Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:22][C:23]1[N:24]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[C:25]([CH3:28])=[CH:26][CH:27]=1>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([N:24]5[C:25]([CH3:28])=[CH:26][CH:27]=[C:23]5[CH3:22])[CH:30]=4)[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: Cc1ccc(C)n1-c1cccc(C(=O)O)c1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(-n3c(C)ccc3C)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (53 mg, 0.189 mmol) and 3-(2,5-dimethylpyrrol-1-yl)benzoic acid (122 mg, 0.57 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 15 min at room temperature. Carbodiimde resin (500 mg) was added and shaking continued for 18 h. The solution was filtered off and concentrated under vacuum. The residue chromatographed on a silica gel flash column eluting with ethyl acetate/hexane (1:1) and the solvent evaporated under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-(2,5-dimethylpyrrol1-yl)benzamide (75 mg, 74%). NMR; δH CDCl3 7.91,(1H, d), 7.83,(2H, d), 7.79,(1H, s), 7.71,(1H, s), 7.61-7.55,(2H, m), 7.49,(1H, s), 7.41,(3H, m), 7.29,(1H, d), 6.24,(1H, m), 5.92,(2H, s), 3.34,(2H, m), 2.23,(3H, s), 2.04,(6H, s), 1.08,(1H, m), 0.57,(2H, m), 0.29,(2H, m). LCMS: retention time 3.80 min, MH+478.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].Br[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[O:10][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C(C)=O)ccc1O
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1cc(C(C)=O)ccc1OC(C)c1ccccc1

Procedure:
A solution of 3′-allyl-4′-hydroxyacetophenone (3.46 g, 19.66), (1-bromoethyl)-benzene (3.05 mL, 21.63 mmol)), and K2CO3 (4.07 g, 29.49 mmol) in acetone (100 mL) is refluxed 20 hours. The mixture is then filtered and the filtrate is concentrated in vacuo. The residue is dissolved in EtOAc (100 mL) and then washed with H2O (1×100 mL) and brine (1×100 mL), dried over MgSO4, and concentrated in vacuo. Chromatography (5:1 hexane/EtOAc) yields 3′-allyl-4′-(1-phenylethoxy)-acetopbenone. To a solution of sodium hydride (0.54 g, 13.5 mmol) in THF (20 mL) is added a solution of ethyl [2-(diethylamino)-2-oxoethyl]-phosphonate (3.13 g. 12.5 mmol) in THF (20 ml). After stirring this mixture for 5 minutes. at room temperature, a solution of 3′-allyl-4′-(1-phenylethoxy)-acetophenone (2.91 g, 10.4 mmol) in ThF (30 mL) is added, and the solution is refluxed 18 hours. After cooling, the mixture is then quenched with saturated aqueous ammonium chloride (50 mL), and extracted with ethyl acetate (4×75 mL). The combined organic phase is washed with water (1×100 mL) and brine (1×100 mL), dried over MgSO4, concentrated in vacuo, chromatographed (silica, 2:1 EtOAc/hexane) to yield N,N-diethyl (E)-3-[3-allyl 4-(1-phenylethoxy)-phenyl)-but-2-enamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.Cl.C([OH:26])C>>[CH3:15][C:14]1[C:3]2[C:2](=[O:26])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[N:13]=1
Reactant: CCO
Reactant: Cc1cccc(-n2nc(C)c3c(Cl)c4ccccc4nc32)n1
Agent: Cl
Product: Cc1cccc(-n2nc(C)c3c(=O)c4ccccc4[nH]c32)n1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 4-chloro-3-methyl-1-(6-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (2.00 g, 6.48 mmol) in ethanol (90 mL), 6N hydrochloric acid (3 mL, 18.0 mmol) was added and the mixture was heated under reflux for 4 hours. The reaction solution was allowed to cool to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with ethanol, air dried, and recrystallized from ethanol to give the title compound (1.55 g, 82% yield).
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[NH2:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>O1CCOCC1>[N:9]([C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]([O:17][CH3:18])=[O:16])=[C:2]=[O:1]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1sccc1N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1sccc1N=C=O
Temperature: 25 °C

Procedure:
Diphosgene (4.6 mL) was added dropwise to a solution of methyl 3-amino-2-thiophenecarboxylate (5.0 g) in p-dioxane (100 mL) at room temperature under N2. Triethylamine (5.3 mL) was then added with concomitant formation of a white precipitate. The resulting reaction mixture was heated at reflux overnight. The reaction was allowed to cool to room temperature and then filtered to remove solid impurities. The precipitate was rinsed with diethyl ether (about 250 mL) and the filtrate was concentrated under reduced pressure to yield 6.4 g of crude title compound of Step A as a brown solid. 1H NMR (CDCl3): δ 7.43 (d,1H), 6.78 (d,1H), 3.92 (s,3H).
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl>N1C=CC=CC=1>[S:9]([O:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CC=CCC1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CC=CCC2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 500 mL round bottom flask equipped with a stirring bar was charged with 67.2 g (0.60 mol) 3-cyclohexene-1-methanol, and 170 mL of pyridine. The mixture was cooled to 0° C. Tosyl chloride (120.8 g, 0.63 mol) was slowly added to above mixture at 0–5° C. The reaction was carried out for 3 hrs. The reaction mixture was poured into 1.2 L of HCl solution (1 M), extracted with chloroform (3×200 mL), washed with water (3×200 mL), dried with sodium sulfate. The solvent was evaporated and the residue distilled under vacuum to give a tosylate.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].[Cl:27][C:28]1[C:29]([CH3:40])=[C:30]([C:34](=O)[C:35]([O:37][CH3:38])=[O:36])[CH:31]=[CH:32][CH:33]=1>CN(C)C=O>[Cl:27][C:28]1[C:29]([CH3:40])=[C:30]([C:34](=[CH:2][O:3][CH3:4])[C:35]([O:37][CH3:38])=[O:36])[CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)C(=O)c1cccc(Cl)c1C
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC=C(C(=O)OC)c1cccc(Cl)c1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
92.3 g of methoxymethyltriphenylphosphonium chloride were suspended in 500 ml of anhydrous dimethylformamide, and 42.3 g of 30% strength sodium methanolate solution were added. After 20 minutes, a solution of 30 g of methyl 3-chloro-2-methylphenylglyoxylate in 200 ml of dimethylformamide was added dropwise to the pale yellow suspension. After a further 3 hours at room temperature, the mixture was poured into ice-water and extracted three times using methyl tert-butyl ether. It was dried over sodium sulfate, concentrated, and the crude product was applied to 100 g of silica gel. The product was eluted through a silica gel column using methyl tert-butyl ether. This gave 29 g of a colorless solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH2:17][CH:18]=[CH2:19])[C:11]2=[O:20])=[N:7][N:6]=1)(=[O:4])=[O:3].[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>C(N(CC)CC)C>[CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:29](=[O:30])[NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:14][CH2:13][N:12]([CH2:17][CH:18]=[CH2:19])[C:11]2=[O:20])=[N:7][N:6]=1)(=[O:4])=[O:3]
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: C=CCN1CCC(O)N(c2nnc(S(C)(=O)=O)s2)C1=O
Solvent: CCN(CC)CC
Product: C=CCN1CCC(OC(=O)Nc2cccc(Cl)c2)N(c2nnc(S(C)(=O)=O)s2)C1=O
Reaction time: 1 h

Procedure:
Tetrahydro-1-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)-3-allyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) and 3-chlorophenyl isocyanate (3.5 ml; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture is stirred and triethylamine (1 drop) is added thereto. After the addition is completed the reaction mixture is allowed to stand for a period of about 1 hour. The mixture is then washed with hexane and is dried to yield the desired product tetrahydro-1-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)-3-allyl-6-[N-(3-chlorophenyl)carbamoyloxy]-2(1H)-pyrimidinone.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:8][CH:9]=1)=[O:4].C1CCC(N=C=NC2CCCCC2)CC1.[C:39](O)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:39]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:46])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(CCCNCCCc2cccc(Cl)c2)s1
Reactant: O=C(O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCN(CCCc2cccc(Cl)c2)C(=O)c2cccnc2)s1
Yield: 116.1 %

Procedure:
A solution of 5-(3-(3-(3-chloro-phenyl)-propylamino)-propyl)-thiophene-2-carboxylic acid methyl ester (from Preparation 8, 0.075 g, 0.213 mmol), DCC (0.0483 g 0.234 mmol) and nicotinic acid (0.0289 g, 0.234 mmol) in 10 mL CH2Cl2 was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in 15 mL EtOAc and the insolubles were removed via filtration. The organic solution was washed with water followed by brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound of Step A as an oil (113 mg). MS 457 (M+).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)(C(C)(C)C)(C)C.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([O-])(O)=O.[Na+]>CCOC(C)=O.O>[F:28][C:25]1[CH:26]=[CH:27][C:22]2[N:23]([C:19]([C:16]3[CH:15]=[CH:14][C:13]4[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=4)[N:17]=3)=[N:20][N:21]=2)[CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4ccc(F)cn34)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Oc1cccc2ccc(-c3nnc4ccc(F)cn34)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
A solution of 8-(tert-butyldimethylsilyloxy)-2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline (560 mg, 1.4195 mmol) in THF (10.13 mL, 1.267 mmol) was cooled to 0° C. in an ice bath. TBAF (1M in THF, 2.122 mL, 2.129 mmol) was added by syringe and the mixture stirred for 1 hour at 0° C. Water was added, followed by saturated aqueous NaHCO3 solution. The mixture was transferred to a separatory funnel, diluting with EtOAc and water. The mixture was extracted with EtOAc, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with 10-15% MeOH 1% NH4OH in EtOAc to give the product as a yellow film (35 mg, 9% yield). MS APCI (+) m/z 281.2 (M+1) detected.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][C:10]([Cl:23])=[CH:11][C:12]=1[C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=2)(=O)=O.[CH2:26]([Sn](CCCC)(CCCC)/C=C\C)[CH2:27][CH2:28]C.[Li+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:23][C:10]1[CH:11]=[C:12]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=3)[C:7](/[CH:26]=[CH:27]\[CH3:28])=[CH:8][N:9]=1
Reactant: C/C=C\[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C/C=C\c1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Temperature: 100 °C
Reaction time: 10 h
Yield: 61.5 %

Procedure:
To a mixture of 6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (200 mg, 0.51 mmol), (Z)-tributyl (prop-1-en-1-yl) stannane (170 mg, 0.51 mmol) and anhydrous LiCl (70 mg, 1.65 mmol) in DMF (2 mL), Pd(PPh3)2Cl2 (30 mg, 0.04 mmol) was added under N2 protection. The reaction mixture was stirred at 100° C. for 10 h. Then it was filtered and concentrated in vacuo. The residue was purified by column chromatography (PE:EA=10:1) to give the product of (Z)-2-(2-chloro-5-(prop-1-en-1-yl)pyridin-4-yl)-4-fluoro-1H-indole (90 mg, yield: 61.9%). 1H-NMR (CDCl3, 400 MHz) δ 12.02 (br s, 1H), 8.33 (s, 1H), 7.87 (s, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.16˜7.21 (m, 1H), 6.98 (d, J=1.2 Hz, 1H), 6.85 (dd, J=10.8, 7.6 Hz, 1H), 6.57 (dd, J=11.2, 1.6 Hz, 1H), 6.06˜6.16 (m, 1H), 1.78 (dd, J=6.8, 1.6 Hz, 3H). MS (M+H)+: 287.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1.[OH-].[Na+].O>CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]1[CH:21]=[CH:20][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1ccc(N2Cc3ccccc3C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(N2Cc3ccccc3C2=O)cc1

Procedure:
A mixture of 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid, ethyl ester (2.55 g, 0.009 mol), NaOH (20 ml), water (70 ml), and methanol (70 ml) is heated to reflux for 20 minutes when a clear solution is formed. The reaction mixture is filtered and the filtrate is carefully acidified with 4N HCl (6 ml) to pH 1.0 when a solid pptd. out. The crude 4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid is filtered, washed with hot CH3OH and dried to give analytical sample. Yield 1.67 g (73%); mp >295° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=[C:10]([C:11]([O:13]C)=O)[C:4]=2[O:3]1.[CH2:19]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][NH2:29])[CH2:20][CH2:21][CH3:22].O>C(O)COCCO>[CH2:19]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][NH:29][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=1)=[O:13])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN1CCCC1CN
Reactant: COC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Solvent: OCCOCCO
Solvent: O
Product: CCCCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A suspension of 4.4 g methyl 2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylate and 3.3 g of 1-butyl-2-aminomethylpyrrolidine in 25 ml of diethylene glycol is heated at 120°-130° C. and stirred for 18-20 hours. The reaction solution is cooled to room temperature and added slowly to 150 ml-200 ml of water while stirring. Under ice-cooling crystals are precipitated thoroughly and collected by suction filtration. The crude crystals are dried and recrystallized from ethyl acetate to give crystals of N-(1-butyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 169.5°-170.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:28]=[CH:27][NH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:23][C:24]4[N:25]([C:14]=2[CH2:15]3)[N:26]=[CH:27][CH:28]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1cc[nH]n1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnc3ccnn3c1C2

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3-aminopyrazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Ni].CO.C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(-c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1

Procedure:
In the presence of 30 mg of Raney nickel, 110 mg (0.30 mmol) of 3-(3-nitro-phenyl)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine are hydrogenated in 3 ml of methanol and 3 ml of THF. The catalyst is filtered off, then 15 g of silica gel are added to the filtrate, which is then concentrated by evaporation. Application of the powder to a silica gel column, elution with methylene chloride/ethanol (15:1) and stirring of the crude product with diethyl ether/hexane yield 3-(3-amino-phenyl)-4-(3-chloro-phenylamino)-1H-pyrazolo-[3,4-d]pyrimidine; m.p. 264-266° C.; TLC: Rf =0.45 (methylene chloride/methanol 10:1); HPLC: TRet (Grad20-100)=9.7.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([Br:12])=[CH:5][N:6]=[CH:7]2.[C:13](Cl)(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[Br:12][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=[N:6][CH:5]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: Nc1cccc2cncc(Br)c12
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1cccc2cncc(Br)c12

Procedure:
5-Amino-4-bromoisoquinoline (prepared according to the process described by Gordon et al., J. Het. Chem., 4, 410 (1967)) was coupled with oleoyl chloride using the procedure described in Example 4, to give the title compound.
Reaction SMILES: [CH3:1][C@@:2]1([OH:26])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]=2[C:12]([C:20]#[C:21][Si](C)(C)C)=[CH:11]1.[NH4+].[OH-]>CO>[CH3:1][C@@:2]1([OH:26])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]=2[C:12]([C:20]#[CH:21])=[CH:11]1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(C#C[Si](C)(C)C)c2c(N)ncnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@]2(C)O)c2ncnc(N)c12
Reaction time: 1 h

Procedure:
The title compound from Example 2 (0.040 g, 0.0132 mmol) was dissolved in methanol and NH4OH was added and the mixture left at ambient temperature for 1 hour. The solvent was evaporated, the residue dissolved in methanol and co-evaporated with silica gel. Dry silica was loaded on the glass filter with silica gel and the desilylated compound was eluted with acetone. Solvent was evaporated and the residue crystallized from methanol/acetonitrile to provide for 7-(2′-C-methyl-β-D-ribofuranosyl)-4-amino-5-(ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: CO[CH:3]([C:6]1[CH:11]=[CH:10][C:9](OC)=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:4][NH2:5].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][C:27](Cl)=[O:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>>[CH3:15][O:14][C:8]1[C:7]([O:14][CH:8]([CH3:9])[CH3:7])=[C:6]([CH2:3][CH2:4][NH:5][C:27](=[O:28])[CH2:26][C:20]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: COc1ccc(C(CN)OC)cc1OC
Product: COc1ccc(CC(=O)NCCc2cccc(OC)c2OC(C)C)cc1OC

Procedure:
prepared by reaction of 2,3,4-trimethoxyphenylethylamine with 3,4-dimethoxyphenyl acetyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:19](=[O:20])[N:18]2[C:12]([C:13]([CH3:22])([CH3:21])[O:14][CH2:15][CH2:16][CH2:17]2)=[N:11][C:10]=1[C:23](O)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:57][CH2:58][C:59]1[CH:68]=[CH:67][C:66]([F:69])=[CH:65][C:60]=1[C:61]([NH:63][CH3:64])=[O:62].CN(C1C=CC=CN=1)C>CN(C)C=O>[F:69][C:66]1[CH:67]=[CH:68][C:59]([CH2:58][NH:57][C:23]([C:10]2[N:11]=[C:12]3[N:18]([C:19](=[O:20])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:22])=[O:24])=[C:60]([C:61](=[O:62])[NH:63][CH3:64])[CH:65]=1
Reactant: CNC(=O)c1cc(F)ccc1CN
Reactant: CC1(C)OCCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCOC2(C)C
Reaction time: 0.17 h

Procedure:
A solution of intermediate 35, 3-(benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylic acid in anhydrous dimethylformamide (4 mL) was treated with HATU (0.278 g, 0.70 mmol) and stirred for 10 minutes. The reaction mixture was treated with 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetic acid salt (0.24 g, 0.8 mmol), followed by dimethylaminopyridine (0.121 g, 0.97 mmol), then stirred for 4 hours at 60° C. Following this, the solvent was removed in vacuo and the remaining residue dissolved in ethyl acetate (15 mL) and washed with 1.0 N HCl (15 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (SiO2), eluting with ethyl acetate. Fractions containing the product were pooled, concentrated to dryness and triturated with ether to provide 0.366 g of the title compound as a white glassy solid. 1H NMR (500 MHz, d6-acetone) δ ppm: 8.71-8.82 (1H, m), 7.84-7.95 (1H, br), 7.47-7.62 (4H, m), 7.27-7.40 (5H, m), 7.20 (1H, dt, J=8.5, 2.7 Hz), 5.15-5.21 (2H, br, s), 4.48-4.60 (4H, m), 2.96 (2H, s), 2.94 (2H, s), 1.62-1.64 (6H, s).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH2:26])=[N:23][C:22]=3[Cl:27])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=1.C([BH3-])#N>C(O)C.C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH:26][CH2:36][C:33]4[CH:34]=[N:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=4)=[N:23][C:22]=3[Cl:27])=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(Cl)c(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Reactant: COc1ccc(C=O)cn1
Agent: [BH3-]C#N
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CNc2nc(Cl)c(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)s2)cn1

Procedure:
5-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine (592, 30 mg, 0.083 mmol, prepared as described in Example 66, Scheme 183) was combined with 6-methoxy-pyridine-3-carbaldehyde (618, 26.2 mg, 0.165 mmol) in a 2 mL microwave reaction vial. The mixture was dissolved in ethanol:acetic acid (95:5, 0.6 mL). Silica supported cyanoborohydride (1.0 mmol/g, 83 mg, 0.083 mmol) was added and the mixture was irradiated with microwave on 300 watts for 5 minutes at 100° C. The silica was separated by centrifuging and the supernatant solution was decanted. The silica residue was rinsed with ethanol (0.500 mL) and centrifuged. The solvents were combined and removed under reduced pressure to give the desired compound 619, which was used without further purification.