Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:45])[C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21](Cl)=[N:22][C:23]=3[NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:15]([OH:43])[C@@H:14]1[OH:44])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:46]([NH:53][C@@H:54]1[CH2:58][CH2:57][NH:56][CH2:55]1)([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47].[I-].[Na+]>C(#N)C>[C:49]([O:48][C:46](=[O:47])[NH:53][C@@H:54]1[CH2:58][CH2:57][N:56]([C:21]2[N:20]=[C:19]3[C:24]([N:25]=[CH:26][N:18]3[C@@H:16]3[CH2:17][C@H:13]([NH:12][C:10](=[O:11])[C@H:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH3:45])[C@@H:14]([OH:44])[C@H:15]3[OH:43])=[C:23]([NH:27][CH2:28][CH:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:22]=2)[CH2:55]1)([CH3:52])([CH3:50])[CH3:51]
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
A suspension of (R)-2-benzyloxy-N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (1 equivalent) and (3R)-(+)-3-(Boc-amino)pyrrolidine (4 equivalents) in acetonitrile is treated with a catalytic amount of sodium iodide and then heated using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 160° C. After 1 hour, the solvent is removed in vacuo; purification by column chromatography/crystallisation affords the title compound.
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[NH:43]=[N+:44]=[N-:45]>C1C=CC=CC=1>[N:43]([CH2:2][C@@H:3]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1)=[N+:44]=[N-:45]
Reactant: COC(=O)[C@H]1CC[C@@H](CO)C1
Reactant: [N-]=[N+]=N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(=O)[C@H]1CC[C@@H](CN=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
To a mixture of methyl cis-3-hydroxymethylcyclopentancarboxylate (4.74 g, 30 mmol) in dry benzene (about 250 mL) was added triphenyl phosphine (7.86 g, 30 mmol), diethyl azodicarboxylate (5.22 g, 30 mmol) and hydrazoic acid (2.5 M in toluene, 14.0 mL, 35 mmol). The mixture was stirred at room temperature for about 16 h. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and hexane was added. A precipitate formed on standing in about 2 h and was removed by filtration. The filtrate was concentrated and the residue was passed through a column of silica gel using chloroform as eluent. The appropriate fractions were combined and concentrated to give 2.6 g (47%) of methyl cis-3-azidomethyl-cyclopentancarboxylate.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH:10]([CH3:30])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]CC)=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]2[CH:31]=[CH:32][CH:33]=[CH:34][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH:10]([CH3:30])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:31]=[CH:32][CH:33]=[CH:34][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1C(C)c1ccc(OC(C(=O)OCC)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2ccccc2n1C(C)c1ccc(OC(C(=O)O)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-1-[4-[(α-ethoxycarbonyl)benzyloxy]-(α-methyl)benzyl]-benzimidazole and 1N sodium hydroxide solution in ethanol.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)COCC4C=CC=CC=4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.Cl[C:58]1[N:66]=[C:65]2[C:61]([N:62]=[CH:63][N:64]2[C@@H:67]2[CH2:71][C@H:70]([NH:72][C:73](=[O:76])[CH2:74][CH3:75])[C@@H:69]([OH:77])[C@H:68]2[OH:78])=[C:60]([NH:79][CH2:80][CH:81]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[N:59]=1.[N:94]1([C:101]2[CH:106]=[CH:105][CH:104]=[CH:103][N:102]=2)[CH2:99][CH2:98][CH:97]([NH2:100])[CH2:96][CH2:95]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:82]1([CH:81]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH2:80][NH:79][C:60]2[N:59]=[C:58]([NH:100][CH:97]3[CH2:98][CH2:99][N:94]([C:101]4[CH:106]=[CH:105][CH:104]=[CH:103][N:102]=4)[CH2:95][CH2:96]3)[N:66]=[C:65]3[C:61]=2[N:62]=[CH:63][N:64]3[C@@H:67]2[CH2:71][C@H:70]([NH:72][C:73](=[O:76])[CH2:74][CH3:75])[C@@H:69]([OH:77])[C@H:68]2[OH:78])[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: NC1CCN(c2ccccn2)CC1
Agent: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)COCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-acetamide trifluoroacetate Example 1 (Step 2) by replacing 2-benzyloxy-N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-acetamide with N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) and by replacing (3R)-3-aminopyrrolidine with 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylamine. (MH+ 331.7)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=2)=[O:10])=[CH:5][CH:4]=1)[CH3:2].[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+].O>CN1CCCC1=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:12]=[N:13][C:14]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)=[O:10])=[CH:5][CH:4]=1)[CH3:2]
Reactant: OCc1ccccc1
Reactant: CCc1ccc(C(=O)c2ccc(Cl)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1ccc(C(=O)c2ccc(OCc3ccccc3)nc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The above 6-chloro-3-pyridyl 4-ethylphenyl ketone (1.68 g) was dissolved in N-methyl-2-pyrrolidinone (20 ml), and thereto were added benzylalcohol (815 ml) and 60% sodium hydride (275 mg). The mixture was stirred at room temperature for 6 hours, and then at 90° C. for one hour. The reaction mixture was cooled to room temperature, and water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and subsequently with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-95:5) to give 6-benzyloxy-3-pyridyl 4-ethylphenyl ketone (1.68 g) as colorless oil. APCI-Mass m/Z 318 (M+H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[OH:15][CH2:16][CH2:17][O:18][CH:19]([C:28]1[NH:29][CH:30]=[N:31][CH:32]=1)[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.O>ClCCl>[CH3:10][S:11]([O:15][CH2:16][CH2:17][O:18][CH:19]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[C:28]1[NH:29][CH:30]=[N:31][CH:32]=1)(=[O:13])=[O:12]
Reactant: N#Cc1ccc(C(OCCO)c2cnc[nH]2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCOC(c1ccc(C#N)cc1)c1cnc[nH]1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.44 mmol of diisopropylethylamine and 1.20 mmol of methanesulphonyl chloride are added to a solution of 1.20 mmol of 4-[(2-hydroxyethoxy)-(3H-imidazol-4-yl)methyl]benzonitrile in 10 ml of dichloromethane at 0° C. The reaction mixture is stirred at 0° C. for 3 hours, tipped into water and extracted with dichloromethane. The combined organic phases are washed with brine, dried over sodium sulphate and evaporated. The crude title compound is used without further purification in the next stage.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:26]>>[CH3:26][N:13]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[S:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:11])=[O:12]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NCCCN2CCCCC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CN(CCCN1CCCCC1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
4-Nitro-N-(3-piperidinopropyl)benzenesulphonamide (Method 14; 1 g, 3.06 mmol) was stirred under nitrogen at ambient temperature. Sodium hydride (60% dispersion in mineral oil) (122 mg, 3.05 mmol) was added in portions. The reaction was stirred for 10 minutes, then iodomethane (210 μl, 3.38 mmol) was added dropwise. After 2 hours, added extra sodium hydride (<30 mg) was added, and the reaction was stirred for 15 minutes, then stood overnight. Volatiles were removed by evaporation, water (20 ml) was added and the solution was extracted with ethyl acetate (2×30 ml). The organic layers were combined, washed with water and the volatiles evaporated to give the title compound (830 mg). NMR: 1.34 (m, 2H), 1.45 (m, 4H), 1.60 (quintet, 2H), 2.19 (m, 2H), 2.24 (m, 4H), 2.72 (s, 3H), 3.02 (t, 2H), 8.02 (d, 2H), 8.40 (d, 2H); m/z: 342.
Reaction SMILES: O=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].Cl.[NH2:21][OH:22].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[OH:22][N:21]=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: NO
Reactant: CC(C)(C)OC(=O)NCCCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC(=NO)c1ccccc1
Yield: 94.8 %

Procedure:
A mixture of 1,1-dimethylethyl 4-oxo-4-phenylbutylcarbamate (2.4 g, 9.1 mmol), hydroxylamine hydrochloride (1.27 g, 2 equiv.) and sodium acetate trihydrate (2.5 g, 2 equiv.) was stirred and heated under reflux in 20% aqueous ethanol (60 ml) for 7 h. The reaction mixture was then concentrated and the residue partitioned between saturated aqueous sodium bicarbonate (100 ml) and ethyl acetate (200 ml). The organic extract was dried over magnesium sulphate and concentrated to afford a colourless solid (2.4 g, 95%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4](C)[C:5](=O)OC(C)(C)C.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18].N1C=CC=CC=1>C(OCC)(=O)C>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([O:1][CH2:2][CH2:3][NH:4][CH3:5])=[O:18]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CNCCOC(=O)c1cccc(Cl)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 146.5 %

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL) were added 3-chlorobenzoyl chloride (1.92 g) and pyridine (0.97 mL). After stirring at room temperature for 1 hr., the mixture was stirred at 60° C. for 6 hrs. Ethyl acetate (80 mL) was added to the reaction mixture, and the mixture was washed with water (20 mL), a saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride—ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 22 hrs., diethyl ether (15 mL) was added, and the precipitated solid was collected by filtration. The solid was washed twice with ethyl acetate (15 mL) and dried under reduced pressure at 60° C. to give the title compound (2.01 g) as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([OH:19])=O)=[CH:14][C:13]=3[CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][NH2:34])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][NH:34][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:20][C:13]=3[CH:14]=2)=[O:19])=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(OCCN)cc1
Reactant: O=C(O)c1cc2cc(OCCN3CCCC3)ccc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OCCNC(=O)c2cc3cc(OCCN4CCCC4)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To a solution of 5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carboxylic acid (156 mg, 0.50 mmol) and 4-(2-aminoethoxy)benzoic acid methyl ester hydrochloride (129 mg, 0.56 mmol) in DMF (4.5 ml) in a 20 ml vial was added diisopropylethylamine (0.88 ml, 5.1 mmol). A solution of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (740 μmL, 0.82 M, 0.61 mmol) in DMF was added to give a bright yellow solution. The vial was purged with nitrogen and stirred at room temperature for 18 h. The solution was removed and the residue was dissolved in EtOAc (25 ml) and washed with H2O, 1.0M aqueous K2CO3, and brine. The organic layer was dried over anhydrous MgSO4 and solvent was removed on a rotary evaporator. Purification of the residue by column chromatography on a silica gel column using 93:5:2 CH2Cl2:MeOH:TEA eluent provided 4-{2-[5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carbonylamino]-ethoxy}-benzoic acid methyl ester as a beige solid (174 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]([CH3:29])[CH2:15][CH2:16][C:17]([NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]([CH3:29])[CH2:15][CH2:16][CH2:17][NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(CCC(=O)Nc1ccc2[nH]ncc2c1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCCNc1ccc2[nH]ncc2c1)Cc1ccccc1
Temperature: 0 °C
Yield: 48.2 %

Procedure:
Lithium aluminum hydride (107 mg, 2.60 mmol) was added to a solution of N3-benzyl-N1-(1H-indazol-5-yl)-N3-methyl-β-alaninamide (200 mg, 0.973 mmol) in tetrahydrofuran (30 ml) at 0° C., and the resulting mixture was refluxed for one and a half hours. Then, the reaction solution was cooled to 0° C. and a mixture of tetrahydrofuran (10 ml) and water (10 ml) was added thereto, followed by filtration. The filtrate was concentrated and the resulting residue was diluted with chloroform and washed with a 1N-aqueous sodium hydroxide solution and then a saturated aqueous sodium chloride solution. The organic layer was dried over potassium carbonate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain N1-benzyl-N3-(1H-indazol-5-yl)-N1-methyl-1,3-propanediamine (138 mg, 72%).
Reaction SMILES: [OH-].[Na+].O.[F:4][C:5]1[CH:17]=[CH:16][C:8](/[CH:9]=[CH:10]/[C:11]([O:13]CC)=[O:12])=[CH:7][CH:6]=1>C(O)C>[F:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CCOC(=O)/C=C/c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(F)cc1

Procedure:
A solution of 4 g. of sodium hydroxide in 30 ml. of water is added to a solution of 19.4 g. (0.1 mole) of ethyl trans-4-fluorocinnamate (Compound LXV) in 350 ml. of ethanol, and the reaction mixture is stirred at 70° C. for 18 hours. The solvent is evaporated at reduced pressure, and the residue is dissolved in water. The solution is washed once with methyl t-butyl ether and acidified with 6N. hydrochloric acid. The resulting precipitate is washed twice with water and dried to obtain the product (15.5 g. (93%)). An analytical sample was recrystallized from ethyl acetate, m.p. 204°-206° C.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C(=O)(O)[O-].[Na+].COCCOCCOC.[C:29]1([C:35]2[NH:44][C:38]3[N:39]=[CH:40][N:41]=[C:42](O)[C:37]=3[CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[C:29]1([C:35]2[NH:44][C:38]3[N:39]=[CH:40][N:41]=[C:42]([SH:2])[C:37]=3[CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Oc1ncnc2[nH]c(-c3ccccc3)cc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: Sc1ncnc2[nH]c(-c3ccccc3)cc12
Reaction time: 1 h
Yield: 94.8 %

Procedure:
After adding 6.19 g of phosphorus pentasulfide, 6.24 g of sodium bicarbonate and 25 ml of diglyme to 2.45 g of the 6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol described in WO97/02266 and PCT/EP96/02728, and stirring the mixture for 1 hour, an additional 3 g of phosphorus pentasulfide and 3 g of sodium bicarbonate were added and the mixture was stirred for 1 hour. There were further added another 3 g of phosphorus pentasulfide and 3 g of sodium bicarbonate, and the mixture was stirred for 1 hour. It was then returned to room temperature, water was added, the mixture was stirred for 10 minutes, and the precipitated crystals were filtered out, washed with water and dried to obtain 2.5 g of the title compound.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:21])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:11]=1[C:19]#[N:20])([CH3:4])([CH3:3])[CH3:2].[OH2:22].NN>C(O)C.[Ni]>[C:1]([NH:5][CH2:6][CH:7]([OH:21])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]=1[C:19]([NH2:20])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)(C)NCC(O)COc1cccc([N+](=O)[O-])c1C#N
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: CC(C)(C)NCC(O)COc1cccc(N)c1C(N)=O

Procedure:
12.2 g of 1-tert.-butylamino-3-(2-cyano-3-nitrophenoxy)-2-propanol are reacted in 200 ml of ethanol with 11 g of hydrazine hydrate and Raney nickel, analogously to Example 4(d), and after filtering and evaporating the filtrate, this gives crude 6-(3-tert.-butylamino-2-hydroxy-propoxy)-anthranilamide in the form of an oil which is used further without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1>S(=O)(=O)(O)O>[Br:18][C:7]1[C:6]([F:10])=[C:3]([C:2]([F:1])=[CH:9][CH:8]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1c(F)cccc1F
Agent: O=S(=O)(O)O
Product: N#Cc1c(F)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of compound 2,6-difluorobenzonitrile (5 g, 36 mmol) in concentrated sulfuric acid (25 mL) was added with NBS (7 g, 39.6 mmol) at 0° C. and stirred at ambient temperature for 2 days. Ice was added to the reaction solution. The mixture was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO3 solution, brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified with fast column chromatograph to give compound 3-bromo-2,6-difluorobenzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.78˜7.83 (m, 1H), 6.98˜7.03 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14][O:15]CC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([F:44])[CH:43]=1)[C:39]#[N:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:14][O:15][C:43]3[C:36]([F:35])=[CH:37][C:38]([C:39]#[N:40])=[CH:41][C:42]=3[F:44])[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Reactant: N#Cc1cc(F)cc(F)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1cc(F)c(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 1, intermediate c), 3,5-difluorobenzonitrile (commercially available), triphenylphosphine and di-tert-butyl azodicarboxylate. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:tert-butyl methyl ether (100:0 to 50:50). The product-containing fractions were pooled and chromatographed on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile and water. Colorless foam (49%). MS (Turbo Spray): m/z=528.1 [M+H].
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:31]([O:32][CH3:33])=[CH:30][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[CH:6]=1)[N:14]=[CH:13][C:12]([C:17]#[N:18])=[C:11]3[NH:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([Cl:28])=[CH:22][C:21]=1[Cl:29].[NH:34]1[CH:38]=[CH:37][N:36]=[N:35]1.[OH-].[Na+]>CN(C)C=O>[Cl:29][C:21]1[CH:22]=[C:23]([Cl:28])[C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:11]1[C:10]2[C:15](=[CH:16][C:7]3[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:35]4[N:36]=[CH:37][CH:38]=[N:34]4)[C:31]([O:32][CH3:33])=[CH:30][C:8]=3[CH:9]=2)[N:14]=[CH:13][C:12]=1[C:17]#[N:18]
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Reactant: c1c[nH]nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCn5nccn5)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 80 °C
Yield: 21.4 %

Procedure:
A mixture of 0.31 g (0.62 mmol) of 8-(2-chloroethoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.36 mL (6.1 mmol) of 1H-1,2,3-triazole and 0.11 g (2.8 mmol) of sodium hydroxide powder in 5 mL of N,N-dimethyl formamide is heated at 80° C. for 4.5 hours, then cooled and poured on to ice. The solid is collected by filtration, washed with water and dried. The two isomers are separated by silica gel flash chromatography, using first 7:3 ethyl acetate/hexane, then a 100:0 to 9:1 gradient of ethyl acetate/methanol. The less polar material, 0.071 g of 4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-[1,2,3]triazol-2-yl-ethoxy)benzo[g]quinoline-3-carbonitrile, is obtained as yellow solid, mp 285-287° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:18]([OH:23])(=O)[CH2:19][CH2:20][CH3:21].Cl.C[N:26](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([CH:19]([CH2:20][CH3:21])[C:18]([NH2:26])=[O:23])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reactant: CCCC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: CCC(C(N)=O)c1cccc(-n2ncc3c(N)ncnc32)c1
Reaction time: 0.17 h
Yield: 12 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (38 mg, 1.1 eq, 0.17 mmol) was added to a solution of butyric acid (13 mg, 1.0 eq, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 1.1 eq, 0.17 mmol), 1-hydroxybenzotriazole (21 mg, 1.0 eq, 0.15 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 18 hours, after which methanol (1 ml) was added and the solvents were removed in vacuo. The resultant solid purified by semi-preparative HPLC to yield the title compound as a white solid (5.4 mg, 0.018 mmol, 12%). LCMS: [M+H]+=297, Rt=1.48 min, 100% purity.