Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C@@H:8]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)[C@@H:9]([OH:30])[CH2:10][C@H:11]([C:14](N1[C@H]2C3C=CC=CC=3C[C@H]2OC1(C)C)=[O:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([C@@H:9]1[CH2:10][C@@H:11]([CH2:12][CH3:13])[C:14](=[O:15])[O:30]1)[CH2:31][C:32]1[CH:33]=[C:34]([F:39])[CH:35]=[C:36]([F:38])[CH:37]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](C[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)C(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@@H]([C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)OC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(1S,2S,4R)-[1-(3,5-Difluorobenzyl)-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazole-3-carbonyl)-2-hydroxyhexyl]-carbamic acid tert-butyl ester (VIII, 60 mg) was dissolved in 5:1 toluene/CH2C12 (3 mL), and p-toluenesulfonic acid monohydrate (23 mg) was added. This was stirred at rt for 18 h. The mixture was then filtered, and partitioned between half-saturated NaHCO3 (3 mL) and 1:1 EtOAc/hexanes (2×3 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. Flash chromatography of the residue afforded desired product as a solid: MH+370.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C@@:15]([NH2:24])([S:19]([CH:21]([CH3:23])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Mn]([O-])(=O)(=O)=[O:27].[K+].[Mn]([O-])(=O)(=O)=O>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C@@:15]([NH2:24])([S:19]([CH:21]([CH3:23])[CH3:22])(=[O:27])=[O:20])[CH:16]([CH3:18])[CH3:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)[C@](N)(C(C)C)S(=O)C(C)C)cc1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(CCNC(=O)[C@](N)(C(C)C)S(=O)(=O)C(C)C)cc1OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3.7 g of (S)-2-(isopropylsulfinyl)-amino-3-methyl-butyric acid N-[2-(3,4-dimethoxyphenyl)-ethyl]-amide (Example 3.90) are dissolved in 50 ml of acetone at room temperature. An acetone solution saturated with potassium permanganate is added dropwise to this stirred solution until the reaction mixture retains the violet colour of the permanganate; the reaction mixture is then stirred at room temperature for 45 minutes. The resulting manganese dioxide is removed by filtration over Celite. The filtrate is evaporated to dryness and the resulting residue is dissolved in 500 ml of methyl acetate. This organic phase is washed once with 200 ml of water, dried over sodium sulfate and concentrated. The resulting residue is chromatographed over silica gel with a mixture of one part of methyl acetate and one part of n-hexane. (S)-2-(isopropylsulfonyl)-amino-3-methyl-butyric acid N-[2-(3,4-dimethoxyphenyl)-ethyl]-amide, which can be further purified by recrystallization from methyl acetate/n-hexane, is obtained, melting point 86°-87° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[Na].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.CN(C)C=O>O>[N:16]1([C:10]2[C:9]3[C:4](=[C:5]([Cl:14])[CH:6]=[C:7]([Cl:13])[CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: Cc1cc(Cl)c2cc(Cl)cc(Cl)c2n1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-n2cncn2)c2cc(Cl)cc(Cl)c2n1
Temperature: 100 °C
Reaction time: 25 h
Yield: 93 %

Procedure:
A mixture of 2.46 g of 2-methyl-4,6,8-trichloro-quinoline, 1.82 g of the sodium salt of 1,2,4-triazole and 10 ml of dimethyl formamide is stirred at 100° C. for 25 hours whereupon the reaction mixture is poured into 100 ml of water. The precipitated product is filtered. Thus 2.59 g of the desired compound are obtained, yield 93%. Mp.: 220°-222° C.
Reaction SMILES: O[C:2]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[Cl:13])([CH3:5])[CH:3]=[CH2:4].N1C=CC=CC=1.S(Cl)([Cl:22])=O>C(Cl)Cl>[Cl:22][CH2:4][CH:3]=[C:2]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[Cl:13])[CH3:5]
Reactant: C=CC(C)(O)c1cc(Cl)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=CCCl)c1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 12.0 grams (0.056 mole) of 3-hydroxy-3-(2,5-dichlorophenyl)-1-butene and 4.7 grams (0.056 mole) of pyridine in 85 mL of methylene chloride is cooled in an ice-water bath, and 6.6 grams (0.056 mole) of thionyl chloride is added dropwise. Upon completion of addition, the reaction mixture is stirred for about one hour. After this time the reaction mixture is diluted with 50 mL of methylene chloride and about 50 grams of ice. The mixture is stirred until the ice melts, and then the organic layer is separated. The organic layer is washed in turn with two 50 mL portions of an aqueous 0.5M solution of hydrochloric acid, two 50 mL portions of an aqueous solution saturated with sodium bicarbonate, two 50 mL portions of water, and two 50 mL portions of an aqueous solution saturated with sodium chloride. The organic layer is then dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 5.5 grams of 1-chloro-3-(2,5-dichlorophenyl)-2-butene. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.[H][H]>[Pd].[OH-].[NH4+]>[CH3:14][O:13][C:11]1[CH:12]=[C:4]([NH2:1])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Product: COc1ccc(C(=O)O)c(N)c1
Yield: 86.2 %

Procedure:
A mixture of 2-nitro-4-methoxybenzoic acid (21.9 g, 0.111 mol), 2N ammonium hydroxide (250 ml) and 5% palladium on strontium carbonate (2.5 g) is shaken under 45 psi of hydrogen pressure for 3-4 hours. The reaction mixture is filtered, and the filtrate is acidified with acetic acid. A solid forms which is collected by filtration, washed with water and dried to afford 16 g of 4-methoxyanthranilic acid, m.p. 194°-195° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24](O)=[O:25])=[C:12]2[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].Cl>CN(C)C=O.COCCOC.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:13]([CH2:24][OH:25])=[C:12]2[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Cn1c(C(=O)O)c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CC(C)Cn1c(CO)c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a mixture of 6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (4.62 g, 10 mmol) and tetrahydrofuran (50 ml) were added oxalyl chloride (1.0 ml, 15.6 mmol) and N,N-dimethylformamide (3 drops), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 ml). The obtained solution was added dropwise to a suspension of sodium tetrahydroborate (1.32 g, 35 mmol) in 1,2-dimethoxyethane (30 ml) at 0° C. The obtained mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 6-benzyloxy-4-(4-chlorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone (4.31 g, 96.4%) as crystals.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[C:8]([CH3:20])[C:9]([O:11][CH2:12][CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)Cl.[F:26][C:27]1[C:35](O)=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([CH3:37])[NH:31]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[F:26][C:27]1[C:35]([O:1][C:2]2[C:7]3=[C:8]([CH3:20])[C:9]([O:11][CH2:12][CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:10][N:6]3[N:5]=[CH:4][N:3]=2)=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([CH3:37])[NH:31]2
Reactant: Cc1c(OCCCNS(C)(=O)=O)cn2ncnc(O)c12
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(F)c(Oc3ncnn4cc(OCCCNS(C)(=O)=O)c(C)c34)ccc2[nH]1
Temperature: 80 °C
Yield: 36.6 %

Procedure:
A mixture of N-[3-(4-hydroxy-5-methylpyrrolo[2,1-f][1,2,4]triazin-6yloxy)-propyl]-methanesulfonamide (530 mg, 1.77 mmol) and POCl3 was heated at 80° C. for 1.5 h. The volatiles were removed and the residue was diluted with dichloromethane, washed successively with cold NaHCO3 solution and brine, dried, and concentrated in vacuo to afford the crude chloroimidate intermediate (610 mg), which was heated with 4-fluoro-2-methyl-1H-indol-5-ol (495 mg, 3.0 mmol) and K2CO3 (3.0 g, 22 mmol) in DMF (8 mL) at 80-85° C. for 2 h. The mixture was diluted with dichloromethane and the solid was filtered. The filtrate was concentrated and the residue was purified by silica gel flash column chromatography eluting with 30% ethyl acetate/dichloromethane. The desired product was further purified by preparative HPLC to afford the title compound (290 mg, 34% yield) as a tan solid. HRMS (M+H)+ Calcd. For C20H22FN5O4S: 447.1376. Found: 448.1476. 1H NMR (CDCl3) δ7.75 (s, 1H), 7.24 (s, 1H), 7.03 (d, 1H, J=8.32 Hz), 6.88 (m, 1H), 4.04 (t, 2H, J=5.72 Hz), 3.31 (t, 2H, J=6.16 Hz), 2.90 (s, 3H), 2.42 (s, 3H), 2.37 (s, 3H), 2.04 (m, 2H). Anal. Calcd. For C20H21FN4O4S:1.0 H2O:0.18 TFA: C, 50.57; H, 4.73; N 14.61; S 6.80. Found: C 50.44; H 4.87; N 14.51; S 6.70.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].N1C=CN=C1.[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14].O>O1CCCC1.C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][Si:17]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCBr
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
A solution of 28 g of crude 5-bromo-1-pentanol in 144 ml of tetrahydrofuran is mixed with 24 g of imidazole. Then, a solution of 30.3 g of tert-butyldimethylchlorosilane in 46 ml of tetrahydrofuran is added in drops, and it is stirred for 4 hours at room temperature. The reaction mixture is poured into water, shaken out with diethyl ether, the organic phase is washed 4 times with water, dried on sodium sulfate and concentrated by evaporation. The crude product is chromatographed on silica gel with hexane/diethyl ether. 42 g of the title compound is obtained as a colorless liquid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>>[CH:33]1([CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:36])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:41])[CH2:39][O:38][CH3:37])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:35]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f33) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:2]1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(#N)C>[CH2:19]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:2]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1nccc2cc(OC3CCCNC3)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Nc1nccc2cc(OC3CCCN(Cc4ccccc4)C3)ccc12
Reaction time: 0.33 h
Yield: 102.3 %

Procedure:
A couple of drops of glacial acetic acid was added to a solution of racemic 6-(piperidin-3-yloxy)-isoquinolin-1-ylamine (52 mg, 0.214 mmol) and benzaldehyde (26 mL, 0.256 mmol) in acetonitrile (2 ml). The mixture was stirred for 20 minutes and then sodium triacetoxyborohydride (68 mg, 0.321 mmol) was added in portions. The mixture was stirred at ambient temperature for 20 h then concentrated in vacuo. The mixture was then partitioned between dichloromethane and saturated aqueous sodium hydrogencarbonate. The organic layer was separated then concentrated in vacuo to give a residue. The residue was purified by prep-HPLC to give 6-(1-benzylpiperidine-3-yloxy)isoquinolin-1-yl amine (73 mg) El-MS: m/z=334.3 [M+H]+.
Reaction SMILES: O[Li].O.O.[C:5]([O:9][C:10]([N:12]([CH3:54])[C@@H:13]([CH3:53])[C:14]([NH:16][C@H:17]1[CH2:23][O:22][C:21]2[C:24]([C:28](=[O:34])[N:29]([CH2:31][CH2:32][OH:33])[CH3:30])=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:35][C:36]2[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[C:42]3[C:37]=2[CH:38]=[CH:39][C:40]([C:48]([O:50]C)=[O:49])=[CH:41]3)[C:18]1=[O:52])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CO.C([O-])(O)=O.[Na+]>[C:5]([O:9][C:10]([N:12]([CH3:54])[C@@H:13]([CH3:53])[C:14]([NH:16][C@H:17]1[CH2:23][O:22][C:21]2[C:24]([C:28](=[O:34])[N:29]([CH2:31][CH2:32][OH:33])[CH3:30])=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:35][C:36]2[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[C:42]3[C:37]=2[CH:38]=[CH:39][C:40]([C:48]([OH:50])=[O:49])=[CH:41]3)[C:18]1=[O:52])=[O:15])=[O:11])([CH3:7])([CH3:8])[CH3:6]
Reactant: COC(=O)c1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc4c(C(=O)N(C)CCO)cccc43)c(OC)ccc2c1
Agent: O=C([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2cc(C(=O)O)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2c(C(=O)N(C)CCO)cccc21
Temperature: 50 °C
Yield: 74.4 %

Procedure:
LiOH.H2O (7.15 mg, 170 μmol, Eq: 2.00) and H2O (200 μl) were added to a solution of methyl 5-(((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-9-((2-hydroxyethyl)(methyl)carbamoyl)-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-6-methoxy-2-naphthoate (59 mg, 85.2 μmol, Eq: 1.00) in MeOH (2 mL) and the mixture heated to 50° C. After 4 h an additional portion of LiOH.H2O (2 mg, 48 μmol, Eq. 0.65) was added. After 1 h the mixture was diluted with sat. NaHCO3 and extracted with Et2O. The aqueous mixture was acidified to pH 2.0 with 1 N HCl, extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to afford 5-(((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-9-((2-hydroxyethyl)(methyl)carbamoyl)-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-6-methoxy-2-naphthoic acid (43 mg, 74%) which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11]N(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:9][O:8][C:6]=2[N:7]=1.[CH:26]1[C:39]2[NH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[S:31][C:30]=2[CH:29]=[CH:28][CH:27]=1.[H-].[Na+].NC1N=C(N)C2C(CCl)=COC=2N=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11][C:36]3[CH:35]=[CH:34][CH:33]=[C:32]4[C:37]=3[NH:38][C:39]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[S:31]4)=[CH:9][O:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N)c2c(CN(c3ccccc3)c3ccccc3)coc2n1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: Nc1nc(N)c2c(CCl)coc2n1
Agent: [H-]
Agent: [Na+]
Product: Nc1nc(N)c2c(Cc3cccc4c3Nc3ccccc3S4)coc2n1

Procedure:
9-[(2,4-Diaminofuro[2,3-d]pyrimidin-5-yl)methyl]phenothiazine (Formula I: Ar=2,4-diaminofuro[2,3-d]pyrimidin-5-yl; W=CH2; X=N; Z=S; m=n=0) is prepared similarly to N-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]-N,N-diphenylamine as disclosed above by using phenothiazine (159 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-5-chloromethylfuro[2,3-d]pyrimidine (60 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.P(C(C)(C)C)(C(C)(C)C)[C:20](C)(C)[CH3:21].[H+].[B-](F)(F)(F)F.N(C(C)C)C(C)C.C[Si](C#C)(C)C.C([O-])([O-])=O.[K+].[K+]>CO.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I.O1CCOCC1>[C:20]([C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1)#[CH:21]
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Reactant: CN(C)CCCN(C)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Solvent: CO
Product: C#Cc1ccc(N(C)CCCN(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To N-(4-bromo-2-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine (940 mg, 2.97 mmol), Pd(PhCN)2Cl2 (34 mg, 0.09 mmol), CuI (11 mg, 0.06 mmol) and dioxane (4 mL) was added P(tBu)3.HBF4 (53 mg, 0.18 mmol), iPr2NH (0.50 mL, 3.6 mmol) and (trimethylsilyl)acetylene (0.49 mL, 3.6 mmol). The mixture was stirred for 3.5 h at RT, diluted with MeOH and stirred at RT with excess saturated aqueous K2CO3 for 2 h. The mixture was filtered through a pad of activated charcoal and concentrated to yield N-(4-ethynyl-2-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine. MS m/z=262 [M+1]+. Calc'd for C14H19N3O2: 261.33.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][N:20]=1)(=[O:12])=[O:11].[C:27]1([CH:37]=O)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][N:20]=1)[CH2:37][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1)(=[O:12])=[O:11]
Reactant: Cc1cnc(CNCCCCS(=O)(=O)c2nc3ccccc3[nH]2)c(C)c1
Reactant: O=Cc1nccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCS(=O)(=O)c2nc3ccccc3[nH]2)Cc2nccc3ccccc23)c(C)c1
Yield: 50 %

Procedure:
Using General Procedure B: Reaction of [4-(1H-benzoimidazole-2-sulfonyl)-butyl]-(3,5-dimethyl-pyridin-2-ylmethyl)-amine and isoquinoline-1-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave COMPOUND 177 as a white foam (50% yield). 1H NMR (CDCl3) δ 1.51-1.63 (m, 4H), 2.10 (s, 3H), 2.27 (s, 3H), 2.42-2.45 (m, 2H), 3.26-3.30 (m, 2H), 3.81 (s, 2H), 4.17 (s, 2H), 7.12 (t, 1H, J=8 Hz), 7.27 (s, 1H), 7.37-7.42 (m, 2H), 7.50-7.55 (m, 2H), 7.69-7.74 (m, 3H), 8.05 (d, 1H, J=8 Hz), 8.28 (br s, 1H), 8.40 (d, 1H, J=6 Hz); 13C NMR (CDCl3) δ 17.9, 18.3, 21.4, 23.7, 53.1, 54.4, 57.7, 58.7, 117.2, 120.8, 124.8, 125.9, 126.9, 127.6, 130.2, 132.4, 133.1, 136.3, 139.5, 140.9, 146.2, 148.0, 153.1, 158.2; ES-MS m/z 514 [M+H]+. Anal. Calcd. for C29H31N5O2S.1.3CH3OH: C, 65.54; H, 6.57; N, 12.61; S, 5.77. Found: C, 65.67; H, 6.41; N, 12.23; S, 5.43.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:4]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[N:3]=1.[NH4+].[Cl-]>C1COCC1.CCO.O.[Fe]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[C:10]3[C:2]([I:1])=[N:3]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1c(I)nn2-c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ncnc2c1c(I)nn2-c1ccc(N)cc1
Temperature: 50 °C
Yield: 86.4 %

Procedure:
To a solution of tert-butyl 3-iodo-1-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (28) (4.29 g, 8.7 mmol) in THF/EtOH/H2O (40 mL/20 mL/10 mL) was added Fe powder (2.43 g, 43.45 mmol) and NH4Cl (4.65 g, 86.9 mmol). The resulting mixture was purged with N2 before heated to 50° C. for 2 h. The mixture was cooled and filtered through a Celite pad. The solvents were evaporated and the residue was separated in DCM and water. The aqueous layer was extracted with DCM (X4). The combined organic layers were dried over Na2SO4. Solvent was removed under vacuum and purified by flash chromatography (0-60% EA in PE with 0.5% TEA) to provide tert-butyl 1-(4-aminophenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (29) (3.4 g, 86%) as a yellow solid. LC-MS (ESI): m/z (M+1) 453.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([OH:14])([CH2:12][CH3:13])[CH2:10][CH3:11].[Li]CCCC.[B:20](OC)(OC)[O:21]C.CC(=O)OCC>C1COCC1>[CH2:10]([C:9]1([CH2:12][CH3:13])[O:14][B:20]([OH:21])[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]1=2)[CH3:11]
Reactant: COB(OC)OC
Reactant: CCC(O)(CC)c1cc(C)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC1(CC)OB(O)c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
To a solution of 3-(2-bromo-5-methylphenyl)pentan-3-ol (6.5 g, 25.2 mmol) in THF (150 ml) at −78° C. was slowly added n-BuLi (30.24 ml, 75.6 mmol). The reaction mixture was warmed to rt and stirred for 2 h. After being cooled to −78° C., trimethyl borate (5.23 g, 50.4 mmol) was added dropwise and the reaction mixture was warmed to rt, stirred for 10 h under nitrogen and quenched with 2N HCl (50 ml). The mixture was extracted with EA (40 ml×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (10:1 to 1:1) to give the product (2.0 g, yield 38.9%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.87 (s, 1H), 7.52-7.47 (d, 1H), 7.11-7.06 (m, 2H), 2.35 (s, 3H), 1.88-1.68 (m, 4H), 0.60-0.45 (m, 6H). MS: m/z=205 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1.[CH3:11][NH2:12].CC([O-])=O.[K+]>CN(C=O)C.[OH-].[NH4+].[Cu]I>[CH3:11][NH:12][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: CN
Reactant: Brc1ccc2ccoc2c1
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1ccc2ccoc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
A mixture of 6-bromo-1-benzofuran (1.0 g, 5.1 mmol), methylamine (2N, 25 mL, 50 mmol), CuI (1.16 g, 6.1 mmol) and KOAc (1.25 g, 12.7 mmol) in DMF (10 mL) was stirred overnight at 100° C. under nitrogen in a sealed tube. The mixture was cooled to r.t., diluted with aqueous ammonium hydroxide, and extracted with EtOAc. The organic layer was concentrated, and the residue was purified by silica gel chromatography to give 250 mg (33%) of the title compound as a yellow oil. [M+H] Calc'd for C9H9NO, 148. Found, 148.