Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].C(=O)(O)[O-].[Na+].[Cl:17][CH2:18][C:19](Cl)=[O:20]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:17][CH2:18][C:19]([NH:5][C:4]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:20]
Reactant: COc1ccc(OC)c(N)c1
Reactant: O=C(Cl)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Product: COc1ccc(OC)c(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,5-dimethoxyaniline (20 g., 130.56 mmol) was suspended in water (300 ml) followed by the addition of sodium bicarbonate (13.4 g., 156.6 mmol)) and tetrabutylammonium bromide (catalytic amount). To the mixture was added chloroacetyl chloride (12.4 ml, 156.6 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h. The solid suspension was filtered off to yield pure 46. Yield=23.6 g (79%). 1H NMR: 9.46 (1H), 7.68 (1H, d, J=2.96 Hz), 6.96 (1H, d, J=8.96 Hz), 6.43 (1H, dd, J=8.95 and 3.06 Hz), 4.37 (s, 2H), 3.79 (s, 3H), 3.67 (s, 3H). 13C NMR: 43.3, 55.9, 56.2, 106.0, 111.0, 127.4, 127.7, 142.7, 154.0, 163.8. ES-HRMS [M+H]+ 230.0509. Calcd for (C10H13NO3): 230.0578.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[O:10][C:11]([CH2:14][CH3:15])=[CH:12][N:13]=2)=[CH:5][N:6]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([C:11]1[O:10][C:9]([CH2:8][S:7][C:4]2[S:3][C:2]([NH:1][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:6][CH:5]=2)=[N:13][CH:12]=1)[CH3:15]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1cnc(CSc2cnc(N)s2)o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cnc(CSc2cnc(NC(=O)c3ccccc3)s2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
A mixture of 2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole (48.2 mg, 0.2 mmol), benzoyl chloride (24.4 mg, 0.21 mmol) and triethylamine (35 mg, 0.35 mmol) in methylene chloride (0.5 mL) was stirred at rt for 10 min. The organic solution was washed with water and concentrated. The residue was purified by a flash column (SiO2; hexanes: ethyl acetate/2:1) to afford N-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]benzamide (41 mg, 59%) as a solid, mp 122-123° C.
Reaction SMILES: CC([O-])(C)C.[K+].[F:7][C:8]([F:45])([F:44])[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]2[CH2:23][C@H:22]([O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:21][C@H:20]2[CH2:42]O)=[O:18])=[CH:12][CH:11]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.O>C1COCC1>[C:38]([Si:25]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[O:24][C@H:22]1[CH2:23][N:19]2[C:17](=[O:18])[N:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][C:8]([F:44])([F:45])[F:7])=[CH:11][CH:12]=3)[CH2:42][C@@H:20]2[CH2:21]1)([CH3:39])([CH3:41])[CH3:40]
Reactant: CC(C)(C)[Si](O[C@@H]1C[C@@H](CO)N(C(=O)Nc2ccc(OC(F)(F)F)cc2)C1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](O[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
t-BuOK (1.0 g, 8.9 mmol) was added to a solution of (2S,4R)-4-(tert-Butyl-diphenyl-silanyloxy)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (2.0 g, 3.6 mmol) in anhydrous THF (50 mL) at 0° C. The mixture was stirred for 15 minutes at 0° C. Then tosyl-chloride (0.88 g, 4.6 mmol) was added to the mixture, and the mixture was stirred for 30 minutes at 0° C. The mixture was poured into water (50 mL), extracted with ethyl acetate (3×50 mL). The organic layers was combined, washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by silica-gel column chromatography (petroleum ether/ethyl acetate=10:1) to give 1.6 g (83%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.68-7.63 (m, 4H), 7.58 (d, 2H, J=9.3 Hz), 7.50-7.39 (m, 6H), 7.19 (d, 2H, J=9.0 Hz), 4.56 (t, 1H, J=5.1 Hz), 4.30-4.22 (m, 1H), 4.04 (t, 1H, J=8.4 Hz), 3.86 (dd, 1H, J1=12.6 Hz, J2=5.7), 3.67 (dd, 1H, J1=9.3 Hz, J2=2.4 Hz), 3.18 (d, 1H, J=12.6 Hz), 2.07 (dd, 1H, J1=12.6, J2=5.4), 1.46-1.37 (m, 1H), 1.11 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[NH:4][CH2:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>ClCCCl>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]2[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)=[O:32])=[CH:26][CH:25]=1
Reactant: CC1(C)CNC(c2ccc(C(F)(F)F)cc2)c2ccccc21
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCCl
Product: CC1(C)CN(C(=O)Nc2ccc(F)cc2)C(c2ccc(C(F)(F)F)cc2)c2ccccc21
Temperature: 80 °C

Procedure:
A 25-mL round-bottomed flask was charged with 4,4-dimethyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (118 mg, 0.39 mmol), 4-fluorophenyl isocyanate (43.4 μL, 0.39 mmol) and DCE (5 mL). The reaction mixture was heated at 80° C. for 2 h and the solvent was then removed under vacuum. Purification by silica gel chromatography (20-30% EtOAc in hexanes) provided the title compound as a white solid. MS (ESI, positive ion) m/z: 443 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:15][Li].C>C1COCC1.CCOCC>[OH:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH3:15]
Reactant: [Li]C
Reactant: O=C(O)c1cccc(C(F)(F)F)c1O
Agent: C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cccc(C(F)(F)F)c1O
Temperature: 10 °C
Yield: 99 %

Procedure:
A solution of Example 42B (14.1 g, 68.4 mmol) in THF (70 mL) was cooled to 5° C. and methyllithium (133 mL of a 1.6M solution in Et2O, 212 mmol) was added, keeping the temperature ≦20° C. (slow addition, methane generation). The cooling bath was removed and after 10 min, the reaction mixture was complete by LCMS. The reaction was cooled to 10° C. and EtOAc (140 mL) and 2N HCl (140 mL) were added. The layers were partitioned and the organic portion was washed with water (70 mL) and brine (28 mL). The organic portion was dried (Na2SO4), filtered, and concentrated, to give the title compound (14.0 g, 68.6 mmol, 99%) as an orange oil that was used without further purification. MS (DCI/NH3) m/z 222 (M+NH4)+.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].C(Cl)Cl.[C:25]([O:29][C:30]([NH:32][CH:33]1[CH2:37][CH:36]([C:38](O)=[O:39])[CH:35]([CH2:41][CH3:42])[CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[C:25]([O:29][C:30](=[O:31])[NH:32][CH:33]1[CH2:37][CH:36]([C:38]([NH:2][NH:1][C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]([S:12]([C:15]4[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=4)(=[O:13])=[O:14])[C:6]3=[N:7][CH:8]=2)=[O:39])[CH:35]([CH2:41][CH3:42])[CH2:34]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: CCC1CC(NC(=O)OC(C)(C)C)CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCC1CC(NC(=O)OC(C)(C)C)CC1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A round-bottomed flask was charged with 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.0 g, 6.6 mmol, Step J) and DCM (40 mL) to give a brown suspension. 4-(tert-Butoxycarbonylamino)-2-ethylcyclopentanecarboxylic acid (2.0 g, 7.8 mmol, Step G), HATU (2.51 g, 6.59 mmol), and TEA (4.59 mL, 33.0 mmol) were added to the suspension and the resulting mixture was stirred at ambient temperature for about 24 h with dissolution occurring after about 2 h. Water (20 mL) was added and the layers were partitioned. The organic layer was washed with additional water (2×15 mL), brine (2×25 mL), dried over anhydrous MgSO4, filtered, and solvent was removed under reduced pressure to give a brown residue. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH/DCM. The recovered impure material was re-purified by silica gel chromatography eluting with a gradient of 0-10% MeOH/DCM. The product-containing fractions from the two columns were combined and concentrated to give tert-butyl-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate (2.45, 69%) as a brown solid: LC/MS (Table 2, Method d) Rt=1.47 min; MS m/z: 543 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH3:11])[N:8](S(C3C=CC=CC=3)(=O)=O)[C:7]=12.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH3:11])[NH:8][C:7]=12
Reactant: Cc1cc2ccnc(Cl)c2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2ccnc(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 7-chloro-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine (220 mg, 0.71 mmol) in ethanol (10 mL), a solution of sodium hydroxide (10%, 6 mL) was added and the reaction mixture was stirred at room temperature for about 16 hours. The solvent was removed under vacuum. The residue was taken up in ethyl acetate washed with water and brine, dried over anhydrous sodium sulfate & concentrated under vacuum to give 7-chloro-2-methyl-1H-pyrrolo[2,3-c]pyridine (110 mg, 92% yield).
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3].[OH:11][CH2:12][C:13]([C@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])=[O:14]>>[CH2:1]([OH:10])[C@@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3].[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14]
Reactant: O=C(CO)[C@@H](O)[C@H](O)CO
Agent: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
Paying attention to the fact that xylitol produced in Candida sp strains is reduced by its conversion to xylulose by xylitol dehydrogenase, the present inventors have developed xylitol dehydrogenase-inactivated Candida tropicalis mutant, in which xylitol produced from xylose can no longer be used for cell growth, and thus xylose can be bioconverted to xylitol with a theoretical yield of 100% (Ko, B. S. et. al., Appl. Environ. Microbiol. 72:4207-4213, 2006). Thus, the present inventors filed an application for the protection of an invention relating to a method of producing xylitol in high yield using a xylitol-producing strain, in which the expression of xylitol dehydrogenase is inhibited (Korean Patent Application No. 10-2005-0079751, filed on Aug. 30, 2005).
Reaction SMILES: [CH:1]([N:4]([C:12](=[O:18])[CH:13]([CH3:17])[C:14]([CH3:16])=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:19]Br.O>C(O)(=O)C>[CH:1]([N:4]([C:12](=[O:18])[CH:13]([CH3:17])[C:14]([CH2:16][Br:19])=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)C(C)C(=O)N(c1ccc(Cl)cc1)C(C)C
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)CBr)C(=O)N(c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a reaction flask which contained 71.6 g (0.267 mole) of N-isopropyl-4'-chloro-2-methylacetoacetanilide dissolved in 360 ml of glacial acetic acid, there was added dropwise a solution of 42.7 g (0.267 mole) of bromine in 30 ml of acetic acid. The solution was stirred overnight at ambient temperature. On the following morning, the reaction solution was added to two liters of cold water and the organic material was extracted into toluene. The latter was washed with water and dried over sodium sulfate. After removal of the solvent, there was obtained 86.6 g (97%) of residual oil. N.M.R. (CDCl3) ∂0.9-1.4 (CH3, 9 protons), 3.3-3.6 (CH), 3.9-4.0 (CH2Br), 4.8-5.2 (CH, isopropyl), 7.1-7.6 (aromatic).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[CH2:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1C[O:28]CC1.[OH-].[Na+].OO.Cl>C1COCC1.CCCCCCC.C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:16][OH:28])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(c1ccc(OCc2ccccc2)cc1)c1ccccc1F
Reactant: C1CCOC1
Agent: B
Agent: Cl
Agent: OO
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: O
Product: OCC(c1ccc(OCc2ccccc2)cc1)c1ccccc1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Compound 2 (4.01 g, 13.1 mmol) was dissolved in THF (30 mL) and the solution was cooled to 0° C. BH3·THF (26.3 mL, 26.3 mmol, 1.0 M) was added drop-wise and the mixture was allowed to stir at room temperature for 3 h. The mixture was cooled to 0° C. and 10% H2O in THF (8 mL), 5.6 g NaOH (dissolved in 30 mL H2O), and 46 g H2O2 (35%) were sequentially added. The mixture was stirred overnight at room temperature. The mixture was acidified with aqueous HCl and extracted with diethyl ether (3×50 mL). The organic phase was washed with NaHCO3 (50 mL, saturated aqueous solution), brine (50 mL), and dried over Na2SO4. Evaporation of the solvent gave 4.20 g as a crude oil. Column chromatography (heptane:ethyl acetate 4:1 to 2:1) gave 3.22 g, 76% as a semisolid. 1H-NMR (CDCl3) δ; 7.46-7.26 (m, 6H), 7.25-7.18 (m, 1H), 7.21 (d, 2H, J=8.6 Hz), 7.11 (ddd, 1H, J=8.0 Hz, J=7.4 Hz and J=1.4 Hz), 7.04 (ddd, 1H, J=10.6 Hz, J=8.2 Hz and J=1.4 Hz), 6.94 (d, 2H, 8.8 Hz), 5.04 (s, 2H), 4.49 (t, 1H, 7.0 Hz), 4.15 (d, 2H, J=7.2 Hz), 1.54 (s, H2O/OH); 13C-NMR (CDCl3) δ 161.0 (d, J=246 Hz), 157.8, 137.0, 132.6, 129.3, 128.9 (d, J=4.6 Hz), 128.8 (d, J=14.6 Hz), 128.6, 128.3, 127.9, 127.4, 124.2 (d, J=3.8 Hz), 115.7 (d, J=22.7 Hz), 115.1, 70.0, 54.2 (d, J=1.5 Hz), 45.8 (d, J=1.9 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:15][NH:16][C:17](=[O:20])[CH:18]=[CH2:19].Cl>>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][N:11]([CH2:19][CH2:18][C:17]([NH:16][CH3:15])=[O:20])[CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CC1=C2CCNCC2c2ccccc21
Reactant: C=CC(=O)NC
Agent: Cl
Product: CNC(=O)CCN1CCC2=C(C)c3ccccc3C2C1

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-C]pyridine and N-methyl acrylamide are reacted in accordance with the process described in Example 6. Reaction period 15 hours. M.P. of the hydrochloride of the title compound 200°-201° from ethanol.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8](C(C)(C)C)[C:4]=2[N:5]=[CH:6][N:7]=1.[BrH:28]>C(O)(=O)C>[BrH:28].[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Agent: Br
Solvent: CC(=O)O
Product: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
A mixture of 4-amino-5-(4-phenoxyphenyl)-7-(tert-butyl)pyrrolo[2,3-d]-pyrimidine (5.8 g), glacial acetic acid (55 ml) and hydrobromic acid (55 ml of a 48% solution) (5.8 g), glacial acetic acid (55 ml) and hydrobromic acid (55 ml of a 48% solution) cool and a solid was collected by filtration. This solid was washed with methanol and then with ether to give 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]-pyrimidine hydrobromide, m.p. 288-292° C. The hydrobromide salt was converted into the free base by warming with dilute sodium hydroxide solution (100 ml of 5% w/v solution) and ethanol (60 ml) with stirring and removing the ethanol by distillation. The mixture was cooled and the solid was collected by filtration and washed well with water to give 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 272° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:11](O)=[O:12])(O)=[O:2].B.C1COCC1.C([O-])(O)=O.[Na+]>C1COCC1>[OH:2][CH2:1][CH2:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][OH:12]
Reactant: O=C(O)Cc1ccoc1CC(=O)O
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccoc1CCO
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 2,3-di(carboxymethyl)furan (35 mmol) in THF (400 mL) is cooled to 0° C. and treated with BH3.THF (174 mmol) over 10 minutes, and stirred for an additional 20 minutes at 0° C. before warming to room temperature overnight. The crude reaction is poured over saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer is dried and concentrated to give 2,3-di(2-hydroxyethyl)furan.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH2:31][CH3:32])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.CN(C)C=O.[N:38]1[CH:43]=[C:42](B(O)O)[CH:41]=[N:40][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:31]([C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[CH:22][C:14]=2[NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:42]4[CH:43]=[N:38][CH:39]=[N:40][CH:41]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)[N:17]=1)[CH3:32]
Reactant: OB(O)c1cncnc1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(Br)ccn34)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5cncnc5)ccn34)c12
Temperature: 90 °C
Yield: 75.1 %

Procedure:
7-Bromo-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.06 g, 0.12 mmol) (Example 127) was dissolved in a 1:1 mixture of dimethoxyethane:dimethylformamide (0.6 mL) in a 2 dram vial. Pyrimidin-5-ylboronic acid (0.02 g, 0.18 mmol), PdCl2(dppf)*dcm (0.005 g, 0.006 mmol), and 2 M sodium carbonate solution (0.17 mL, 0.34 mmol) were added. Nitrogen was bubbled through the reaction mixture for 5 minutes before sealing the vial and heating at 90° C. for 16 hours. The reaction mixture was filtered over a 25 mm nylon filter 0.2 μM. The solids were washed with dimethylformamide (1 mL). The filtrate was concentrated under reduced pressure and dried under high vacuum to give N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(pyrimidin-5-yl)imidazo[1,2-a]pyridine-3-carboxamide (44 mg) as a beige solid. MS (APCI), positive scan, m/z=489.2 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[CH:12]=2)[NH:7][CH:6]=1.[OH-].[K+].Cl>C(O)C>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[NH:7][CH:6]=1
Reactant: COC(=O)c1ccc2[nH]cc(CCCO)c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2[nH]cc(CCCO)c2c1
Temperature: 0 °C
Yield: 91.4 %

Procedure:
To a solution of methyl 3-(3-hydroxypropyl)-1H-indole-5-carboxylate (5.0 g, 21.46mmol) in 50 mL ethanol was added 30 mL of 15% potassium hydroxide in ethanol. The mixture was heated to reflux for 1 h. The mixture was cooled to 0° C. and acidified with concentrated hydrochloric acid to pH 6. The ethanol was removed in vacuo. The residue was diluted with 250 mL of ethyl acetate and washed with 50 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 3-(3-hydroxypropyl)-1H-indole-5-carboxylic acid (4.30 g, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1O)[CH3:8])=[O:6].[C:20]([O-:23])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:23][CH2:20][CH2:5][N:7]([CH3:9])[CH3:8])[CH3:8])=[O:6]
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccccc1N(C)C(=O)c1ccc(Cl)c(Br)c1
Yield: 39.9 %

Procedure:
A mixture of 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (404 mg, 1.18 mmol, Step 3B), β-dimethylaminobromide hydrobromide (553 mg, 2.38 mmol) and K2CO3 (655 mg, 4.75 mmol) was heated in DMF (7 mL) at 80° C. for 14 hrs. The mixture was then diluted with ethyl acetate and water. The organic layer was separated and washed with water and brine, dried over Na2SO4, then purified by silica gel column chromatography eluting with DCM/MeOH (95/5 with gradient to 9/1) to yield 3-bromo-4-chloro-N-[2-(2-dimethylamino-ethoxy)-phenyl]-N-methyl-benzamide (97 mg). MS [M+H]+: 412.7; tR=2.24 min. (method 1)
Reaction SMILES: N1C2C=CC=CC=2CCCC1.[Br:12]Br.[Br:14][CH:15]1[CH2:21][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[NH:17][C:16]1=[O:26]>C(O)(=O)C>[Br:14][CH:15]1[CH2:21][CH2:20][C:19]2[CH:22]=[C:23]([Br:12])[CH:24]=[CH:25][C:18]=2[NH:17][C:16]1=[O:26]
Reactant: BrBr
Reactant: O=C1Nc2ccccc2CCC1Br
Agent: c1ccc2c(c1)CCCCN2
Solvent: CC(=O)O
Product: O=C1Nc2ccc(Br)cc2CCC1Br
Temperature: 25 °C

Procedure:
Scheme 5 describes an example of bromination of a tetrahydrobenzazepine intermediate. Bromine can be added slowly to commercially available 3-bromo-1,3,4,5-tetrahydro-1-benzazepin-2-one in acetic acid with stirring at room temperature to provide the useful intermediate 3,7-dibromo-1,3,4,5-tetrahydro-1-benzazepin-2-one, which can be used in many transformations described herein. Bromination using similar conditions can be carried out on other amino aryl cores described herein to provide intermediates for transformation to the compounds of the invention described in Schemes 8, 9 and 10.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].C(N=[N+]=[N-])C>CC([O-])=O.CC([O-])=O.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.[Pd+2].CC#N>[CH3:23][Si:24]([C:27]#[C:28][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1)([CH3:26])[CH3:25]
Reactant: Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCN=[N+]=[N-]
Solvent: CC#N
Product: Cc1nnc2n1-c1ccc(C#C[Si](C)(C)C)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
(XLi269). A mixture of 8 (8-bromo-1-methyl-6-phenyl-4-H-s-triazolo-[4,3-a][1,4]benzodiazepine, 300 mg, 0.85 mmol), trimethylsilylacetylene (208.5 mg, 2.12 mmol) and bis(triphenylphosphine)-palladium (II) acetate in a mixed solvent system of EtN3 (5 mL) and CH3CN (8 mL) was heated to reflux under nitrogen. After stirring for 6 hours at reflux. The mixture was cooled to room temperature. The mixture was concentrated under reduced pressure and H2O (30 mL) was added. The mixture was extracted with CH2Cl2 (3×50 mL). The combined extracts were washed with brine and dried (Na2SO4). After removal of solvent under reduced pressure, the residue was purified by flash chromatography (silica gel, EtOH/EtOAc) to afford benzodiazepine 9 (185 mg, 60% yield) as a white solid: mp 229-233° C.; IR (KBr) 2957, 2156, 1609, 1537, 1491, 1424, 1315, 1249, 881, 844, 750 cm−1; 1H NMR (CDCl3) δ 0.23 (s, 9H), 2.68 (s, 3H), 4.11 (d, 1H, J=12.5 Hz), 5.49 (d, 1H, J=13.0 Hz), 7.21-7.68(m, 7H), 7.75(dd, 1H, J=8.5 Hz, J=1.5 Hz); MS (EI) m/e (relative intensity) 370 (M+, 80), 355 (44), 341 (60), 286 (34), 177 (51), 163 (52) 143 (100), 129 (19), 115 (28). Anal. Calcd. for C22H22N4Si: C, 71.31; H, 5.98; N, 15.12. Found: C, 70.90; H, 5.93; N, 15.08.