Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:11](=O)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:13])C.Cl.[C:15]([NH:19]N)([CH3:18])([CH3:17])[CH3:16]>C(O)CCC.C(O)(=O)C>[C:15]([N:19]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:13])[C:5]=2[CH:4]=[N:2]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)NN
Reactant: CN(C)C=C1C(=O)CCCCC1=O
Agent: Cl
Solvent: CCCCO
Solvent: CC(=O)O
Product: CC(C)(C)n1ncc2c1CCCCC2=O

Procedure:
A solution of 1,3-cycloheptadione (2 g, mmol) was heated to reflux for 1 hour with dimethylforamide dimethylacetal (15 mL). The reaction mixture was concentrated and triturated with ether to yield 1.8 g of 2-dimethylaminomethylene-cycloheptane-1,3-dione. A solution of 2-dimethylaminomethylene-cycloheptane-1,3-dione (0.52 g, 2.9 mmol) and t-butylhydrazine hydrochloride (0.44 g, 3.5 mmol) in n-butanol (25 mL) and 0.3 mL of acetic acid was heated to reflux for 16 hours. The solvents were evaporated and the residue was chromatographed, eluting with 30% ethyl acetate/hexane to yield the title compound: 1H NMR (300 MHz, CDCl3) δ 7.85 (s, 1 H), 3.17 (m, 2 H), 2.68 (m, 2 H), 1.98 (m, 2 H), 1.89 (m, 2H) 1.68 (s, 9 H); MS (DCI/NH3) m/z 207 (M+H)+.
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[NH:20][N:19]=[N:18][C:13]=2[N:14]=[C:15]([NH2:17])[N:16]=1>O>[C:3]1([CH2:2][O:9][C:11]2[C:12]3[NH:20][N:19]=[N:18][C:13]=3[N:14]=[C:15]([NH2:17])[N:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1nc(Cl)c2[nH]nnc2n1
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: O
Product: Nc1nc(OCc2ccccc2)c2[nH]nnc2n1
Reaction time: 16 h
Yield: 61.4 %

Procedure:
Sodium metal (3.7 g, 0.162 mol) was added in pieces to benzyl alcohol (117 ml, 1.13 mol) under nitrogen over 20 minutes. The reaction was then heated to 80° for 90 minutes. All of the sodium metal dissolved, and the reaction was left at room temperature for 16 hours. 7-Chloro-1H-1,2,3triazolo[4,5-d]pyrimidin-5-amine (9.23 g. 0.0541 mol) was then added, and the reaction was heated to 60° for 5 hours. The reaction was cooled and left at 5° for 16 hours. Water (500 ml) was added to dissolve the precipitate and then the mixture was extracted with ether (3×200 ml). The pH of the water layer was lowered to 7.0 with concentrated HCl and then to 5.5 with 1N HCl. The precipitate was filtered and dried at room temperature over P2O5 in vacuo to give 8.05 g of desired product.
Reaction SMILES: [CH3:1][O:2][P:3]([O:16][CH3:17])([CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[O:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1C(=O)N([Br:35])C(=O)C1.[Cl-].[NH4+]>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([Br:35])[P:3]([O:16][CH3:17])([O:2][CH3:1])=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COP(=O)(CC(=O)OCc1ccccc1)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COP(=O)(OC)C(Br)C(=O)OCc1ccccc1
Temperature: 10 °C

Procedure:
To a solution of benzyl dimethyl phosphonoacetate (1.94 g, 7.5 mmol) in THF (15 mL) cooled to −78° C. in a dry ice/isopropanol bath was added LHMDS (9.0 mL of a 1 M solution in THF, 9.0 mmol). The reaction was allowed to warm to 10° C. over 30 min, then recooled to 78° C. NBS (1.6 g, 9.0 mmol) was added as a solution in THF (20 mL), and the reaction was allowed to warm to room temperature over 18 h. Saturated ammonium chloride was added to quench any remaining base, and the reaction was concentrated to dryness. Ethyl acetate was added, and the organic layer was washed with water and brine, and dried over sodium sulfate. The crude product was obtained as a yellow oil and was subsequently purified by flash column chromatography on silica gel eluting with 30% ethyl acetate in hexanes to afford the desired product, bromo-(dimethoxy-phosphoryl)-acetic acid benzyl ester, as a pale yellow oil, 1.61 g (63%). 1H NMR (300 MHz, CDCl3): δ 7.36 (m, 5H), 5.24 (s, 2H), 4.44 (d, J=14.1 Hz, 1H), 3.83 (q, J=4.8 Hz, 6H). LC-MS m/z=417 [C11H15O5P+H]+.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28]COC)=[CH:24][CH:23]=2)(O)[CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:7][CH:6]=1)C.Cl>CCO>[OH:28][C:25]1[CH:26]=[CH:27][C:22](/[C:11](/[C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][CH:9]=2)=[C:12](\[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)/[CH2:13][CH3:14])=[CH:23][CH:24]=1
Reactant: CCOC(OCC)c1ccc(C(O)(c2ccc(OCOC)cc2)C(CC)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: CC/C(=C(/c1ccc(O)cc1)c1ccc(C=O)cc1)c1ccccc1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
To a solution of 16 (194 g, 0.42 mol) in EtOH (1.25 L) was added 12 M HCl (250 mL). The reaction mixture was refluxed for 3 h, cooled to RT, and the volatiles were removed under reduced pressure. H2O (750 mL) was added and the mixture was extracted with ether (3×500 mL). The combined ethereal extracts were washed with H2O (750 mL), brine (750 mL), and dried over MgSO4. Concentration followed by recrystallization from hexanes afforded 52.8 g (38%) of 10 as a white solid. 1HNMR (400 MHz, DMSO-d6): δ 0.83 (t, J=7.3 Hz, 3H), 2.33 (q, J=7.3 Hz, 2H), 6.40 (d, J=8.4 Hz, 2H), 6.60 (d, J=8.4 Hz, 2H), 7.10-7.20 (m, 5H), 7.40 (d, J=7.9 Hz, 2H), 7.90 (d, J=8.1 Hz, 2H), 9.23 (s, 1H), 9.98 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[C:18]2[N:19]=[CH:20][N:21]=[C:22]([NH2:23])[C:17]=2[C:16](I)=[CH:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[C:18]2[N:19]=[CH:20][N:21]=[C:22]([NH2:23])[C:17]=2[C:16]([C:35]2[CH:36]=[CH:37][C:32]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:33][CH:34]=2)=[CH:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Yield: 91.1 %

Procedure:
A solution of (S)-2-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (500.00 mg, 1.13 mmol, 1.0 eq), 4-phenoxyphenyl-boronic acid (240.00 mg, 1.13 mmol, 1.0 eq), Pd(PPh3)4 (100.00 mg), and Na2CO3 (300.00 mg, 2.83 mmol, 2.5 eq) in Dioxane/H2O (40/10 ml) was stirred at 90° C. for 4 h. The reaction mixture was concentrated and purified by Pre-TLC to afford (S)-2-[4-amino-5-(4-phenoxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-ylmethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 91% in yield).
Reaction SMILES: [C:1]([N:4]1[CH2:19][CH2:18][CH2:17][C:7]2=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]([CH3:16])=[C:6]2[CH2:5]1)(=[O:3])[CH3:2].[OH:20]O>C(O)(=O)C>[C:1]([N:4]1[CH2:19][CH2:18][CH2:17][C:7]2=[N+:8]([O-:20])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]([CH3:16])=[C:6]2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: OO
Reactant: CC(=O)N1CCCc2nc3ccccc3c(C)c2C1
Solvent: CC(=O)O
Product: CC(=O)N1CCCc2c(c(C)c3ccccc3[n+]2[O-])C1

Procedure:
6 gm (23.8 millimols) of 2-acetyl-2,3,4,5-tetrahydro-11-methyl-1H-azepino[4,3-b]quinoline were dissolved in 7 ml of glacial acetic acid, and 4 ml of 30% hydrogen peroxide were added to the solution at room temperature. The mixture was subsequently heated at 60° to 80° C. for 2 hours. After distilling off the solvent, the mixture was dissolved in 2 N sodium hydroxide, the resulting solution was extracted with chloroform, the solvent was distilled out of the chloroform extract, and the residue was recrystallized from ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33](Br)(Br)([Br:35])[Br:34].O>ClCCl>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:33]([Br:35])[Br:34])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C=O)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C=C(Br)Br)cc1
Reaction time: 1.5 h
Yield: 72 %

Procedure:
Ethyl-4-formylbenzoate (2.46 g) (ex Lancaster) in dichloromethane (30 ml) under nitrogen was treated with triphenylphosphine (15.7 g) and carbon tetrabromide (9.9 g) at 0°. After 1.5 hours at 25°, water was added and the mixture worked up in the normal manner. Purification by chromatography (silica, ether/hexane) gave ethyl-4-(2,2-dibromoethenyl)benzoate (3.32 g). NMR 1H 8.0(2H,d), 7.50(2H,d), 7.45(1H,s), 3.85(3H,s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([NH2:22])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([NH:22][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(N)c3O2)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Nc4ccc(Cl)cc4)c3O2)cc1
Yield: 59.7 %

Procedure:
Treatment of (±)-(7-amino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) with 1-bromo-4-chlorobenzene (0.570 g, 3.0 mmol) generally according to the procedure described for Intermediate 37 provided 0.77 g (57%) of (±)-{7-[(4-chlorophenyl)amino]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a white solid. mp 132-134° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1Br)([CH3:26])[CH3:25]>>[F:1][C:2]1[CH:7]=[C:6]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC(C)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC(C)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-isopropylbromobenzene. MS (ESI): mass calcd. for C19H18FN3, 307.15; m/z found, 308.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.03 (s, 1H), 7.91 (m, 1H), 7.49-7.34 (m, 2H), 7.27-7.17 (m, 4H), 6.71 (s, 2H), 3.06-2.97 (m, 1H), 1.14 (d, J=6.8, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:15])[C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1.[C:16]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.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]>[CH3:16][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:15])[C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1
Reactant: Cc1ccc2nc(Cl)ccc2c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2c([N+](=O)[O-])c(C)ccc2n1
Temperature: 105 °C
Yield: 61.4 %

Procedure:
To a solution of 2-chloro-6-methyl-5-nitro-quinoline (350 mg, 1.57 mmol) in dioxane (6.7 mL) and water (0.7 mL) were added K2CO3 (652 mg, 4.72 mmol), trimethylboroxine (0.22 mL, 1.57 mmol) and PdCl2(dppf) (129 mg, 0.157 mmol) under Ar. The mixture was heated at 105° C. overnight, then cooled and the resulting solid was collected by filtration, washed with ethyl acetate, and dried. Purification by flash column (hexane/ethyl acetate gradient) gave 2,6-dimethyl-5-nitro-quinoline (195 mg, 61%).
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][C:10]=1[CH3:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].C(OCC)(=O)C.[Cl-].[Na+].O>CO.O>[CH2:2]([N:9]1[CH:10]([CH3:19])[CH2:11][CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(C)[n+](Cc2ccccc2)c1
Agent: [BH4-]
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1=CCC(C)N(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84.4 %

Procedure:
To a suspension of 1-benzyl-5-(methoxycarbonyl)-2-methylpyridinium bromide (3.2 g, 9.9 mmol) in methanol (50 ml) was added at −70° C. a solution of sodium borohydride (0.75 g, 20 mmol) in water (10 ml). The mixture was raised to 0° C. and stirred for 20 minutes. The reaction mixture was added to ethyl acetate/brine and the mixture was separated with a separating funnel. The aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was removed in vacuo. The residue (2.34 g) was purified with silica gel (60 g) chromatography (hexane/ethyl acetate=4/1) to give methyl 1-benzyl-6-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate (2.05 g, 84%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[CH3:13])=[CH:5][CH:4]=1)[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:24][C:11]1[O:12][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[C:9]([CH3:13])[N:10]=1
Reactant: CCc1ccc(-c2ocnc2C)s1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccc(-c2oc(Cl)nc2C)s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 61.6 %

Procedure:
A solution of Example 33A (0.94 g, 4.8 mmol) in THF (20 mL) was cooled to −78° C., then treated slowly with LiHMDS (1M in THF, 6.3 mL, 6.3 mmol). The reaction was stirred at −78° C. for 20 min and then treated all at once with solid hexachloroethane (2.31 g, 9.75 mmol). The flask was removed from the cold bath, and the reaction mixture was allowed to stir overnight at room temperature. After this time, it was poured into water and extracted with Et2O. The combined Et2O extracts were concentrated in vacuo, and the residue was chromatographed on silica gel (Analogix® SF25-60 column; 100% hexane for 10 minutes, then 0% to 15% EtOAc/hexanes over 10 minutes) to afford 0.673 g (61%) of the title compound as a bright yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.17 (d, J=3.6, 1H), 6.93 (dt, J=3.7, 1.0 1H), 2.86 (qd, J=7.6, 1.0 2H), 2.27 (s, 3H), 1.26 (t, J=7.5, 3H). MS (DCI+) m/z 228 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[C:21]3[CH2:20][CH2:19][CH2:18][C:17]4(OCC(C)(C)C[O:22]4)[C:16]=3[CH:15]=[N:14][CH:13]=1)[C:5]2([CH3:30])[CH3:29].Cl.O1CCOCC1>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8]([C:7](=[O:11])[N:6]([C:12]3[C:21]4[CH2:20][CH2:19][CH2:18][C:17](=[O:22])[C:16]=4[CH:15]=[N:14][CH:13]=3)[C:5]2([CH3:30])[CH3:29])=[CH:9][CH:10]=1
Reactant: CC1(C)COC2(CCCc3c(N4C(=O)c5ccc(Cl)cc5C4(C)C)cncc32)OC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a solution of 5-chloro-2-(5,5-dimethyl-6′,7′-dihydro-5′H-spiro[1,3-dioxane-2,8′-isoquinolin]-4′-yl)-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (0.66 g, 1.55 mmol) in MeOH (2 mL) was added 4 N HCl in dioxane (1.5 mL, 6 mmol) and the reaction mixture was stirred at room temperature for 2 hours. After evaporation of the solvent, the residue was diluted with DCM (20 mL) and washed with satd. aq. NaHCO3 (10 mL) solution. The organic layer was dried over anhy. Na2SO4, filtered and evaporated to dryness. The residue obtained was purified by silica gel flash chromatography eluting with a 0 to 50% hexane-ethyl acetate gradient to give the title compound (421 mg, 80%) as a light yellow solid. MS: 341.1 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:3][CH2:4][CH3:5].C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:30][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][CH:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC(C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCC(C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 102.6 %

Procedure:
To a solution of 2-[(1-methylbutyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (382 mg) in dry chloroform (4.52 mL) at 0° C. was added NBS (234 mg) in a single portion. The reaction was warmed to room temperature and stirred for 5 h. The reaction mixture was taken up in DCM (20 mL) and was washed with water (30 mL). The organics were separated, dried by passing through a hydrophobic frit and concentrated in vacuo to give a green/brown foam (493 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([OH:11])[N:5]=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1.N1C(C)=CC(C)=CC=1C.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].O.C(#N)C>C(#N)C.CCCCCC.C(Cl)Cl.O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[N:5]=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCOc1nc(N)c([N+](=O)[O-])c(O)n1
Solvent: CC#N
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: CCCCOc1nc(N)c([N+](=O)[O-])c(OS(=O)(=O)c2ccc(C)cc2)n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
A solution of 4-amino-2-butoxy-5-nitro-6-hydroxypyrimidine BL (nitrate salt form, 8.00 g, 27.5 mmol, 1.00 equiv, see note below) in acetonitrile (80.0 ml) was treated with 2,4,6-collidine (distilled under vacuum from NaH, 10.90 ml, 82.4 mmol, 3.00 equiv), followed by TsCl (26.21 g, 0.138 mol, 5.00 equiv). The reaction was stirred for 4 h at 60° C. By this point, 95% conversion to the product was observed using LC-MS as the analytical method (Water/Acetonitrile (with trace AcOH) 95:5-2:98 on a C-18 gemini column). The reaction was added dropwise to a 0° C. mixture of H2O (400 mL) and CH2Cl2 (200 mL). After 10 min, the mixture was extracted (3×200 mL CH2Cl2). All organic layers were combined, dried (Na2SO4), filtered, and concentrated to a total volume of 50 mL. The crude solution of product was purified by directly loading onto a 330 g column of silica gel, followed by chromatography (Eluent hexane/EtOAc 9:1→0:100) giving semipure BM contaminated with 2,4,6-Collidine. The oily solid was taken up in hexane (50 mL) and agitated, then filtered over glass frits. The filter cake was washed with several 30 mL portions of hexane until no collidine was present, giving pure product BM (5.44 g, 52% yield). 1H NMR in CDCl3 was obtained, along with LCMS analysis. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.99 (d, J=8.2 Hz, 2H), 7.95 (s, broad, 1H), 7.39 (d, J=8.2 Hz, 2H), 6.19 (s, broad, 1H), 4.26 (t, J=7.4 Hz, 2H), 2.48 (s, 3H), 1.73 (app. quintet, J=7.4 Hz, 2H), 1.43 (app. sextet, J=7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[OH:34][CH2:33][CH2:35][NH:36][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccccc4Cl)c3)csc12
Reactant: NCCO
Product: O=C(Nc1cccc(OCc2csc3c(C(=O)NCCO)cncc23)c1)c1ccccc1Cl

Procedure:
3-[3-(2-Chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide was prepared from 3-[3-(2-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 11 supra) and ethanolamine (Aldrich) following the procedure described in Example 16 as a light-yellow solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=1)(=[O:18])=[O:17])[CH:6]([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8])C.[Li+].[BH4-].Cl>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:15][CH:5]([CH2:4][OH:3])[CH:6]([C:7]([F:8])([F:9])[F:10])[C:11]([F:14])([F:12])[F:13])(=[O:17])=[O:18])=[CH:20][C:21]=1[F:26]
Reactant: CCOC(=O)C(NS(=O)(=O)c1ccc(Cl)c(F)c1)C(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
2-(4-Chloro-3-fluoro-benzenesulfonylamino)-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl ester (150 mg, 0.337 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0° C. 2M LiBH4 in THF (168 μL in THF) was added and the solution allowed to warm to 25° C. After 18 h, LC-MS revealed unreacted starting ester present. Additional 2M LiBH4 (200 μL) was added and the solution stirred for 24 h. The solution was cooled in an ice bath and 1N hydrochloric acid was added to quench the reaction. The solvent was removed in vacuo and the aqueous phase transferred to a separatory funnel with EtOAc (100 mL) and washed with distilled water (100 mL). The organic layer was removed and the aqueous phase extracted with EtOAc (100 mL×2). The organic extracts were combined, dried (MgSO4), filtered and evaporated to give a white solid (111 mg). This material was purified by Gilson RP-HPLC (column YMC Combiprep 50×20 mm, gradient 10-100% CH3CN: H2O) to afford a white solid (63 mg, 46%). Mass Spectrum (+ESI): 401.8 [M−H]+.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[CH:6]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([N:22]([CH3:21])[C:2]1[CH:20]=[CH:19][C:5]2[CH:6]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCC1CCOc2cc(Br)ccc21
Reactant: CNCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CN(Cc1ccccc1)c1ccc2c(c1)OCCC2CNC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a solution of tert-butyl N-[(7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]carbamate (500 mg, 1.46 mmol) in toluene (10 mL) was added N-methyl-benzylamine (212 mg, 1.75 mmol), Cs2CO3 (950 mg, 2.92 mmol), BINAP (44 mg, 0.07 mmol) and Pd(OAc)2 (16 mg, 0.07 mmol). The mixture was stirred overnight at 100° C. under nitrogen. The mixture was filtered and concentrated, and the residue was purified by prep-HPLC to give 362 mg (65%) of the title compound as a colorless gum. [M+H] Calc'd for C23H30N2O3, 383. Found, 383.