of AcOH and stirred for 2 h. The solid was collected by filtration to give 3.2 of the title compound as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([C:9]([CH2:12][CH2:13]I)([F:11])[F:10])([F:8])[F:7])([F:4])([F:3])[F:2].CNC=[O:18].O>CCOCC>[C:1]([O:5][C:6]([C:9]([CH2:12][CH2:13][OH:18])([F:11])[F:10])([F:8])[F:7])([F:4])([F:3])[F:2]
Reactant: FC(F)(F)OC(F)(F)C(F)(F)CCI
Reactant: CNC=O
Solvent: O
Solvent: CCOCC
Product: OCCC(F)(F)C(F)(F)OC(F)(F)F
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
A mixture of CF3OCF2CF2CH2CH2I, (92 g, 0.27 mol) and N-methyl-formamide (119 mL), was heated to 150° C. for 26 hours. Then the reaction was cooled to 100° C., followed by the addition of water to separate the crude ester. Ethyl alcohol (30 mL) and p-toluene sulfonic acid (1.03 g) were added to the crude ester, and the reaction was stirred at 70° C. for 15 minutes. Then ethyl formate and ethyl alcohol were distilled out to give a crude product. The crude product was dissolved in ether, washed with aqueous sodium sulfite, water, and brine in turn, then dried over magnesium sulfate. The product was then distilled to give 44 g of CF3OCF2CF2CH2CH2OH (compound B1) in 71% yield.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:32]([O:39][CH2:40]Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:17]1([CH2:16][C@H:15]([CH2:40][O:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:14]([N:9]2[C@@H:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12][O:11][C:10]2=[O:13])=[O:22])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: ClCOCc1ccccc1
Reactant: O=C(CCC1CCCC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](COCc1ccccc1)CC1CCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71.8 %

Procedure:
To a solution of (4S)-benzyl-3-(3-cyclopentylpropanoyl)oxazolidin-2-one (42.4 g, 141 mmol) in dichloromethane (500 mL) at 0° C. under nitrogen was added titanium (IV) chloride (1 M in DCM, 155 mL, 155 mmol) in a slow steady stream. After 5 min, diisopropylethylamine (27 mL, 155 mmol) was added dropwise. After stirring at 0° C. for 1 h, benzyloxymethylchloride (TCI-America) (39 mL, 280 mmol) was added in a slow steady stream to the resulting titanium enolate, and the mixture was maintained at 0° C. for 3.5 h. The reaction mixture was then quenched with water (400 mL). The aqueous layer was extracted with dichloromethane (150 mL×2). The organic extracts were washed with saturated NaHCO3, were dried (MgSO4) and were evaporated. The residue was washed with ether (2×), and then was triturated with hexanes/ether to provide 2 crops of (4S)-3-((2R)-3-cyclopentyl-2-{[(phenylmethyl)oxy]methyl}propanoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one as a pale yellow solid (42.7 g, 72%). LCMS: (M+H)+: 422.2.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1)(=[O:10])[CH3:9].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:8]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:10])[CH3:9]
Reactant: Ic1cccnc1
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CC(=O)Nc1ccc(Sc2cccnc2)cc1
Yield: 82.7 %

Procedure:
The general procedure in example 39 was followed. 3-Iodopyridine (205 mg, 1.0 mmol), 4-acetamidothiophenol (167 mg, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 3-(4-acetamidophenyl)sulfanylpyridine (202 mg, 83% yield) as white solid. Column chromatographic solvent (ethyl acetate). Rf=0.4 (ethyl acetate). Melting point; 138-140° C. 1H NMR (CDCl3, 300 MHz) δ 8.42 (d, 1 H, J=1.8 Hz), 8.38 (dd, 1 H, J=0.9 Hz, 4.5 Hz), 8.29 (s, 1 H), 7.52 (d, 2 H, J=8.7 Hz), 7.35 (d, 2 H, J=8.4 Hz), 7.18 (dd, 1 H, J=3.0 Hz, 7.8 Hz), 2.17 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 169.0, 149.5, 147.1, 138.9, 136.8, 135.3, 134.0, 127.3, 124.2, 120.9, 24.9. IR (neat, cm−1) 3286, 3245, 3176, 3105, 2360, 2342, 1650. MS (EI) m/z (relative intensity) 244 (100), 202 (100). Anal. Cald. for C13H12N2OS, Cald. C: 63.91, H: 4.95; Found C: 63.80, H: 4.93.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:17])=[C:12]([C:14](=O)[CH3:15])[CH:13]=1.C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:17])=[C:12]([C:14]([CH3:1])=[CH2:15])[CH:13]=1
Reactant: CC(=O)c1cc(Br)ccc1F
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (58.92 g, 162 mmol) in tetrahydrofuran (400 ml) was treated at room temperature with potassium tert-butylate (18.51 g, 162 mmol), and the mixture was stirred for 30 minutes. While cooling with ice, a solution of 1-(5-bromo-2-fluoro-phenyl)-ethanone [CAS No. 198477-83-3] (29.23 g, 135 mmol) in tetrahydrofuran (50 ml) was added. Thereafter, the mixture was warmed to room temperature and stirred for 1.5 hours. For the workup, the mixture was treated with ethyl acetate (650 ml) extracted with water (450 ml). The organic layer was separated, washed with brine (220 ml), dried over sodium sulfate and evaporated at reduced pressure. After chromatography on silica gel using a mixture of hexane and ethyl acetate as the eluent, the 4-bromo-1-fluoro-2-isopropenyl-benzene (intermediate C2A) was obtained as a yellow oil (28.49 g, 98% of theory). Rf: 0.7 (silica gel; eluent: heptane).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(N1[C:18](=[O:19])[CH:17]=[CH:16][C:15]1=[O:20])(OC)=O.S(=O)(=O)(O)O>C(=O)(O)[O-].[Na+].O>[CH:16]1[C:15](=[O:20])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:18](=[O:19])[CH:17]=1
Reactant: NCCCCCC(=O)O
Reactant: COC(=O)N1C(=O)C=CC1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A solution of 4.2 g (32.3 mmol) of 6-aminocaproic acid in 163 ml of saturated sodium bicarbonate solution is treated at 0° C., with vigorous stirring, with 5 g (32.3 mmol) of N-carbomethoxymaleimide. After 1 hour, the solution is diluted with 256 ml of water and stirred at room temperature for 1 hour. The pH of the solution (8.2) is then brought to 6.4 by adding concentrated sulfuric acid. The solution is then concentrated to 100 ml and acidified to pH 2 by adding 1 M sulfuric acid, and is extracted three times with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue is purified by chromatography on a silica column (elution: chloroform/acetic acid, 95:5). In this manner, 4.7 g of N-maleoyl-6-aminocaproic acid are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:22]1[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[C:24]([CH3:32])[N:23]=1.C(N(C(C)C)CC)(C)C>>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:22]3[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[C:24]([CH3:32])[N:23]=3)[CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC)nc1Cl
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)cc(C(=O)OC)n3)C[C@H]2OC)nc1Cl
Yield: 49.5 %

Procedure:
The same operation as in Example (158a) was performed using cis(±)-4-chloro-5-ethyl-N-(3-methoxypiperidin-4-yl)-1H-imidazole-2-carboxamide hydrochloride obtained in Example (159a) (90.9 mg, 0.28 mmol), methyl 2-chloro-6-methylpyrimidine 4-carboxylate (50 mg, 0.27 mmol) and diisopropylethylamine (104 mg, 0.8 mmol), to obtain 58.4 mg of the title compound as a yellow brown oily substance (50%).
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:41][CH3:42])[C:24]([Cl:43])=[CH:23][N:22]=1>>[Cl:43][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:41][CH3:42])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CNC(=O)CN1CCc2cc(N)c(OC)cc2CC1
Product: CNC(=O)CN1CCc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCN(C)CC5)cc4OC)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.005 g, 10%). MP: 82-100° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.20 (d, 1H, J=8.8 Hz), 8.12 (s, 1H), 8.02 (s, 1H), 7.50 (s, 1H), 7.44 (s, 1H), 7.39-7.31 (m, 1H), 6.63 (s, 1H), 6.56 (d, 1H), J=2.0 Hz), 6.50 (dd, 1H, J=8.7 and 2.4 Hz), 3.91 (s, 3H), 3.86 (s, 3H), 3.23-3.16 (m, 4H), 3.11 (s, 2H), 2.90 (d, 3H, J=5.1 Hz), 2.88-2.83 (m, 2H), 2.83-2.78 (m, 2H), 2.72-2.65 (m, 4H), 2.65-2.58 (m, 4H), 2.38 (s, 3H). MS: 595 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18]#[N:19])=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:22]=[CH:21][S:20][C:7]=12.[ClH:23].[OH-].[Na+]>O1CCCC1>[ClH:23].[NH2:19][CH2:18][C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2](=[O:1])[N:3]2[C:8]=1[C:7]1[S:20][CH:21]=[CH:22][C:6]=1[CH2:5][CH2:4]2
Reactant: N#Cc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Temperature: 25 °C

Procedure:
A solution of 1.5 g of 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carbonitrile in 15 ml of tetrahydrofuran was treated with 20 ml of a 1M BH3 /tetrahydrofuran solution and stirred at room temperature until the reaction was finished. The mixture was then acidified cautiously with 2N hydrochloric acid while cooling with ice, heated to boiling for a short time and made alkaline with 2N sodium hydroxide solution. The tetrahydrofuran was removed in vacuo and the aqueous residue was extracted with chloroform. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with chloroform/methanol (19:1). After treatment with methanolic hydrochloric acid. there was obtained pure 10-(aminomethyl)-4,5-dihydro-8-phenyl-7H-thieno[2,3-a]quinolizin-7-one hydrochloride of m.p. 254°-255°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:17]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:29].[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:17]=2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1cccc(CCN2CCCC2)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1cccc(CCN2CCCC2)c1
Yield: 94.8 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{3-[2-(pyrrolidin-1-yl)ethyl]phenylamino}-1,5-naphthyridin-3-yl)ethanone (59 mg, 0.15 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (63 mg, 72%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.30 (s, 1H), 8.43 (d, J=9.0 Hz, 1H), 8.34 (d, J=8.9 Hz, 1H), 7.54-7.30 (m, 4H), 7.23 (br s, 1H), 7.13 (br s, 1H), 3.68-3.60 (m, 2H), 3.35-3.23 (m, 2H), 3.11-2.99 (m, 4H), 2.80 (br s, 3H), 2.19-2.07 (m, 2H), 2.05-1.96 (m, 2H); ESI MS m/z 505 [M+H]+; HPLC>99% (AUC), tR=10.17 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.[Li]CCCC.[CH2:19]([O:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][C:30]([CH2:35][CH:36]=[O:37])=[CH:29][C:28]=1[O:38][CH3:39])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([O:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][C:30]([CH2:35][C:36]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]3)=[O:37])=[CH:29][C:28]=1[O:38][CH3:39])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)C=Cc2cc(Br)ccc2O1
Reactant: COc1cc(CC=O)cc(OC)c1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(CC(=O)c2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 20 %

Procedure:
To a cooled (−78° C.) stirring solution of 6-bromo-2,2-dimethyl-2H-chromene, which was prepared according to Chemistry and Biology, 2000, Vol. 7, p. 979, (567.7 mg, 2.38 mmol) in THF (7 mL) was added n-BuLi (2.88 M, 0.94 mL, 2.71 mmol). After completion of addition, the reaction mixture continued to stir at −78° C. After 25 minutes, (4-benzyloxy-3,5-dimethoxy-phenyl)-acetaldehyde (619.6 mg, 2.17 mmol) dissolved in THF (7.0 mL) was added. After completion of addition the reaction continued to stir for 15 minutes and was then quenched with saturated ammonium chloride. The aqueous layer was separated and extracted with ethyl acetate. All Combined organic layers were dried over sodium sulfate, filtered, and concentrated to yield a crude oil. The crude material was purified by silica gel chromatography (3:1 ethyl acetate:hexanes) to yield the desired product (200.5 mg, 20% yield).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37]>CN(C)C=O>[CH3:5][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH2:3][CH2:2][S:1][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37]
Reactant: CC(C)(CCS)NC(=O)OCc1ccccc1
Reactant: COCCOCCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOCCOCCOCCSCCC(C)(C)NC(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 98.4 %

Procedure:
To a solution of benzyl 4-mercapto-2-methylbutan-2-ylcarbamate (20 mmol) in N,N-dimethylformamide (20 ml) was added cesium carbonate (6.49 g, 19.9 mmol) and 13-bromo-2,5,8,11-tetraoxatridecane (5.00 g, 18.4 mmol). The solution was stirred for 16 hours, concentrated in vacuo, and the residue dissolved in 500 ml ethylacetate, washed with 3 times with 100 ml 5% NaHSO4, 1×200 ml sat. NaCl, dried on MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography (10% to 60% ethylacetate in hexanes) to give the titled compound as a clear oil (7.47 g, 18.1 mmol, 98%). 1H NMR (400 MHz, CDCl3) δ 1.31 (s, 6H), 1.95-1.99 (m, 2H), 2.51-2.55 (m, 2H), 2.69-2.73 (m, 2H), 3.38 (s, 3H), 3.54-3.58 (m, 2H, 3.6-3.7 (m, 14H), 4.77 (br s, 1H), 5.06 (s, 2H), 7.3-7.4 (m, 5H). LRMS (ESI/APCI): 466 [M+Na]+.
Reaction SMILES: [CH:1]([N:5]=[C:6]=[S:7])([CH2:3][CH3:4])[CH3:2].[Cl:8][C:9]1[C:10]([CH3:17])=[C:11]([NH:15][NH2:16])[CH:12]=[CH:13][CH:14]=1>C1(C)C=CC=CC=1>[Cl:8][C:9]1[C:10]([CH3:17])=[C:11]([NH:15][NH:16][C:6]([NH:5][CH:1]([CH3:2])[CH2:3][CH3:4])=[S:7])[CH:12]=[CH:13][CH:14]=1
Reactant: CCC(C)N=C=S
Reactant: Cc1c(Cl)cccc1NN
Solvent: Cc1ccccc1
Product: CCC(C)NC(=S)NNc1cccc(Cl)c1C

Procedure:
1.44 g (10 mmole) of sec-butyl isothiocyanate were added to 1.56 g (10 mmole) of 3-chloro-2-methylphenyl hydrazine dissolved in 120 ml of toluene, and the mixture was refluxed for 2 hours and then evaporated. The remanence was stirred with a small amount of hexane, separated by filtration and dried.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=1[CH3:14].[CH3:15][Mg]Br>O1CCCC1.O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([CH3:15])([OH:13])[CH3:12])=[CH:4][C:3]=1[CH3:14]
Reactant: C[Mg]Br
Reactant: CC(=O)CCc1cc(C)c(Br)c(C)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(CCC(C)(C)O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-bromo-3,5-dimethylphenyl)butan-2-one (100 mg) in tetrahydrofurane (2 mL) is added at 0° C. methylmagnesium bromide (840 μL of a 1.4 M solution in tetrahydrofurane/toluene 1:3). The mixture is stirred for 2 hours while warming to room temperature and then partitioned between saturated aqueous NH4Cl solution and diethylether. The organic phase is dried (MgSO4) and concentrated to give the title compound. Yield: 105 mg; LC (method 8): tR=0.47 min; Mass spectrum (ESI+): m/z=271 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1>>[N:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)[CH:22]=[N:21][CH:20]=1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: OB(O)c1cncnc1
Product: c1ncc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cn1

Procedure:
The title compound was prepared from the product of Example 65A and pyrimidin-5-ylboronic acid according to General Method B: LC-MS Method B (ESI+) m/z 308.0 (M+H)+, retention time 1.45 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8](P(OC)(OC)=O)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1.[CH3:30][C:31]1([CH3:42])[O:35][C:34]2[CH:36]=[CH:37][C:38]([CH:40]=O)=[CH:39][C:33]=2[O:32]1>C(Cl)Cl.[Cl-].[NH4+]>[C:1]([O:5][C:6](/[C:8](=[CH:40]\[C:38]1[CH:37]=[CH:36][C:34]2[O:35][C:31]([CH3:42])([CH3:30])[O:32][C:33]=2[CH:39]=1)/[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: CC1(C)Oc2ccc(C=O)cc2O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)/C(=C/c1ccc2c(c1)OC(C)(C)O2)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of methyl 2-(tert-butoxycarbonyl)-2-(dimethoxyphosphoryl)acetate (5255 mg, 17678 μmol) in 25 mL of DCM at 0° C. was added DBU (2665 μl, 17678 μmol) dropwise. To the mixture was then added a solution of 2,2-dimethylbenzo[d][1,3]dioxole-5-carbaldehyde (3000 mg, 16836 μmol) in 10 mL of DCM over 5 minutes so as to maintain internal temperature below 10° C. The reaction was warmed to rt and stirred overnight before being diluted with DCM (25 mL) and poured in saturated ammonium chloride (100 mL). The aqueous layer was extracted with DCM (1×50 mL). The combined organic layers were washed with 10% aqueous sodium bicarbonate then water then brine and dried over Na2SO4. Concentration under reduced pressure and purification by silica gel provided (Z)-methyl 2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)acrylate (5005 mg, 85.1% yield) as a white solid.