Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][C:8]=2[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:6]=1)=[O:4].[Na+].[I-].C(N(CC)CC)C.[CH3:31][Si:32](Cl)([CH3:34])[CH3:33].C(=O)(O)[O-].[Na+]>CC#N>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:12]([O:14][Si:32]([CH3:34])([CH3:33])[CH3:31])=[CH:11][CH2:10][CH2:9][C:8]=2[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:6]=1)=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CCC2
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(O[Si](C)(C)C)=CCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.1 %

Procedure:
To a solution of 4-oxo-4,5,6,7-tetrahydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1.10 g, 3.74 mmol), NaI (841 mg, 5.61 mmol) and triethylamine (1.56 mL, 11.22 mmol) in CH3CN (15 mL), is added trimethylsilyl chloride (0.707 mL, 5.61 mmol) via syringe. The reaction mixture is stirred at room temperature for 15 h., 30 mL of ethyl acetate/hexanes (1:1 with a few drops of triethylamine) is added to dilute the solution. Saturated sodium bicarbonate solution (20 mL) is added. The layers are separated and the aqueous phase is extracted with ethyl acetate/hexanes (1:1) (3×10 mL). The combined organic layers are dried (Na2SO4) and evaporated to provide 4-trimethylsilanyloxy-6,7-dihydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1.3 g, 100%) as a viscous red oil. 1H NMR (400 MHz, CDCl3) δ0.180 (9H, s), 1.576 (9H, s), 2.343 (2H, m), 2.930 (2H, t), 3.781 (3H, s), 4.826 (1H, t), 7.580 (1H, s). MS (ES+) 366 (M+1)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)=[CH:17][CH:16]=1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: COc1ccc(C=O)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C=C2N=C(c3cccs3)OC2=O)cn1
Temperature: 90 °C
Yield: 65.2 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 6-methoxy-3-pyridinecarboxaldehyde (45 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 56 mg of the above-captioned compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][SH:6].[O-]CC.[Na+].Cl.[NH:12]([C:16]1[S:17][CH:18]=[C:19]([CH2:21][Cl:22])[N:20]=1)[C:13]([NH2:15])=[NH:14]>C(O)C>[ClH:22].[NH:12]([C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:6][CH2:5][CH2:4][CH2:3][NH2:2])[N:20]=1)[C:13]([NH2:15])=[NH:14]
Reactant: NCCCS
Reactant: N=C(N)Nc1nc(CCl)cs1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N=C(N)Nc1nc(CSCCCN)cs1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-Aminopropanethiol hydrochloride (2.54 g.) in ethanol (20 ml.) was added to a solution of sodium ethoxide (1 g. Na in 25 ml. ethanol) at 0° C. under a nitrogen atmosphere. The suspension was stirred at 0° C. for 2 hours and a solution of 2-guanidino-4-chloromethylthiazole hydrochloride (2.27 g.) in ethanol (25 ml.) was then added. The suspension was allowed to reach room temperature and stirred for 16 hours. Filtration of the suspension and acidification of the filtrate with concentrated hydrochloric acid gave a precipitate of 2-guanidino-4-[(3-aminopropyl)thiomethyl]thiazole hydrochloride, m.p.> 350° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:18]([CH:19]([C:21]5[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=5[Cl:29])[CH3:20])=[CH:17][NH:16][C:13]4=[N:14][CH:15]=3)[CH:7]=[N:6]2)[CH2:2]1.C[Si]([N:34]=[C:35]=[O:36])(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:29][C:22]1[C:23]([F:28])=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[CH:19]([C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([C:8]3[CH:7]=[N:6][N:5]([CH:3]4[CH2:2][N:1]([C:35]([NH2:34])=[O:36])[CH2:4]4)[CH:9]=3)[CH:11]=2)[NH:16][CH:17]=1)[CH3:20]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CNC4)c3)cc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CN(C(N)=O)C4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(1-azetidin-3-yl-1H-pyrazol-4-yl)-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine (6.0 mg, 0.014 mmol), trimethylsilyl isocyanate (5.0 μL, 0.037 mmol), DIPEA (0.02 mL, 0.09 mmol) and DCM (2 mL) was stirred at rt for 30 min. The solution was concentrated in vacuo, redissolved in MeOH and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 1.89 (d, J=7.1 Hz, 3 H), 4.29-4.36 (m, 2 H), 4.42 (t, J=8.5 Hz, 2 H), 5.20-5.34 (m, 2 H), 7.14-7.23 (m, 1 H), 7.37 (d, J=1.3 Hz, 1 H), 7.39-7.52 (m, 2 H), 7.69 (s, 1 H), 7.94 (s, 1 H), 8.33 (s, 1 H). MS (ES+): m/z 473.11 (100) [MH+]. HPLC: tR=2.86 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[CH:30]=O)[C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH3:2].[CH2:33]([NH2:35])[CH3:34]>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][C:21]=2[CH2:30][NH:35][CH2:33][CH3:34])[C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)Cc1ccc(OCc2ccccc2)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (6-benzyloxy-2′-formyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([C:9](I)=[N:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[CH2:21]([Sn:25]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])Cl)[CH2:22][CH2:23][CH3:24]>C1COCC1>[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([Sn:25]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH3:24])=[N:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(I)c2ccc(C(C)(C)C)cc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(C(C)(C)C)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-tert-butyl-3-iodo-1-methyl-1H-indazole (150 mg, 0.45 mmol) in THF (3 mL) at 0° C. was slowly added isopropylmagnesium chloride (2.0 M in THF, 0.27 mL, 0.54 mmol). The bright yellow heterogeneous reaction mixture was stirred at 0° C. for 1 h then tributylchlorostannane (0.15 mL, 0.54 mmol) was added dropwise. Stirring was continued at 0° C. for 20 min then at room temperature for 3 h. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated to afford 6-tert-butyl-1-methyl-3-tributylstannanyl-1H-indazole as a viscous yellow oil which was used in the next step without further purification.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Br:6][C:7]1[CH:8]=[N+:9]([O-])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH-].[Na+]>>[Br:6][C:7]1[C:8]([Cl:3])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc(Br)cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: Clc1nc2ccccc2cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To POCl3 (7.5 ml, 80 mmol) was added in portions solid 6 (2.25 g, 10 mmol). The mixture was stirred at room temperature for 30 min and then 60° C. for 10 min. The mixture was then poured into cold 1M NaOH extracted with CH2C2. The combined extracts were dried (K2CO3) and concentrated to a residue which was purified by flash chromatography (EtOAc) to afford 3-Bromo-2-chloroquinoline 7 (1.95 g, 80%). 1H NMR d (ppm): 7.6 dd (CH atom), 7.7 m (2 CH atom), 8.0 d (CH atom), 8.5 s (CH arom)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[C:11]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:43])[O:39][CH:40]([CH3:42])[CH3:41]>ClCCl>[C:18]1([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:12]=2[C:11]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[N:10][N:9]=[C:8]3[C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:43])[O:39][CH:40]([CH3:42])[CH3:41])[CH:7]=[N:6][CH:5]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)Nc1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.5 %

Procedure:
To a solution of 4-(5-aminopyridin-3-yl)-8-phenyl-N-(pyridin-2-ylmethyl) phthalazin-1-amine (50.0 mg, 0.124 mmol) in dichloromethane (5 mL) at room temperature was added pyridine (0.0200 mL, 0.247 mmol) followed by isopropyl carbonochloridate (18.2 mg, 0.148 mmol). The reaction mixture was stirred at ambient temperature for 12 h then diluted with dichloromethane (50 mL) and the organic portion washed with water (10 mL) followed by brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition 32 as described in general methods) to afford isopropyl (5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)pyridin-3-yl)carbamate (35.0 mg, 57.7%). LCMS (Condition 4): retention time 2.16 min, [M+1]=491.0. HPLC (Condition 28): retention time=6.66 min, purity 95.13%. 1H NMR (400 MHz, DMSO-d6) δ 1.29 (d, J=6.0 Hz, 6 H), 4.65 (d, J=4.0 Hz, 2 H), 4.93 (sept, J=6.0 Hz, 1 H), 6.28 (t, J=4.0 Hz, 1 H), 7.22 (dd, J=6.0 Hz, J=7.6 Hz, 1 H), 7.28 (d, J=8.0 Hz, 1 H), 7.45-7.60 (m, 5 H), 7.68-7.73 (m, 2 H), 7.84-7.93 (m, 2 H), 8.17 (t, J=2.0 Hz, 1 H), 8.22-8.24 (m, 1 H), 8.48 (d, J=2.0 Hz, 1 H), 8.81 (d, J=2.0 Hz, 1 H), 10.00 (s, 1 H).
Reaction SMILES: [O:1]1[C:5]2[C:6]([NH2:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CO.[CH:13](I)([CH3:15])[CH3:14]>C(N(CC)CC)C>[CH:13]([NH:10][C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)([CH3:15])[CH3:14]
Reactant: Nc1cccc2c1OCC2
Reactant: CC(C)I
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)Nc1cccc2c1OCC2

Procedure:
To a solution of 15 g. of 2,3-dihydro-7-benzofuranamine in 150 ml. of methanol is added 8.5 ml. of isopropyl iodide and 13.4 ml. of triethylamine. The solution is refluxed for 45 hours and then concentrated in vacuo. The resulting oil is extracted several times with diethyl ether, the ether extracted combined filtered through Celite, and the ether removed in vacuo to obtain an oil of N-isopropyl-2,3-dihydro-7-benzofuranamine.
Reaction SMILES: [I:1][C:2]1[C:3]([NH2:13])=[N:4][CH:5]=[C:6]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:7]=1.Br[CH2:15][CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Si:19]([O:18][CH2:17][CH2:16][CH2:15][N:10]1[N:11]=[N:12][C:8]([C:6]2[CH:7]=[C:2]([I:1])[C:3]([NH2:13])=[N:4][CH:5]=2)=[N:9]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: Nc1ncc(-c2nn[nH]n2)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cnc(N)c(I)c2)n1
Temperature: 80 °C

Procedure:
The reaction mixture of 3-iodo-5-(2H-tetrazol-5-yl)pyridin-2-amine (0.61 g, 2.12 mmol, 1 eq), (3-bromopropoxy)-tert-butyldimethylsilane (0.66 mL, 1.3 eq), and potassium carbonate (0.44 g, 1.5 eq) in anhydrous dimethylformamide (8 mL) was stirred and heated at 80° C. under nitrogen atmosphere for 2 hours. It was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated under reduced pressure with silica gel. A gradient column chromatography [Hexane to EtOAc-Hex (1:2)] rendered 5-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)-3-iodopyridin-2-amine as a white solid in the amount of 797 mg.
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.[N+:31]([C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=O)([O-:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].O>CO>[N+:31]([C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1/[CH:36]=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2][N:3]=1)([O-:33])=[O:32]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
(1H-indazol-3-ylmethyl)triphenylphosphonium iodide (3.12 g, 6.00 mmol) was dissolved in methanol (50 mL) and the solution was added with o-nitrobenzaldehyde (1.00 g, 6.60 mmol) and potassium carbonate (2.82 g, 20.40 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with water. The precipitated solid was collected by filtration and then dried. The obtained solid was triturated in methanol to obtain Compound 1 (1.05 g, 76%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][O:49][Si](C(C)C)(C(C)C)C(C)C)[CH2:43][CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:42][CH2:43][N:44]([CH2:47][CH2:48][OH:49])[CH2:45][CH2:46]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCN(CCO[Si](C(C)C)(C(C)C)C(C)C)CC5)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCN(CCO)CC5)n4c3)c3ccccc32)cc1

Procedure:
A solution of Intermediate 94d (243 mg, 0.29 mmol) and TBAF (1M in THF, 0.53 mL, 0.53 mmol) in THF (3.5 mL) was stirred at RT for 45 min, then diluted with water and extracted with DCM (3×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-7.5% (2M NH3 in MeOH) in DCM, to give the title compound as a white powder after freeze-drying (135 mg, 58%). LCMS (Method 5): Rt 3.52 min, m/z 664 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.86-1.92 (2H, m), 2.04-2.11 (2H, m), 2.36 (3H, s), 2.48 (2H, q, J 5.8), 2.66 (4H, t, J 4.8), 3.19 (4H, t, J 4.5), 3.55 (2H, q, J 5.8), 4.44 (1H, t, J 5.4), 4.79-4.82 (1H, m), 5.57 (1H, t, J 4.4), 6.32 (1H, s), 7.07 (1H, d, J 8.5), 7.15 (1H, dd, J 9.9, 2.1), 7.32-7.44 (8H, m), 7.60-7.63 (1H, m), 7.68 (1H, d, J 2.0), 8.04 (1H, s).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=[O:15]>>[F:23][C:18]1[CH:17]=[C:16]([C:14]2[O:15][C:5]3[C:6](=[C:7]([OH:9])[CH:8]=[C:3]([OH:2])[CH:4]=3)[CH:13]=2)[CH:21]=[C:20]([F:22])[CH:19]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Product: Oc1cc(O)c2cc(-c3cc(F)cc(F)c3)oc2c1
Yield: 60 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(3,5-difluorophenyl)ethanone: Yield 60% following procedures A.2 and A.5; m.p. 208-209° C.; IR 3353, 3092, 1615, 1780, 1432, 1349, 1125 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 10.05 (s, 1H), 9.54 (s, 1H), 7.49 (d, J=6.8 Hz, 2H), 7.47 (s, 1H), 7.15 (t, J=8.6 Hz, 1H), 6.43 (s, 1H), 6.21 (s, 1H); 13C-NMR (126 MHz, δ ppm, CDCl3) 165.1 (dd, J=246.3 Hz, 13.3 Hz), 158.9, 158.9, 152.9, 151.65, 135.7 (t, J=10.6 Hz), 112.7, 107.7 (dd, J=21.0 Hz, 6.8 Hz), 103.3 (t, J=26.1 Hz), 102.6, 99.2, 90.8.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:17]2[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1OS(C(F)(F)F)(=O)=O)#[N:2].C(=O)([O-])[O-].[K+].[K+].O.[NH2:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>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.C1(C)C=CC=CC=1>[NH2:33][C:34]1[CH:39]=[C:38]([C:8]2[CH:7]=[CH:6][C:5]([C:17]3[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=3)=[CH:4][C:3]=2[C:1]#[N:2])[CH:37]=[CH:36][CH:35]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c2)s1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(-c3cccc(N)c3)c(C#N)c2)s1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A toluene (0.5 ml) suspension of 20 mg of methyl 5-(3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)thiophene-2-carboxylate and 10 mg of potassium carbonate was added to 15 mg of 3-aminobenzeneboronic acid monohydrate, and in an argon atmosphere, 8 mg of tetrakis(triphenylphosphine)palladium was added thereto. The mixture was stirred overnight at 100° C., then cooled to room temperature, and filtered through Celite. The solvent was evaporated under reduced pressure to obtain methyl 5-(3′-amino-2-cyanobiphenyl-4-yl)thiophene-2-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1.[I:26]C1C=CC(C2N=CN(C)C=2C2SC3N=CN=C(SC)C=3C=2)=CC=1>>[I:26][C:23]1[CH:24]=[CH:25][C:20]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:6]=2[C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[CH:21][CH:22]=1
Reactant: CSc1ncnc2sc(-c3c(-c4ccc(I)cc4)ncn3C)cc12
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1cnc(-c2ccc(I)cc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 17 but using 6-[4-(4-iodophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 62) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (example 7). Solid (200 mg, 100%);
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:14][CH2:15][CH2:16][Cl:17])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1ccc(OCCCCl)cc1

Procedure:
A mixture of 47.4 g of methyl p-hydroxyphenylacetate, 28.5 ml of 3-bromo-1-chloropropane, 38.6 g of potassium carbonate and 700 ml of acetone is stirred and refluxed for 24 hours. The mixture is chilled, filtered and the solvent removed under reduced pressure. Distillation of the residue gives 52.1 g of colorless oil, bp 144°-146° C. at 0.25mm.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2.[H-].[Na+].BrC[CH2:20][CH2:21][CH2:22][C:23]#[N:24].CCOCC>CN(C)C=O>[CH3:1][S:2][C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2
Reactant: N#CCCCCBr
Reactant: CSc1ccc2c3c(cccc13)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSc1ccc2c3c(cccc13)C(=O)N2CCCC#N
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A mixture of 2.15 g of 6-(methylthio)-benz-[cd]indol-2(1H)-one (Example 2), 0.6 g of 60% sodium hydride in 70 ml of N,N-dimethylformamide is heated at 50° C. for 30 minutes then cooled. A solution of 2.22 g of 1-bromo-4-cyano-butane in 25 ml of N,N-dimethylformamide is added dropwise to the reaction mixture and stirring continued for 3 hours. The reaction mixture is quenched in 400 ml of ice water and extracted with (2×300 ml) of ethyl acetate. The organic layer is dried with magnesium sulfate and evaporated to afford a solid which is stirred with ether, filtered and dried to yield 2.5 g of the desired product as a solid, m.p. 120°-122° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][O:20][CH:21]([CH3:23])[CH3:22].C(N(CC)CC)C>[Pd].CO>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][O:20][CH:21]([CH3:23])[CH3:22])=[CH:2][N:10]=1
Reactant: CC(C)OCOCCCOn1cnc2c(Cl)nc(NC=O)nc21
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)OCOCCCOn1cnc2cnc(N)nc21
Temperature: 20 °C
Reaction time: 4 h
Yield: 41.5 %

Procedure:
A mixture of 6-chloro-2-formamido-9-[3-(isopropoxymethoxy)propoxy]purine (1.86 g, 5.40 mmol), 10% palladium on charcoal (190 mg), triethylamine (3.8 ml, 27 mmol) and methanol (30 ml) was stirred under an atmosphere of hydrogen at 20° C. for 4 hr. The suspension was filtered, the catalyst washed with chloroform and the combined filtrates evaporated under reduced pressure. The residue was dissolved in dichloromethane (50 ml), washed with saturated brine-water (2:1), dried (magnesium sulphate) and evaporated. The residue was dissolved in 0.5M sodium methoxide in methanol (21.6 ml) and heated at reflux for 1 hr. The solution was taken to neutrality using AMBERLITE IR 120(H) and evaporated. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (20:1) affording the title compound (630 mg, 41%) after recrystallisation from acetone-hexane; νmax (KBr) 3333, 3192, 1661, 1623, 1577, 1516, 1433 cm-1 ; δH [(CD3 )2SO] 1.09 (6H, d, J 6.05 Hz, 2×CH3), 1.95 (2H, quintet, J 6.6 and 6.3 Hz, CH2CH2CH2), 3.63 (2H, t, J=6.3 Hz, CH2OC), 3.77 (1H, septet, J=6.0 Hz, CH), 4.39 (2H, J=6.6 Hz, CH2ON), 4.64 (2H, s, OCH2O), 6.69 (2H, br.s, D2O exchangeable, NH2), 8.31 (1H, s, H-8), 8.59 (1H, s, H-6). Found: C, 51.21; H, 6.84; N, 24.82%; C12H19N5O3 requires: C, 51.22; H, 6.82; N, 24.89%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.C(OCC)C.[Pt]=O>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: OCCCCCc1ccccc1
Agent: O=[Pt]
Solvent: CCOCC
Solvent: CC(=O)O
Product: OCCCCCC1CCCCC1

Procedure:
To a solution of 5-phenylpentanol (2.21 g., 13.5 mmol) in ten ml glacial acetic acid was added amorphous platinum oxide (0.40 g., 1.76 mmol, oxygen activated). This mixture was subjected to three atm. of hydrogen with agitation (Parr hydrogenator) at room temperature for four hours. The reaction mixture was diluted with ethyl ether, filtered through celite, washed repeatedly with saturated sodium bicarbonate, followed by water and saturated sodium chloride solution. The organic portion was filtered, dried over magnesium sulfate, filtered and concentrated to give the desired alcohol.