Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13]([CH3:32])=[C:14]([C:28]([O:30]C)=[O:29])[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:10][C:11]1[NH:12][C:13]2[CH2:32][O:30][C:28](=[O:29])[C:14]=2[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(Br)c1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a similar manner, 2.02 grams (2.52 grams of 80 percent; 6.31 millimoles) of pyridinium bromide perbromide was added in a single portion to a solution of 2 grams (5.26 millimoles) of dimethyl 2,6-dimethyl-4-(3-bromophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.79 gram (10.0 millimoles) of pyridine in 40 milliliters of chloroform (distilled from P2O5) which had been cooled to 0° C. The resulting mixture was stirred at this temperature for 30 minutes and then heated at reflux temperature for 1.5 hours. Thereafter, the mixture was allowed to cool to room temperature and diluted with chloroform; the diluted solution washed with 2N hydrochloric acid and brine, dried, and the solvent evaporated to obtain methyl 2-methyl-4-(3-bromophenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate product as a yellow foamy material. The latter was chromatographed on silica gel employing 60 percent ethyl acetate--40 percent hexane as eluant to obtain 790 milligrams (41 percent yield) of purified methyl 2-methyl-4-(3-bromophenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate product as a white crystalline solid. An analytical sample of m.p. 229°-231° C. was prepared by recrystallizing from ethyl acetate-hexane. Elemental analyses were as follows:
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C-:15]#[N:16].[K+].[CH2:18]=O>O1CCCC1>[CH2:2]([N:9]([CH2:18][C:15]#[N:16])[CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)CNCc1ccccc1
Reactant: [C-]#N
Reactant: C=O
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CN(CC#N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.5 %

Procedure:
Part B 1 N Hydrochloric acid solution (119 mL) was added to N-benzyl-N-trimethylsilanylmethyl-amine (23.00 g, 119 mmol) and white precipitate formed. Tetrahydrofuran (650 mL), potassium cyanide (9.3 g, 143 mmol), and aqueous formaldehyde solution (37 wt. %, 12 mL, 155 mmol) were added to the reaction mixture and stirred at ambient temperature for 15 hours. The mixture was extracted with ether and separated and the combined organic layers were washed with water, dried over magnesium sulfate, and concentrated sequentially under reduced pressure and high vacuum at ambient temperature to afford 27.80 g of (N-Benzyl-N-trimethylsilanylmethyl-amino)acetonitrile. Part C
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:19][CH:18]=[O:20]
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=CCc1ccc2oc3ccccc3c2c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of dibenzofuran (0.5 mmol) in anhydrous DCM was cooled to 0° C. AlCl3 (1.5 eq., 0.75 mmol) was added followed by a slow addition of acetyl chloride (1.5 eq., 0.75 mmol). The reaction mixture was stirred at 0° C. for 2-3 h or until the completion of reaction. The product was extracted with DCM and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concenterated in vacuo to give dibenzofuran-2-ylethan-2-one.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][OH:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCO
Reactant: BrCCCCCCOCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3ccccc3c2n1CCOCCCCCCOCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
A solution of 2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol (1.0 g, 3.7 mmol) in N,N-dimethylformamide (20 ml) was added dropwise to a suspension of sodium hydride (0.19 g of a 60% dispersion in mineral oil, 4.8 mmol) in N,N-dimethylformamide (10 ml). The reaction was maintained for 45 minutes followed by the dropwise addition of {4-[(6-bromohexyl)oxy]butyl}benzene (1.6 g, 5.1 mmol). The reaction was stirred overnight at room temperature and then partitioned between ethyl acetate and water. The two phases were separated and the aqueous fraction was extracted with additional ethyl acetate. The organic fractions were combined, washed with water, dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 4:1 ethyl acetate/hexanes) to provide 0.81 g of 2-(ethoxymethyl)-1-(2-{[6-(4-phenylbutoxy)hexyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline as a brown oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:37])[NH:9][C:10]([C:12]1[S:13][C:14]([S:35][CH3:36])=[C:15]([S:17]([C:20]2[CH:21]=[C:22]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:33][OH:34])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:16]=1)=[NH:11])([CH3:6])([CH3:5])[CH3:4].Br[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CN(C=O)C>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][CH2:39][O:34][CH2:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([CH3:32])[C:26]=1[C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([C:15]2[CH:16]=[C:12]([C:10]([NH:9][C:8]([O:7][C:3]([CH3:5])([CH3:6])[CH3:4])=[O:37])=[NH:11])[S:13][C:14]=2[S:35][CH3:36])(=[O:19])=[O:18])[CH:21]=1)[CH3:45]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CO)c1
Reactant: CCOC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCOCc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
To a suspension of NaH (2.7 mg, 68 μmol, 60% oil dispersion) in DMF (0.1 mL) was added a solution of {[4-(2′-hydroxymethyl-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (30 mg, 56.4 μmol) in DMF (0.1 mL), as prepared according to the procedure of step b of Example 213. The mixture was stirred at ambient temperature for 30 min, and then placed in an ice-water bath. After 20 min, a solution of ethyl 3-bromopropionate (8.6 μL, 67.0 μmol) in DMF (0.05 mL) was added once. Ice-water bath was removed, and the mixture was stirred for 16 h. H2O was added, and the mixture was extracted with EtOAc (3×). The extracts were combined, washed with H2O, dried over Na2SO4, concentrated, and flash chromatographed on silica gel, eluting with EtOAc/DCM (15%) followed by EtOAc/hexane (40%) to give the title compound (9 mg, 25%) yield) as an oil.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[C:18]([CH3:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[CH3:29][NH:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.C(N(CC)CC)C.[S:43](Cl)([CH3:46])(=[O:45])=[O:44]>CN1CCCC1=O>[NH2:23][C:20]1[N:19]=[C:18]([CH3:24])[C:17]([C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([N:33]4[CH2:34][CH2:35][CH:31]([N:30]([CH3:29])[S:43]([CH3:46])(=[O:45])=[O:44])[CH2:32]4)[N:3]3[CH2:25][CH:26]3[CH2:28][CH2:27]3)=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:7]=2)=[CH:22][N:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC1CCNC1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(N3CCC(N(C)S(C)(=O)=O)C3)n(CC3CC3)c2n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and 3-methylaminopyrrolidine (130 mg, 1.5 mmol) and the resulting mixture was stirred at 120° C. for 0.5 hours. The reaction mixture was partitioned with chloroform and saturated brine and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, triethylamine (100 μl, 0.75 mmol) and mesyl chloride (60 μl, 0.75 mmol) were added to the residue, and the resulting mixture was stirred for 1 hour. The reaction mixture was partitioned with ethyl acetate (containing a small amount of tetrahydrofuran) and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel chromatography (chloroform:methanol=9:1) to give a pale yellow solid (75 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:3]=1[C:16]#[N:17].[CH3:18][O-].[Na+].CI>CO>[NH2:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:5]([C:9]#[N:10])=[C:6]([S:8][CH3:18])[N:7]=1
Reactant: N#Cc1c(N)[nH]c(=S)c(C#N)c1-c1ccco1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1nc(N)c(C#N)c(-c2ccco2)c1C#N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
To a stirred solution of 210 mg (0.87 mmol) 6-amino-4-furan-2-yl-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile in 25 ml methanol were added 0.16 ml (0.87 mmol) sodium methylate solutiuon (5.4M in methanol) and 0.11 ml (1.73 mmol) methyl iodide and stirring continued for 90 minutes at room temperature. The reaction mixture was then poured onto 100 ml ice-water and the resulting crystals collected by filtration and dried in vacuo to afford 135 mg (61%) 2-amino-4-furan-2-yl-6-methylsulfanyl-pyridine-3,5-dicarbonitrile as a light brown crystalline solid. EI-MS m/e (%): 256 (M+, 49), 255 ([M—H]+, 100).
Reaction SMILES: I[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].OC1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C([I:18])C=CC=1.[OH2:30]>CS(C)=O>[OH:30][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[I:18])=[O:4]
Reactant: O=C(CI)c1ccccc1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Solvent: CS(C)=O
Product: O=C(CO)c1ccccc1I
Yield: 12 %

Procedure:
A mixture of 2-iodoacetophenone (1 g, 4.1 mmol) and hydroxy(tosyloxy)iodobenzene (1.86 g, 4.92 mmol) in dimethylsulfoxide:water (40 mL:2 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 40% ethyl acetate/isohexane, to give 2-hydroxy-1-(2-iodophenyl)ethanone (126 mg, 12%). δH (400 MHz, d6 DMSO): 7.94 (1H, dd, J=0.9, 7.8 Hz), 7.54 (1H, dd, J=1.8, 7.7 Hz), 7.49–7.45 (1H, m), 7.25–7.21 (1H, m), 5.37 (1H, t, J=6.0 Hz), 4.52 (2H, d, J=6.0 Hz).
Reaction SMILES: [CH2:1]([CH:7]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:8][C:9]1[S:13][C:12]([C:14]2[C:25]3[S:24][CH:23]=[CH:22][C:21]=3[C:20]([C:26]3[S:27][C:28]([CH2:31][CH:32]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:29][CH:30]=3)=[C:19]3[C:15]=2[CH:16]=[CH:17][S:18]3)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1COCC1.C([Li])CCC.[CH3:65][Sn:66](Cl)([CH3:68])[CH3:67]>CCCCCC>[CH2:41]([CH:32]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:31][C:28]1[S:27][C:26]([C:20]2[C:19]3[S:18][C:17]([Sn:66]([CH3:68])([CH3:67])[CH3:65])=[CH:16][C:15]=3[C:14]([C:12]3[S:13][C:9]([CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:10][CH:11]=3)=[C:25]3[C:21]=2[CH:22]=[C:23]([Sn:66]([CH3:68])([CH3:67])[CH3:65])[S:24]3)=[CH:30][CH:29]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCC(CCCCCC)Cc1ccc(-c2c3ccsc3c(-c3ccc(CC(CCCCCC)CCCCCCCC)s3)c3ccsc23)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCC(CCCCCC)Cc1ccc(-c2c3cc([Sn](C)(C)C)sc3c(-c3ccc(CC(CCCCCC)CCCCCCCC)s3)c3cc([Sn](C)(C)C)sc23)s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4,8-Bis-[5-(2-hexyl-decyl)-thiophen-2-yl]-1,5-dithia-s-indacene (2.06 g, 2.56 mmol) was added into a 200-mL flask. The system was vacuumed and backfilled with argon 3 times before 80 mL of anhydrous THF was injected. n-Butyl lithium (2.5 M in hexane, 2.3 mL, 5.6 mmol) was added after the mixture was cooled to −78° C. The mixture was stirred at −78° C. for 30 minutes and then at room temperature for one more hour. The system was cooled down to −78° C. again before trimethyltin chloride (0.5 g, 2.5 mmol) was added in portions. Stirring was continued overnight at room temperature. Hexane (200 mL) was added and the organic layer was washed with 150 mL of water. The aqueous layer was extracted with 100 mL of hexane twice. The combined organic layer was dried over anhydrous Na2SO4. Removal of the solvent under vacuum yielded a yellow liquid (2.2 g, 76.0% yield) as the final product after drying in vacuo overnight. 1H NMR (CDCl3, 500 MHz): δ 7.57 (s, 2H), δ 7.21 (d, 2H, J=3.0 Hz), δ 6.78 (d, 2H, J=3.5 Hz), δ 2.76 (d, 4H, J=6.5 Hz), δ 1.62 (s, 2H), δ 1.26˜1.19 (m, 48H), δ 0.76 (m, 12H), δ 0.29 (m, 18H).
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]([F:34])([F:33])[CH2:5][O:6][C:7]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:23][C:8]=1[C:9]([N:11]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:10]>>[C:28]([OH:1])(=[O:27])[CH3:29].[F:34][C:4]([F:3])([F:33])[CH2:5][O:6][C:7]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:23][C:8]=1[C:9]([N:11]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]1)=[O:10]
Reactant: CCCCN(Cc1ccccn1)C(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: [OH-]
Agent: [Na+]
Product: CC(=O)O
Product: CCCCN(CC1CCCCN1)C(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
Using the method of Example 12 except omitting the treatment with sodium hydroxide, 4.64 g. of 2,5-bis(2,2,2-trifluoroethoxy)-N-n-butyl-N-(2-pyridylmethyl)benzamide is reduced to provide white solid product, 2,5-bis(2,2,2-trifluoroethoxy)-N-n-butyl-N-(2-piperidylmethyl)benzamide acetate, m.p. 119°-120° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(Cl)Cl.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>O>[CH3:33][S:34]([O:27][CH2:26][CH2:25][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:28])[CH3:29])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:22][CH2:23][O:24][S:34]([CH3:33])(=[O:36])=[O:35])(=[O:36])=[O:35]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCO)CCO)c3)ncnc21
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCOS(C)(=O)=O)CCOS(C)(=O)=O)c3)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
A mixture of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-1,5-diol (50 mg, 0.0001 mol) in DCM (2 mL, 0.03 mol) was cooled at 0° C. To this mixture, TEA (50 μL, 0.0004 mol) was added. The reaction was stirred for 15 minutes. Methanesulfonyl chloride (23 μL, 0.00030 mol) was added and the resulting mixture was stirred for 1 hour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentane-1,5-diyl dimethanesulfonate (57 mg, 80%) as an oil. MS(ES): 574(M+1).
Reaction SMILES: C[N:2](C)[C:3]([C@@H:5]1[C@@H:10]2[CH2:11][CH2:12][N:7]([CH:8]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=O)[CH2:6]1)=[O:4].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:31]=1[CH2:32][NH2:33].O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:31]=1[CH2:32][NH:33][C@@H:9]1[C@H:8]([CH:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:7]2[CH2:12][CH2:11][C@H:10]1[C@@H:5]([C:3]([NH2:2])=[O:4])[CH2:6]2
Reactant: COc1ccc(OC)c(CN)c1
Reactant: CN(C)C(=O)[C@H]1CN2CC[C@@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(OC)c(CN[C@H]2[C@H]3CCN(C[C@@H]3C(N)=O)[C@H]2C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.7 %

Procedure:
A mixture of 48 (1.2 g, 3 mmol), 2,5-dimethoxybenzyl amine (0.6 g, 3.3 mmol) camphor sulfonic acid (45 mg) in toluene (15 ml) was heated at reflux with removal of water for 3 hours and then the solvent was removed. The residue was dissolved in small amount of THF (3 ml) and this solution was added to a solution of sodium triacetoxyborohydride (1.7 g, 8 mmol) in acetic acid (40 ml) at room temperature. The mixture was stirred at room temperature for 3 hours and the solvent was removed. Water was added and the mixture was neutralized with NaHCO3 and extracted with EtOAc three times. The combined extracts were dried over Na2SO4 and concentrated. Recrystallization from MeOH/acetone to give by-product. The mother liquor was concentrated and the residue was purified by recrystallization from MeOH/EtOAc to give 50 (0.27 g, 0.56 mmol, 19%)
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:9]2[C:5](=[C:6](SC)C(=O)[N:8]=2)[CH:4]=1)#[N:2].[OH-:15].[K+].C[OH:18]>O>[NH2:8][C:9]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[C:6]([OH:18])=[O:15]
Reactant: CSC1=c2cc(C#N)ccc2=NC1=O
Reactant: [OH-]
Reactant: CO
Agent: [K+]
Solvent: O
Product: N#Cc1ccc(N)c(C(=O)O)c1
Reaction time: 8 h
Yield: 34 %

Procedure:
Air was bubbled through a stirred solution of 5-cyano-3-methylthio-2-oxoindole (18.0 g, 88.1 mmol) and potassium hydroxide (5.9 g, 105.2 mmol) in a 9:1 mixture of methanol:water at room temperature for 5 hours. Further potassium hydroxide (5.9 g, 105.2 mmol) was added and the air bubbling continued overnight. The methanol was removed in vacuo, and the residue was carefully acidifed with 2N aq. HCl. The resulting precipitate was collected by filtration, and triturated with ethyl acetate to give 2-amino-5-cyanobenzoic acid as a pale brown solid (4.8 g, 29.6 mmol, 34%); δH [2H6]DMSO 8.02 (1H,d), 7.55 (1H,dd), 7.50 (2H,br s), 6.86 (1H,d).
Reaction SMILES: [OH-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.BrC([Cl:16])CC.[I-].[CH2:18]([NH+](CCCC)CCCC)[CH2:19][CH2:20]C>C1C=CC=CC=1>[Cl:16][C:6]1[CH:7]=[CH:8][C:3]([CH:9]([C:10]#[N:11])[CH2:18][CH2:19][CH3:20])=[CH:4][CH:5]=1
Reactant: N#CCc1ccccc1
Reactant: CCC(Cl)Br
Reactant: CCCC[NH+](CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCC(C#N)c1ccc(Cl)cc1

Procedure:
Into 4 ml of benzene and 10 ml of 50% sodium hydroxide aqueous solution were added 1.2 ml of α-phenylacetonitrile, 1 ml of bromochloropropane and a catalytic amount of tri-n-butylammonium iodide, and the whole mixture was stirred at room temperature overnight under nitrogen gas stream. Then 0.5 ml of bromochloropropane was further added to the reaction mixture and reacted at 40° C. for 3 hours. After the reaction was completed, the reaction mixture was extracted with diethyl ether, and the extract was washed with an aqueous solution saturated with sodium chloride, and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the thus obtained residue was purified by means of a silica gel column chromatography (eluent: n-hexane:ethyl acetate =5:1) to yield 1.7 g of 4-chloro-1-cyanobutylbenzene.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][N:33]=[N:32][N:31]=4)=[CH:20][CH:19]=3)[C:13]([CH2:15][CH3:16])=[N:14][C:9]2=[C:8]([CH3:35])[CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.CC(O)=O>C1COCC1>[CH2:15]([C:13]1[N:12]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=2)[C:10]2=[N:11][C:6]([CH2:4][OH:3])=[CH:7][C:8]([CH3:35])=[C:9]2[N:14]=1)[CH3:16]
Reactant: CCOC(=O)c1cc(C)c2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(CO)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To 5-(ethoxycarbonyl)-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (50 mg) in THF (1 mL) at -78° C. was added Diisobutylaluminum hydride (0.534 mL, 1M/THF). After 1 hour at -78° C., the mixture was warmed to RT and 1% aqueous HOAc (2 mL) was added. Extractive workup (EtOAc), and purification (SiO2, 80/20/1 CH2Cl2 /MeOH/NH4OH) gave 28 mg of a solid. 1H NMR (300 MHz, CD3OD) δ7.57 (t, 2H, J=7.5 Hz), 7.48 (t, 2H, J=7.5 Hz), 7.26 (s, 1H), 7.08-7.02 (AB quartet, 4H), 5.54 (s, 2H), 4.74 (s, 2H), 2.85 (q, 2H, J=7.5 Hz), 2.66 (s, 3H), 1.26 (t, 3H, J= 7.5 Hz).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:28]([OH:30])=[O:29])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2].[N+](=[CH2:33])=[N-]>CO.C(OCC)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:28]([O:30][CH3:33])=[O:29])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)Oc1cc(C(=O)O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2NC21
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cc(OC(C)=O)c2c(c1)N1CC3NC3C(OC(C)=O)(O1)C2COC(N)=O
Reaction time: 0.33 h

Procedure:
To a solution of 6,9-diacetoxy-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4-6-triene-4-carboxylic acid (12 mg) in methanol (2 ml) was added a solution of diazomethane (excess) in diethyl ether at room temperature. The mixture was allowed to stand at room temperature for 20 minutes and then evaporated to dryness in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (15:1, v/v) to afford methyl 6,9-diacetoxy-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carboxylate (5 mg).