Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O+](CC)CC)[CH3:7].[C:13]1([C:19]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:27]3[CH:23]([CH2:24][N:25]([C:28](=[O:38])[CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])[CH2:26]3)[C:22](=[O:39])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOCC>ClCCl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O:38][C:28](=[N+:25]1[CH2:24][CH:23]2[CH:27]([C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:20][CH2:21][C:22]2=[O:39])[CH2:26]1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[CH3:7]
Reactant: COc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(Cc1ccccc1OC)=[N+]1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
Triethyloxonium tetrafluoroborate (2.35 g) is added to a solution of (3aRS,7aRS)-7,7-diphenyl-2-[(2-methoxyphenyl)acetyl]perhydro-4-isoindolone (5 g) in dichloromethane (10 cc). The reaction mixture is left stirring for 20 hours at room temperature; it is then treated with ether (100 cc) and the precipitate obtained is drained, washed with ether (100 cc) and dried. (3aRS,7aRS)-2-[1-Ethoxy-2-(2-methoxyphenyl)ethylidene]-4-oxo-7,7-diphenylperhydroisoindolium tetrafluoroborate (5.75 g) is obtained in the form of a yellow powder, which is used in the crude state for the following manipulation.
Reaction SMILES: [NH2:1][C:2](=[O:37])[CH:3]([OH:36])[CH:4]([NH:12][C:13]([C:15]1[C:16]([N:21]2[CH:25]=[C:24]3[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][C:23]3=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.C(#N)C>[NH2:1][C:2](=[O:37])[C:3](=[O:36])[CH:4]([NH:12][C:13]([C:15]1[C:16]([N:21]2[CH:25]=[C:24]3[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:28][C:23]3=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(O)C(N)=O)nc2C1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2cn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(=O)C(N)=O)nc2C1
Yield: 62.6 %

Procedure:
Oxidation of tert-butyl 2-(3-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-ylcarbamoyl)pyridin-2-yl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate (88 mg, 0.174 mmol) as described in example 1.4 and purification by chromatography over Chromabond RP-C18 (eluent: water/acetonitrile) gave 55 mg of an amorphous solid; ESI-MS [M+H]+: 505.2. 1H-NMR (400 MHz, DMSO), δ[ppm]: 8.83 (m, 1H), 8.52 (m, 1H), 8.15 (m, 1H), 8.06 (m, 1H), 7.84 (m, 1H), 7.72 (m, 1H), 7.44 (m, 1H), 7.23 (m, 4H), 7.17 (m, 1H), 5.26 (m, 1H), 4.35 (m, 2H), 4.18 (m, 1H), 4.0 (m, 1H), 3.09 (m, 1H), 2.73 (m, 1H), 1.49 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([OH:1])[CH:11]=[C:10]([O:12][C:17]2[CH:18]=[CH:19][C:14]([Br:13])=[CH:15][CH:16]=2)[CH:9]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(O)cc(Oc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.1 %

Procedure:
To a solution of methyl 3,5-dihydroxybenzoate (8.0 g, 47.6 mmol) in DCM (800 mL) was added 4-bromophenylboronic acid (9.56 g, 47.6 mmol), copper(II) acetate (8.6 g, 47.6 mmol), 4 A molecular sieves (4 g), and pyridine (19.4 mL, 238.0 mmol). After stirring at rt for 72 h, more 4-bromophenylboronic acid (7 g, 35 mmol) was added and stirring continued for another 16 h. The solvent was evaporated and the reaction mixture was re-dissolved in diethyl ether. Washed with 1N HCl, brine, dried (MgSO4) and evaporated. The residue was subjected to silica gel chromatography using an ethyl acetate-hexane gradient to afford 3.4 g (22%) of 3-(4-Bromophenoxy)-5-hydroxybenzoic acid methyl ester. 1H NMR (300 MHz, DMSO-d6) δ 3.78 (s, 3H), 6.64-6.66 (m, 1H), 6.89 (dd, 1H, J=2, 1 Hz), 7.02 (dd, 2H, J=7, 2 Hz), 7.12 (dd, 1H, J=2, 1 Hz), 7.57 (dd, 2H, J=7, 2 Hz).
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][C:13]=2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=O)=O)=CC=1.[OH-].[K+]>C(O)C.O>[CH2:22]([O:21][C:13]1[CH:14]=[C:15]([CH2:18][CH2:19][CH3:20])[CH:16]=[CH:17][C:12]=1[OH:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCc1ccc(OS(=O)(=O)c2ccc(C)cc2)c(OCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1ccc(O)c(OCc2ccccc2)c1
Yield: 85.7 %

Procedure:
To a solution of 2-(benzyloxy)-4-propylphenyl 4-methylbenzenesulfonate (0.07 mmol; 28 mg) under argon, in a mixture of ethanol (0.2 mL) and water (0.1 mL), was added KOH (0.09 mmol; 5 mg). The reaction was refluxed for 1 hr, then hydrolysed with NH4Cl sat. (3 mL), and extracted with ethyl acetate (3*5 mL). Combined organic phases were washed with saturated NaHCO3 (3 mL), dried over MgSO4, concentrated. The residue was purified by preparative TLC (cyclohexane/dichloromethane) to yield the title compound as a clear oil (16 mg; 0.06 mmol; 86%).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:6][OH:7]>>[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([Cl:11])[C:10]=1[C:6](=[O:7])[C:5]1[CH:8]=[CH:9][C:10]([Cl:1])=[CH:3][CH:4]=1)[CH2:6][OH:7]
Reactant: OCc1cc(Cl)cc(Cl)c1
Reactant: Cl
Product: O=C(c1ccc(Cl)cc1)c1c(Cl)cc(CO)cc1Cl
Temperature: 25 °C

Procedure:
Concentrated aqueous HCl (25 ml) is added to the above reaction mixture, which is allowed to warm to room temperature and aged for 12 hours. The reaction is monitored by silica gel TLC eluted with 10% EtOAc in hexane (Rf 5: 0.03). Upon completion the reaction mixture is partitioned between EtOAc (100 ml) and cold H2O (300 ml) and the layers are separated. The organic layer is washed with H2O (150 ml), 1N aqueous NaOH (2×150 ml, thoroughly to remove 4-chlorobenzoic acid), H2O (150 ml), and 0.1N aqueous HCl. The organic layer is dried (Na2SO4), filtered, and concentrated to give crude crystalline 3,5-dichloro-4-(4-chlorobenzoyl)-benzyl alcohol, 5 (9.97 g), 60 weight percent pure (70% assay yield from alcohol 2) by HPLC assay on DuPont Zorbax ODS-C8 eluted isocratically at ambient temperature at 2 ml/min with 55% H2O, 45% CH3CN, and 0.1% H3PO4 and monitored by UV detection at 230 mn (retention times, alcohol 2: 5.1 min; benzophenone 5: 14.4 min; 4-chlorobenzoic acid: 2.9 min).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:49][CH2:50][N:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:49][CH2:50][N:51]3[CH2:55][CH2:54][CH2:53][CH2:52]3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Reactant: OCCN1CCCC1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCCC2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 11 %

Procedure:
1,4-Diethylazodicarboxylate (205 μL) is added to a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41, triphenylphospine (341 mg), and 1-(2-hydroxyethyl)pyrrolidine (292 μL) in THF (10 mL). The reaction mixture is stirred at room temperature for 20 h and then poured into 0.5 N aqueous NaOH solution (25 mL). The mixture is extracted with EtOAc (3×25 mL). The organic layer is dried (Na2SO4) and concentrated. The crude product is purified by column chromatography (CH2Cl2/methanol, 100/1; 50/1; 20/1; 10/1) followed by recrystallization from ethanol to afford 54 mg (11%) of the title compound as a white solid.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[OH-].[K+].[C:14](=S)=[S:15]>C(O)C>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:4]2[N:5]=[C:14]([SH:15])[O:2][C:3]=2[CH:9]=1
Reactant: COc1ccc(N)c(O)c1
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2nc(S)oc2c1
Reaction time: 24 h

Procedure:
A 50 mg portion of 2-hydroxy-4-methoxyaniline hydrochloride dissolved in 15 ml of ethanol was mixed with 16 mg of potassium hydroxide. After 10 minutes of reaction, to this was added 50 ml of carbon disulfide to carry out 24 hours of heating under reflux. The reaction mixture was concentrated under a reduced pressure, and the resulting residue was dissolved in 100 ml of dichloromethane, washed with water, dehydrated with magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (dichloromethane:methanol=30:1) to obtain 46 mg of 6-methoxy-2-mercaptobenzoxazole.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.BrBr.[C:12](=O)(O)[O-].[Na+]>C(O)(=O)C.CCCCCC>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: O=C([O-])O
Reactant: c1ccc2c(c1)CCO2
Agent: BrBr
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)CCO2
Reaction time: 1 h
Yield: 28 %

Procedure:
To a chilled (10° C.) solution of 10 g (83 mmol) of 2,3-dihydrobenzofuran in 50 mL of acetic acid, 4 mL (78 mmol) of bromine in 6 mL of acetic acid was added dropwise over a 10 minute period. After 1 hour, the mixture was made basic by cautiously pouring the reaction mixture into saturated/solid aqueous sodium bicarbonate and stirring overnight. The mixture was then extracted with three 100 mL portions of EtOAc. The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, three 50 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated to afford a yellow oil. The oil was diluted with hexane and passed through a pad (600 mL funnel) of silica gel eluting with hexane to afford a white solid which was diluted with cold (dry ice-acetone) hexane and collected by filtration to afford 4.7 g (28%) of the title compound as a white solid, m.p. 45° C.-48° C. The filtrate was concentrated to afford 5.1 g of 5-bromo-2,3-dihydrobenzofuran which was 70% pure.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16]Br>CN(C)C=O>[C:1]([C:3]1([C:4]([O:6][CH3:7])=[O:5])[CH2:16][CH2:15]1)#[N:2]
Reactant: COC(=O)CC#N
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C#N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a mixture of methyl cyanoacetate (21.6 ml, 244.0 mmol) and potassium carbonate (52.9 g, 383.0 mmol) in N,N-dimethylformamide (200 ml) was added 1,2-dibromoethane (15.0 ml, 174.0 mmol). The reaction mixture was stirred at room temperature for 16 h and then filtered. The filtrate was partitioned between diethyl ether and brine and the organic phase was separated, washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (15.1 g).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:36][NH2:37]>>[CH3:36][NH:37][C:25]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:14][CH:15]=2)[N:24]=1)=[O:26]
Reactant: CN
Reactant: C[C@@H](c1ccc(-c2cccc(C(=O)O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CNC(=O)c1cccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)n1

Procedure:
The title compound was prepared from (6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylic acid and methylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Example 203. Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([O:22][C:23](=[O:37])[N:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[N:9]=[CH:10][N:11]([C:20]=2[N:21]=1)[C@@H:12]1[O:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[CH2:13]1)(=[O:3])[NH2:2].[CH3:38][O:39][C:40]1[CH:61]=[CH:60][C:43]([C:44](Cl)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[CH:42][CH:41]=1.O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[N:6]=[C:7]([O:22][C:23](=[O:37])[N:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[N:9]=[CH:10][N:11]([C:20]=2[N:21]=1)[C@@H:12]1[O:19][C@H:16]([CH2:17][O:18][C:44]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[C:43]2[CH:42]=[CH:41][C:40]([O:39][CH3:38])=[CH:61][CH:60]=2)[C@@H:14]([OH:15])[CH2:13]1)(=[O:3])[NH2:2]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: NC(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(OC(=O)N(c5ccccc5)c5ccccc5)nc(NC(N)=O)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
The above-obtained 2-N-carbamoyl-6-O-diphenylcarbamoyldeoxyguanosine (1.19 g, 2.35 mmol) was azeotroped with anhydrous pyridine three times and dissolved in anhydrous pyridine (23 mL), and 4,4′-dimethoxytrityl chloride (917 mg, 2.70 mmol) was added thereto. The mixture was stirred at room temperature for 2 hours, and sodium bicarbonate water (8 mL) was added thereto to terminate the reaction. Then, the reaction solution was extracted with ethyl acetate (150 mL)/sodium bicarbonate water (120 mL) once and then with ethyl acetate (150 mL)/brine (100 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (N60: spherical neutral silica gel) with methanol/2% to 3% chloroform containing 1% triethylamine to give 2-N-carbamoyl-5′-O-(4,4′-dimethoxytrityl)-6-O-diphenylcarbamoyldeoxyguanosine (1.45 g, 76%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:29])=[C:25]([CH2:27][OH:28])[CH:26]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:29][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)=[CH:26][C:25]=1[CH2:27][OH:28]
Reactant: Nc1ccc(F)c(CO)c1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)Nc2ccc(F)c(CO)c2)nc(N2CCOCC2)cc1=O
Yield: 45.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 184 mg of (5-amino-2-fluorophenyl)methanol, and 285 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of N,N-dimethylformamide. 157 mg of N-[4-fluoro-3-(hydroxymethyl)phenyl]-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a grey solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CCCc3ccc(Cl)cc3)n2)ccc1F
Yield: 80.8 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(4-chlorophenyl)-1-propanol methanesulfonate were reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 1(7) to yield the title compound as a yellow crystalline powder (yield: 80.8%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2cc(O)ccc2[nH]1)N1CCOCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A mixture of 1.77 g (0.01 mol) 5-hydroxy-indole-2-carboxylic acid in 25 ml DMF were cooled to 0° C. and treated with 3.53 g (0.011 mol) 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborat, 0.96 g (0.011 mol) morpholine and 8.6 ml (0.05 mol) N-ethyldiisopropylamine. The mixture was allowed to warm to room temperature and stirred for additional 16 h. After evaporation to dryness the residue was taken up in 75 ml ethyl acetate, 75 ml THF, 100 ml water and 50 ml 10% NaHCO3 solution. The aqueous phase was extracted with 50 ml ethyl acetate and 50 ml THF. The combined organic layers were washed with 100 ml NaCl satur.aq., dried with Na2SO4, filtered and evaporated to dryness. The residue was suspended in 30 ml of a mixture of ethyl acetate/methanol 9/1, filtered and again suspended in 20 ml of a mixture of ethyl acetate/methanol 9/1. The residue was washed in diethyl ether and dried at 40° C. under vacuum to yield 2.04 g (83%) of the title compound as white solid. MS (m/e): 247.4 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[O:38]1C(C(Cl)=O)=C[CH:40]=[N:39]1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([C:18]3[O:38][N:39]=[CH:40][CH:19]=3)=[O:20])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:3]=1
Reactant: O=C(Cl)c1ccno1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)c1ccno1

Procedure:
This compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate JJ4) by replacing propionyl chloride with isoxazole-5-carbonyl chloride. (MH+ 560.28)
Reaction SMILES: [C:1]1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(Cl)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:16].[K+]>CC(C)=O.O>[C:1]1([Si:7]2([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:16][Si:7]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:16][Si:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:16][Si:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: c1ccc([Si]2(c3ccccc3)O[Si](c3ccccc3)(c3ccccc3)O[Si](c3ccccc3)(c3ccccc3)O[Si](c3ccccc3)(c3ccccc3)O2)cc1
Yield: 94.1 %

Procedure:
A mixture of 510 g of diphenyldichlorosilane in 500 ml of acetone was added dropwise in the course of 3 hours to a hot solution, at 60° C, of 340 g of KOH in 1 l of water, while stirring vigorously. The acetone and a little water were then distilled off and, after cooling the residue, the crystalline octaphenylcyclotetrasiloxane was filtered off and washed with water. After drying, 376 g (94% yield) of octaphenylcyclotetrasiloxane of melting point 187° C (metastable crystal modification) were obtained. After recrystallization from toluene, the product had a melting point of 201° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([O:51][CH3:52])[C:37]=1[OH:53]>>[NH2:26][CH:23]1[CH2:24][CH2:25][N:21]([C:18]2[N:19]=[CH:20][C:15]([NH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([C:40]5[CH:39]=[C:38]([O:51][CH3:52])[C:37]([OH:53])=[C:36]([Cl:35])[CH:41]=5)[CH:11]=4)[N:6]=[CH:5][C:4]=3[C:1](=[O:3])[CH3:2])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(C)=O)c(Nc4ccc(N5CCC(N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 14.6 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(3-acetyl-6-bromoquinolin-4-ylamino) pyridin-2-yl)pyrrolidin-3-ylcarbamate (80 mg, 0.15 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.23 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (11 mg, 15% over two steps) as a yellow-brown: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.28 (s, 1H), 8.31-8.25 (m, 2H), 8.06-7.99 (m, 2H), 7.83 (dd, J=9.2, 2.7 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 7.98 (d, J=9.2 Hz, 1H), 6.71 (d, J=2.2 Hz, 1H), 4.16-4.07 (m, 1H), 4.07-3.96 (m, 2H), 3.91 (s, 3H), 3.88-3.79 (m, 1H), 3.79-3.69 (m, 211), 2.80 (s, 3H), 2.63-2.53 (m, 1H), 2.34-2.23 (m, 1H); ESI MS m/z 504 [C27H26ClN5O3+H]+; HPLC 95.4% (AUC), tR=9.37 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].CC(C)([O-])C.[K+].[NH2:20]Cl>CN(C=O)C.CCOCC>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([NH2:20])[CH:9]=[CH:8]2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Reactant: NCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc2c(ccn2N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of 5-methanesulfonyl-1H-indole (4.1 mmol) and potassium tert-butoxide (8.2 mmol) in DMF (20 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl in ether (41 mL) is added drop-wise for 15 min at rt and the reaction mixture is stirred at rt for 2 h. The reaction mixture is quenched with 10% Na2S2O3 aqueous solution, and extracted with ether (3×40 mL). The combined organic layer is washed with water (2×30 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with EtOAc and heptane to afford 5-methanesulfonyl-indole-1-ylamine (230 mg, 32%) as a solid. MS: 211 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.08 (s, 3H), 4.94 (br, 2N—H), 6.55 (d, H), 7.34 (m, H), 7.57 (d, H), 7.73 (m, H), 8.21 (m, H).