Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9](C(OC(C)(C)C)=O)[C:10]2[C:15]([C:16]=1[CH:17]([CH:19]1[C:23](=O)N(C(OC(C)(C)C)=O)[N:21]([CH:32]3C4CC5CC(C[CH:33]3C5)C4)[CH2:20]1)O)=[C:14]([Cl:42])[CH:13]=[C:12]([Cl:43])[CH:11]=2)=[O:7])(C)(C)C.[OH2:51].[OH-].[Li+]>C(O)C>[Cl:42][C:14]1[CH:13]=[C:12]([Cl:43])[CH:11]=[C:10]2[C:15]=1[C:16](/[CH:17]=[C:19]1/[C:20](=[O:51])[NH:21][CH2:32][CH2:33][CH2:23]/1)=[C:8]([C:6]([OH:5])=[O:7])[NH:9]2
Reactant: CC(C)(C)OC(=O)c1c(C(O)C2CN(C3C4CC5CC(C4)CC3C5)N(C(=O)OC(C)(C)C)C2=O)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C1NCCC/C1=C\c1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12
Reaction time: 0.5 h
Yield: 176.8 %

Procedure:
Example 4 (490 mg) and lithium hydroxide monohydrate (200 mg) were dissolved in ethanol (95%) (20 ml) and the resulting solution refluxed for 1.5 h. The solvent was evaporated and the residue treated at 50° with 6 M hydrochloric acid for 30 min, then at room temperature for further 30 min. The resulting white solid was filtered, washed and vacuum dried to yield the title compound (400 mg) as a white solid.
Reaction SMILES: CO[C:3](=O)[CH2:4][C:5]1[C:6]([CH3:21])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[CH2:23]([O:25][C:26](=[O:36])CCC1C(C)=NNC=1C)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:36])[CH2:3][CH2:4][C:5]1[C:6]([CH3:21])=[N:7][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[C:9]=1[CH3:10])[CH3:24]
Reactant: CCOC(=O)CCc1c(C)n[nH]c1C
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2)c1C
Product: CCOC(=O)CCc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2)c1C

Procedure:
Intermediate 8.1.1 can be prepared according to the method described for intermediate 1.1.2, employing in the alkylation reaction 3-(3,5-dimethyl-1H-pyrazol-4-yl)-propionic acid ethyl ester (Akos, MFCD03834497) instead of (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([OH:27])[CH3:26])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
To a solution of 1-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)propan-2-one (0.076 g, 0.20 mmol) in methanol (5 mL) was added sodium borohydride (0.015 g, 0.40 mmol). The mixture stirred at rt for 30 min. After this time, the mixture was diluted with a saturated solution of NaHCO3 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.015 g, 20%) as a white solid. MW=378.89. 1H NMR (DMSO-d6, 500 MHz) δ 8.07 (s, 1H), 7.91-7.88 (m, 1H), 7.76-7.72 (m, 1H), 7.46-7.39 (m, 2H), 7.22-7.15 (m, 5H), 4.53 (d, J=4.5 Hz, 1H), 3.87-3.79 (m, 1H), 2.90 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.71-2.65 (m, 1H), 2.58-2.53 (m, 1H), 2.08 (quin, J=7.5 Hz, 2H), 1.05 (d, J=6.0 Hz, 3H); APCI MS m/z 379 [M+H]+.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:18])[C@:11]([CH2:15][O:16][CH3:17])([CH3:14])[CH:12]=[CH2:13])([CH3:3])[CH3:2].Br[C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([C@H:30]([O:32][C:33](=[O:35])[CH3:34])[CH3:31])=[N:27]2)=[CH:22][CH:21]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:18])[C@:11]([CH2:15][O:16][CH3:17])([CH3:14])/[CH:12]=[CH:13]/[C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([C@H:30]([O:32][C:33](=[O:35])[CH3:34])[CH3:31])=[N:27]2)=[CH:22][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)c1ccc2ccc(Br)cc2n1
Reactant: C=C[C@](C)(COC)C(=O)N1C(=O)OC[C@H]1C(C)C
Agent: [Pd+2]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC[C@@](C)(/C=C/c1ccc2ccc([C@@H](C)OC(C)=O)nc2c1)C(=O)N1C(=O)OC[C@H]1C(C)C
Reaction time: 0.75 h
Yield: 72.7 %

Procedure:
To a mixture of (R)-4-isopropyl-3-((R)-2-methoxymethyl-2-methyl-but-3-enoyl)-oxazolidin-2-one (226 mg, 0.769 mmol), acetic acid (R)-1-(7-bromo-quinolin-2-yl)-ethyl ester (196 mg, 0.666 mmol), palladium(II) acetate (35 mg, 0.154 mmol) and tri(o-tolyl)phosphine (47 mg, 0.154 mmol) were suspended in anhydrous 1,4-dioxane (15 mL) and N,N-dicyclohexylmethylamine (222 mg, 244 μL, 1.14 mmol) was added. The mixture was stirred at reflux for 90 minutes under nitrogen and more palladium(II) acetate (35 mg, 0.154 mmol) and tri(o-tolyl)phosphine (47 mg, 0.154 mmol) were added and the mixture heated for 2 h. More palladium(II) acetate (18 mg, 0.077 mmol) and tri(o-tolyl)phosphine (24 mg, 0.077 mmol) were added and heated continued for 45 minutes. The reaction was allowed to cool and diluted with ethyl acetate and washed with saturated ammonium chloride solution (2×), saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 4:1 to 7:3 to give the title compound (227 mg, 73%) as a yellow foam. 1H NMR (300 MHz, CDCl3) δ 0.90 (d, J=7.1 Hz, 3H), 0.94 (d, J=7.1 Hz, 3H), 1.64 (s, 3H), 1.68 (d, J=6.7 Hz, 3H), 2.18 (s, 3H), 2.36-2.48 (m, 1H), 3.40 (s, 3H), 3.59 (d, J=8.9 Hz, 1H), 4.19 (dd, J=9.1, 3.1 Hz, 2H), 4.23-4.32 (m, 2H), 4.55-4.61 (m, 1H), 6.05 (q, J=6.7 Hz, 1H), 6.49 (d, J=16.3 Hz, 1H), 6.79 (d, J=16.3 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.65 (dd, J=8.5, 1.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.94 (s, 1H), 8.11 (d, J=8.5 Hz, 1H). LCMS (m/z) 469.2 [M+H], Tr=2.91 min.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]2[CH2:15][CH2:16][N:2]1[CH2:3][CH2:4]2.Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)[N:19]=1>>[N:24]1([C:20]2[N:19]=[C:18]([N:7]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]4[CH2:1][N:2]5[CH2:3][CH2:4][CH:5]([C:6]3=4)[CH2:15][CH2:16]5)[CH:23]=[CH:22][CH:21]=2)[CH:28]=[CH:27][CH:26]=[N:25]1
Reactant: Brc1cccc(-n2cccn2)n1
Reactant: c1ccc2c3c([nH]c2c1)C1CCN(CC1)C3
Product: c1cc(-n2cccn2)nc(-n2c3c(c4ccccc42)CN2CCC3CC2)c1

Procedure:
The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (212 mg, 1.0 mmol; Example 187A) and 2-bromo-6-(1H-pyrazol-1-yl)pyridine (336 mg, 1.5 mmol; Maybridge) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.99-2.12 (m, 2H) 2.17-2.30 (m, 2H) 3.09-3.30 (m, 5H) 4.33 (s, 2H) 6.52-6.57 (m, 1H) 7.09-7.19 (m, 2H) 7.36-7.50 (m, 3H) 7.79 (s, 1H) 7.96 (d, J=7 Hz, 1H) 8.12-8.22 (m, 1H) 8.50 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 356 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[N:27]2[C:22]([O:23][CH2:24][CH2:25][CH2:26]2)=[CH:21][C:20]=1[C:28](O)=[O:29]>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:20]3[CH:21]=[C:22]4[O:23][CH2:24][CH2:25][CH2:26][N:27]4[N:19]=3)=[O:29])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc2n(n1)CCCO2
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc2n(n1)CCCO2

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.767 mmol) and 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid (168 mg, 0.997 mmol). The product was purified with flash-chromatography. Yield 251 mg (80%). 1H-NMR (400 MHz; CDCl3): δ 1.21 (d, 3H), 2.27-2.32 (m, 2H), 4.14-4.20 (m, 2H), 4.26-4.43 (m, 4H), 4.51-4.60 (m, 1H), 6.01 (s, 1H), 6.62 (d, 1H), 7.49 (d, 1H), 7.51 (d, 1H), 7.66 (d, 1H), 7.81-7.84 (m, 1H), 8.03 (d, 1H).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.O=C1[N:14]2[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH:13]2[CH2:12]O1>CN(C=O)C>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH2:12][C@@H:13]2[NH:14][CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:18]2)[CH:4]=1
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OCC2C1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN[C@@H](COc2cccnc2)C1
Temperature: 120 °C
Yield: 50.8 %

Procedure:
3-Hydroxypyridine sodium salt (Acros, 7.23 g, 61.7 mmol) was added to a solution of tert-butyl tetrahydro-3-oxo-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (5.00 g, 20.6 mmol) in DMF (50 mL). The reaction mixture was heated to 120° C. for 60 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The material was dissolved in H2O (100 mL) and was extracted with EtOAc (3×150 mL). The combined organics were washed with 1 N NaOH (3×200 mL) and brine (200 mL), dried over dried over Na2SO4, filtered, and concentrated under reduced pressure. Recrystallization from EtOAc/Hexanes (1:4) gave 3.068 g (51%) of the desired product as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C)C=O>O>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccccc3)n2)n[nH]1
Temperature: 180 °C
Yield: 34.5 %

Procedure:
The mixture of (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg), phenylboronic acid (84 mg), Na2CO3 (145 mg), Tetrakis(triphenyl-phosphine)palladium(0) (40 mg), N,N-dimethylformamide (DMF) (1 ml) and water (1 ml) was heated at 180° C. for 30 minutes under microwave irradiation. After reaction finished, the reaction mixture was purified by preparative LC-MS to give (5-methyl-1H-pyrazol-3-yl)-(1-phenyl-isoquinolin-3-yl)-amine (40 mg). LC-MS m/e 301(MH+).+.) 1H NMR(CDCl3): δ 2.23(s, 3H), δ 5.86(s, 1H), δ 7.22(m, 1H), δ 7.40(m, 1H), δ 7.55(m, 5H), δ 7.70(m,4H), δ 7.90(d, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:11][C:10]2[C:5](=[N:6][C:7]([CH:12]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH3-]C#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1([CH3:14])[O:11][C:10]2[C:5](=[N:6][C:7]([CH2:12][NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: Nc1ccccc1
Reactant: CC1(C)C=Cc2nc(C=O)ccc2O1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)C=Cc2nc(CNc3ccccc3)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 2,2-dimethyl-2H-pyrano[3,2-b]pyridine-6-carbaldehyde (434 mg, 2.28 mmol) in methanol (3 mL) was added aniline (0.3 mL, 2.52 mmol) and zinc chloride (621 mg, 4.56 mmol) and stirred at room temperature for 2 hours. Then NaCNBH3 (287 mg, 4.56 mmol) was added and stirred overnight. Purification by column: 4:1 Hx/EtOAc to give an off-white solid. Yield: 48%. 1H NMR (CDCl3) δ 1.49 (s, 6H), 4.361 (s, 2H), 5.91 (d, 1H, J=10), 6.55 (d, 1H, J=10), 6.68-6.71 (m, 3H), 7.01 (d, 1H, J=8.4), 7.08 (d, 1H, J=8.4), 7.18-7.38 ppm (m, 2H).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[CH2:20]([O:22]C=O)C>O1CCCC1.O>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[CH:20]=[O:22]
Reactant: CCOC=O
Reactant: Clc1ccncc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cnccc1Cl
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
35.8 ml of n-BuLi (1.6 M in hexane; 57 mmol, 1 eq.) is added to a solution of 7.5 ml of N,N-diisopropylamine in 100 ml of tetrahydrofuran at −60° C. in nitrogen. The mixture is then left under stirring at 0° C. for 45 min before being cooled to −90° C. To this solution, a solution of 6.5 g of 4-chloropyridine (57 mmol, 1 eq.) in 25 ml of tetrahydrofuran is added drop by drop such that the temperature remains between −70 and −60° C. The mixture is left under stirring at −70° C. for 3 hrs. Then, a solution of 5.1 ml of ethylformate (63 mmol, 1.1 eq.) in 10 ml of tetrahydrofuran is added. The mixture is left under stirring for 1 hr at −65/−70° C. and the reaction mixture is then returned to −10° C. and hydrolysed with water. The organic phase is separated and the aqueous phase is extracted 3 times with ethyl acetate. The combined organic phases are dried on Na2SO4 and the solvent is evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.Cl[C:21]([O:23][CH3:24])=[O:22].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:21](=[O:22])[O:23][CH3:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: NCCCNc1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)NCCCNc1cccc(Cl)c1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of N1-(3-chlorophenyl)propane-1,3-diamine (1 g, 5.4 mmol) in dry CH2Cl2 (10 mL), Et3N (1.65 g, 2.27 mL) was added. The resulting mixture was cooled to 0-5° C., a solution of methyl chloroformate (4.0 g, 43 mmol, 5 eq) in dry CH2Cl2 (5 mL) was added drop wise. After addition, the reaction mixture was stirred for 1-2 h at 0-5° C. Upon completion of the reaction, water (15 mL) was added. The aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers were washed with 10% citric acid (2×10 mL) and brine, then dried over Na2SO4, filtered and concentrated to the crude product which was purified by preparative HPLC to afford methyl 3-(3-chlorophenylamino)propylcarbamate (1.18 g, yield 98%).
Reaction SMILES: [C:1]([O:4]C=C)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]([CH:16]=[CH:17][CH:18]=[CH2:19])[CH2:12][CH2:13]CC>C1(C)C=CC=CC=1>[C:1]([O:4][CH:11]1[CH2:16][CH2:17][C:18]([CH3:19])=[CH:13][CH2:12]1)(=[O:3])[CH3:2]
Reactant: C=COC(C)=O
Reactant: C=CC=CCCCCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(=O)OC1CC=C(C)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of vinyl acetate 4A (20 mL) in anhydrous toluene (220 mL) is added aluminum chloride (2.89 g). The flask is cooled to 0° C., and the isoprene 1C (R=methyl) (21.7 mL) is added dropwise. The reaction mixture is stirred 5 hours at 0° C., then allowed to stand at 4° C. for a further 16 hours. The reaction mixtire is then sequentially extracted with two portions (150 mL each) of 1% hydrochloric acid solution, water (75 mL), and brine (75 mL). It is dried over sodium sulfate, filtered through Celite, and concentrated in vacuo. The product is distilled to give 30 g of clear, colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.Cl[C:23]1[C:32]2[C:27](=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:30][CH:31]=2)[N:26]=[CH:25][C:24]=1[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38]>>[C:37]([C:24]1[CH:25]=[N:26][C:27]2[C:32]([C:23]=1[C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:21])=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:34])[F:35])(=[O:38])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: O=C(NCc1ccc(B(O)O)cc1)Nc1ccccc1F
Product: O=C(NCc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1F

Procedure:
The title compound was prepared from 4-[3-(2-Fluoro-phenyl)-ureidomethyl]phenylboronic acid and [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone according to the procedure of Example 1. MS (ES) m/z 541.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23].[CH:26](=O)[CH3:27].[Na]>O1CCCC1.C(O)(=O)C.C(OC(=O)C)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:21][CH2:20][N:19]([CH2:26][CH3:27])[CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23]
Reactant: CC=O
Reactant: O=C(NC1CCNC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To a solution of 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(pyrrolidin-3-yl)thiophene-2-carboxamide (0.1 g, 0.24 mmol) and acetaldehyde (31.9 mg, 0.72 mmol) in tetrahydrofuran (3.0 mL) under nitrogen, was added 2 drops of acetic acid. The resulting mixture was stirred at ambient temperature for 30 minutes. Then sodium triacetoxyboronhidride was added and the reaction mixture was stirred at ambient temperature for additional 12 hours. After this time, the reaction mixture was diluted with ethylacetate and washed with brine and water. The organic layer was separated, dried (Na2SO4) and concentrated. The crude residue was purified by silica gel chromatography using a 90:10 mixture of dichloromethane and methanol as eluent to afford the title product as a solid (40 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO) δ: 7.57 (1H, m), 7.44 (1H, m), 7.06 (1H, m), 4.07 (2H, m), 3.81 (3H, s), 3.812 (3H, s), 3.807 (2H, s), 2.33 (2H, m), 2.13 (6H, s), 1.86 (2H, m). MS m/z: 268.26 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][CH2:7][C@@H:6]2[CH2:9][S:10][CH2:11][N:5]2[CH2:4]1.[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([OH:40])=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][C:25]=1[Cl:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:40][CH2:2][CH:3]4[O:8][CH2:7][C@@H:6]5[CH2:9][S:10][CH2:11][N:5]5[CH2:4]4)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Reactant: ClCC1CN2CSC[C@H]2CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CN2CSC[C@H]2CO1
Yield: 9.6 %

Procedure:
A solution of (8aR)-6-(chloromethyl)tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazine (11.6 mg, 0.0599 mmol), 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetate (salt) (30.0 mg, 0.0644 mmol), and potassium carbonate (45.0 mg, 0.326 mmol) in N,N-dimethylacetamide (1.0 mL) was heated in a sealed tube to 150° C. for 12 h. The crude reaction mixture was directly purified via reverse-phase preparative HPLC (acetonitrile/water/0.1% TFA). Lyophillization of the pure fractions yielded 3.5 mg (8.9%) of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(8aR)-tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazin-6-ylmethyl]oxy}quinazolin-4-amine trifluoroacetate. 1H NMR (400 MHz, d6-DMSO): 8.80 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.74 (s, 2H), 7.29 (s, 1H), 4.29 (d, 2H), 4.11 (m, 2H), 4.00 (s, 3H), 3.96 (m, 1H), 2.99 (m, 2H), 2.56 (t, 1H), 2.367 (m, 1H); MS (EI) for C22H22N4O3SCl2: 492 (MH+).
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[OH:16][CH2:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>CN(C=O)C>[Si:8]([O:16][CH2:17][C:18]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: OCc1nc2ccccc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1nc2ccccc2[nH]1
Reaction time: 3.5 h
Yield: 96.5 %

Procedure:
At room temperature, triethylamine (2.27 ml, 163 mmol) and TBDMS chloride (1.65 g, 10.95 mmol) were added to a solution of 2-hydroxymethylbenzimidazole (1.4 g, 9.95 mmol) in DMF (30 ml). After 3.5 h, the reaction was terminated by addition of water, the mixture was extracted with diethyl ether and the organic phase was dried over sodium sulphate. Chromatography (silica gel, cyclohexane:ethyl acetate 2:1, Rf=0.35) gave 2.52 g of 2-tert-butyldimethylsilyloxymethylbenzimidazole (97% of theory) as a brownish powder. MS (DCl, NH3)=263 (M+H+). 1H-NMR (DMSO-d6): 0.00 (6H, s); 0.80 (9H, s); 4.75 (2H, s); 7.0-7.1 (2H, m); 7.4-7.5 (2H, m); 12.15 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([Cl:1])[CH:3]=2)[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1cc(Br)c2occc2c1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Product: CC1CN(Cc2ccccc2)CCC1(O)c1cc(Cl)cc2ccoc12
Yield: 91 %

Procedure:
Beginning with 4.0 gm (17.3 mMol) 5-chloro-7-bromobenzofuran and 3.86 gm (19.0 mMol) 1-benzyl-3-methyl-4-oxo-piperidine, 5.6 gm (92%) of the desired compound were recovered essentially as described in EXAMPLE 3.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:8](I)=[C:9]2[CH:15]=[CH:14][N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:10]2=[N:11][CH:12]=1.[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37]([CH:40]=[O:41])[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37]([CH:40]([C:8]2[C:7]([Cl:6])=[CH:12][N:11]=[C:10]3[N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][C:9]=23)[OH:41])[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)c(Cl)cnc21
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CCN(Cc4ccccc4)CC3)c(Cl)cnc21
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
n-BuLi (1.6 M in hexanes, 5.17 mL, 8.28 mmol) was added dropwise to a solution of 5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.0 g, 6.9 mmol, Adesis) in THF (120 mL) at about −78° C., keeping the internal temperature of the reaction below about −70° C. during the addition. After stirring for about 40 min, 1-benzylpiperidine-4-carbaldehyde (2.1 g, 10.3 mmol) was added dropwise and the resulting mixture was stirred at about −75° C. for about 1 h. The reaction was quenched by the dropwise addition of saturated aqueous ammonium chloride (60 mL). The mixture was concentrated under reduced pressure and the remaining aqueous portion was extracted with EtOAc (125 mL). The organic layer was washed with brine (80 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to afford crude (1-benzylpiperidin-4-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)methanol (3.53 g, quantitative) as a yellow oil: LC/MS (Table 2, Method n) Rt=1.82 min; MS m/z: 512 and 514 (M+H)+. The crude material was used directly in the next step without further purification.