Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[BrH:7].[CH3:8][N:9]1[CH2:15][CH2:14][C:13]2=[CH:16][C:17](=[O:21])[C:18](=[O:20])[CH:19]=[C:12]2[CH2:11][CH2:10]1>CO>[BrH:7].[OH:21][C:17]1[C:18]([OH:20])=[CH:19][C:12]2[CH2:11][CH2:10][N:9]([CH3:8])[CH2:15][CH2:14][C:13]=2[C:16]=1[S:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC2=CC(=O)C(=O)C=C2CC1
Reactant: Sc1ccco1
Agent: Br
Solvent: CO
Product: CN1CCc2cc(O)c(O)c(Sc3ccco3)c2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.1 g. (0.0011 mole) of 2-furanthiol in 200 ml. of methanol is added portionwise 2.3 g. (0.0084 mole) of 3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione hydrobromide. After stirring for 1 hour at room temperature the reaction mixture is filtered and the filtrate concentrated in vacuo to give 7,8-dihydroxy-6-(2-furylthio)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: [NH2:1][C:2]1[C:16]2[C:15](=[O:17])[C:14]([C:18]([OH:20])=[O:19])=[CH:13][N:7]3[C@@H:8]([CH2:11][F:12])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:22].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][CH2:30][CH2:31][NH2:32].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:16]2[C:15](=[O:17])[C:14]([C:18]([OH:20])=[O:19])=[CH:13][N:7]3[C@@H:8]([CH2:11][F:12])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][CH2:31][CH2:30][NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[C:3]=1[F:22]
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](CF)CO2
Reactant: NCCNc1ccccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c(F)c(NCCNc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](CF)CO2
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 67.1 %

Procedure:
A mixture of (3R)-8-amino-9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (200 mg, 0.636 mmol), 2-(2-pyridylamino)ethylamine (131 mg, 0.955 mmol), and triethylamine (0.13 mL, 0.933 mmol) in DMSO (2.0 mL) was stirred at 120° C. for 2.5 h. After dilution of the reaction mixture with 10% MeOH in CHCl3, the whole mixture washed with water and the washing was extracted with 10% MeOH in CHCl3 three times. The combined the organic layer and the extracts washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography of the residue (10% MeOH in CHCl3) gave (3R)-8-amino-9-fluoro-3-fluoromethyl-2,3-dihydro-7-oxo-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (184 mg, 67%) as a yellow powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([CH3:35])[CH3:34]>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:39]1[CH2:40][CH2:41][N:36]([CH:33]([CH3:35])[CH3:34])[CH2:37][CH2:38]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(C(=O)[C@@H]2C[C@H](NCc3ccc(F)cc3F)CN2Cc2ccccc2)CC1
Yield: 9.3 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-isopropyl-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (6.2 mg, 9.3%) as light yellow oil. MS m/e=457.4 [M+H]+.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[NH:27][C:28](=[O:44])[NH:29][C:30]1[C:31]2[S:38][C:37](/[CH:39]=[CH:40]/[C:41]([OH:43])=O)=[CH:36][C:32]=2[N:33]=[CH:34][N:35]=1.[N:45]1([CH2:51][CH2:52][NH2:53])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.C(N(CC)CC)C>CN(C=O)C>[Cl:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[C:21]=1[NH:27][C:28](=[O:44])[NH:29][C:30]1[C:31]2[S:38][C:37](/[CH:39]=[CH:40]/[C:41]([NH:53][CH2:52][CH2:51][N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)=[O:43])=[CH:36][C:32]=2[N:33]=[CH:34][N:35]=1
Reactant: O=C(O)/C=C/c1cc2ncnc(NC(=O)Nc3c(Cl)cccc3Cl)c2s1
Reactant: NCCN1CCCCC1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1cc2ncnc(NC(=O)Nc3c(Cl)cccc3Cl)c2s1)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
Diphenylphosphoryl azide (0.085 ml) was added to a mixture of (E)-3-{4-[3-(2,6-dichlorophenyl)ureido]thieno[3,2-d]pyrimidin-6-yl)acrylic acid hydrochloride salt (0.11 g), 2-piperidinoethylamine (0.064 g), triethylamine (0.07 ml) and DMF (1.5 ml). The mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. The material so obtained was triturated under diethyl ether, isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.087 g); NMR Spectrum: (DMSOd6 and CF3COOD) 1.3-1.5 (m, 1H), 1.6-1.8 (m, 4H), 1.85 (d, 2H), 2.95 (t, 2H), 3.2 (t, 2H), 3.55 (d, 2H), 3.6 (t, 2H), 6.82 (d, 1H, J=16 Hz), 7.4 (t, 1H), 7.6 (d, 1H), 7.86 (s, 1H), 7.86 (d, 1H), 8.95 (s, 1H); Mass Spectrum: M+H+ 519 and 521.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]Br)=[CH:5][CH:4]=1.NC(N)=[S:15].[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][SH:15])=[CH:5][CH:4]=1
Reactant: NC(N)=S
Reactant: COc1ccc(CCCBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(CCCS)cc1
Reaction time: 2 h

Procedure:
A mixture of 3-(p-methoxyphenyl)-1-propylbromide (14 g; 61 mmol) and thiourea (5.1 g; 67 mmol) in ethanol (150 mL) was refluxed for 48 hours. Evaporation of the solvent provided a clear glassy compound, which was dissolved in 50 mL of water and treated with 100 mL of 40% aqueous sodium hydroxide. After stirring the resulting mixture for two hours, the product was extracted into ether (3×), and the combined organic extracts were washed with sodium bicarbonate and brine, dried, and concentrated. Chromatographic purification of the crude thiol on a silica gel column eluting with 2% either in hexane delivered 10.2 g of 3-(p-methoxyphenyl)-1-propylmercaptan as a clear liquid 1H NMR (300 MHz, CDCl3):δ 1.34 (t, 1H); 1.88-1.92 (m,2H); 2.49-2.53 (m,2H); 2.64-2.69 (m, 2H); 3.77 (s, 3H); 6.80-6.84 (m,2H); 7.06-7.24 (m,2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][N:13]([C@@H](C3C=CC=CC=3)C)[CH2:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.ClC(OC(Cl)C)=O.CO>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][NH:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccccc1)N1CCCOC(c2cccc(Br)c2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCCl
Product: Brc1cccc(C2CNCCCO2)c1
Temperature: 25 °C
Yield: 111 %

Procedure:
To a solution of diastereomerically pure 2-(3-bromophenyl)-4-((R)-1-phenylethyl)-[1,4]oxazepane (8.92 g, 24.8 mmol) in 1,2-dichloroethane (42 ml) was added 1-chloroethyl chloroformate (8.85 g, 61.9 mmol) at room temperature. The mixture was refluxed for 5 hours and cooled to room temperature. After methanol (20 ml) was added, the solution was refluxed for another 5 hours. The mixture was concentrated under reduced pressure to afford the crude product. This crude product was washed with ether, dried under reduced pressure to yield 2-(3-bromophenyl)-[1,4]oxazepane as white solid (7.05 g, 97%). An analytical sample for X-ray was obtained by crystallization from ethanol, and the absolute configuration of this compound was found to be the (R)-configuration by a method using a Flack parameter. The absolute configuration was determined by X-ray crystallography of a sample crystallized from ethanol.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][C:22]1[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:25][CH:26]=1)(=O)=O>>[N:1]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:25][CH:26]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCCc1ccccc1OCc1coc(/C=C/c2ccccc2)n1
Product: C(=C/c1nc(COc2ccccc2CCCn2ccnc2)co1)\c1ccccc1
Yield: 80 %

Procedure:
In substantially the same manner as in Working Example 8, imidazole was allowed to react with 3-[2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate to give 4-[2-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole as an oily product. The yield was 80%.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:14]([F:19])([F:18])C([O-])=O.[Na+]>COCCOCCOC.C(Cl)Cl>[F:18][C:14]1([F:19])[C:2]2([CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:1]1
Reactant: C=C1CCC(C(=O)OCC)CC1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: ClCCl
Product: CCOC(=O)C1CCC2(CC1)CC2(F)F
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-methylenecyclohexanecarboxylate (0.15 g, 0.892 mmol) in diglyme (3 mL) was added a solution of sodium 2-chloro-2,2-difluoroacetate (0.544 g, 3.57 mmol) in 5 ml of diglyme via syringe pump at 0.5 ml/h at 150° C. The reaction was cooled to rt, then diluted with DCM and washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was charged to a 40 g silica gel cartridge which was eluted with a 20 min gradient of 0-20% EtOAc in hexane to yield ethyl 1,1-difluorospiro[2.5]octane-6-carboxylate. 1H NMR (400 MHz, CDCl3) ppm 4.09-4.19 (2H, m), 2.29-2.45 (1H, m), 1.89-2.03 (2H, m), 1.55-1.72 (5H, m), 1.45-1.54 (1H, m), 1.31-1.39 (1H, m), 1.21-1.30 (3H, m), 0.84-0.94 (1H, m).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20].[CH:22]1([O:27][C:28]2[C:29]([O:38][CH3:39])=[N:30][CH:31]=[C:32]([CH:37]=2)[C:33](OC)=[O:34])[CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>O1CCCC1>[CH:22]1([O:27][C:28]2[CH:37]=[C:32]([C:33](=[O:34])[CH2:20][C:19]3[C:18]([Cl:21])=[CH:17][N:16]=[CH:15][C:14]=3[Cl:13])[CH:31]=[N:30][C:29]=2[O:38][CH3:39])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COC(=O)c1cnc(OC)c(OC2CCCC2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ncc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
n-Butyl lithium (4.9 mL of a 2.5M solution in hexanes) is added dropwise to a stirred solution of diisopropylamine (1.7 mL) in dry tetrahydrofuran (20 mL) at −78° C. under a nitrogen atmosphere. After 30 minutes. a solution of 3,5-dichloro-4-methylpyridine (1.95 g) in dry tetrahydrofuran (10 mL) is added dropwise and the solution stirred at −78° C. for a further 30 minutes. A solution of methyl 5-cyclopentyloxy-6-methoxynicotinoate (1.5 g) in dry tetrahydrofuran (15 mL) is added and the red mixture stirred and allowed to warm to room temperature during 4 hours. After stirring overnight at room temperature the mixture is treated with saturated aqueous ammonium chloride. The tetrahydrofuran layer is separated and the aqueous phase is extracted with ethyl acetate. The combined organic layers are washed with saline and dried over anhydrous magnesium sulphate. Concentration gives a light brown oil which is triturated with a mixture of n-pentane and methyl t-butyl ether to give 1-(5-cyclopentyloxy-6-methoxypyridin-3-yl)-2-(3,5-dichloropyrid-4-yl)ethanone (1 g) in the form of a beige solid, m.p. 118-9° C. [Elemental analysis: C, 56.8; H, 4.82; Cl, 18.5; N, 7.40% calculated: C, 56.7; H, 4.76; Cl, 18.6; N, 7.35%.]
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:20]=[C:19]([CH2:21]Br)[S:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]([F:34])[C:25]=1[C:26]([NH2:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:20]=[C:19]([CH2:21][O:33][C:32]2[C:24]([F:23])=[C:25]([C:29]([F:34])=[CH:30][CH:31]=2)[C:26]([NH2:28])=[O:27])[S:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nsc(CBr)n2)c(OCc2ccccc2)c1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(Cl)cc3OCc3ccccc3)ns2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
To a solution of 3-(2-(benzyloxy)-4-chlorophenyl)-5-(bromomethyl)-1,2,4-thiadiazole (0.33 g, 0.83 mmol) in DMF (10 ml) was added 2,6-difluoro-3-hydroxybenzamide (0.13 g, 0.75 mmol) and potassium carbonate (0.403 g, 2.92 mmol). The reaction mixture was stirred at room temperature for 16 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under vacuum, added 25 ml water and extracted with ethyl acetate (3×25 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 40% EtOAc-Hexane) to get the desired product (0.123 g, 30%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:13]O>S(=O)(=O)(O)O>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[C:3]=1[O:11][CH3:12]
Reactant: CO
Reactant: COc1c(Br)cccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Br)c1OC
Temperature: 25 °C

Procedure:
Approximately two drops of sulfuric acid were added to a solution of 3-bromo-2-methoxy-benzoic acid (10.00 g, 43.30 mmol) in methanol and the resulting reaction mixture was refluxed for 14 hours. The reaction mixture was cooled to room temperature, and concentrated, then diluted with EtOAc. The organic layer was washed with saturated NaHCO3 (3×150 mL), H2O (2×250 mL), brine (1×250 mL) and dried over MgSO4. The crude product was purified by column chromatography using hex:EtOAc (4.5:0.5) as the eluant to give the title ester. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 3.91 (s, 3H), 3.94 (s, 3H), 6.92 (d, J=8.79 Hz, 1H), 7.99 (dd, J=8.79 Hz, 1H), 8.24 (d, J=2.35 Hz, 1H).
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:24]3[C:23]([NH2:25])=[N:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(O[CH:31]1[CH2:37][CH:36]2[N:38]([CH3:39])[CH:33]([CH2:34][CH2:35]2)[CH2:32]1)(C)(=O)=O>CN(C)C=O>[NH2:25][C:23]1[C:24]2[C:16]([C:13]3[CH:12]=[CH:11][C:10]([O:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:15][CH:14]=3)=[CH:17][N:18]([CH:31]3[CH2:32][CH:33]4[N:38]([CH3:39])[CH:36]([CH2:35][CH2:34]4)[CH2:37]3)[C:19]=2[N:20]=[CH:21][N:22]=1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: CN1C2CCC1CC(OS(C)(=O)=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C2CCC1CC(n1cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc31)C2
Temperature: 75 °C
Reaction time: 168 h

Procedure:
Sodium hydride (168 mg, of a 60% dispersion in mineral oil) was added to a mixture of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (770 mg, in dimethylformamide (30 ml). 3-Mesyloxy-8-methyl-8-azabicyclo[3.2.1 ]octane (900 mg, prepared as described in J.A.C.S. 1958, 80, 4679) in dimethylformamide (10 ml) was added under nitrogen with stirring. The mixture was warmed at 75° C. for 5 hours (and left standing at ambient temperature for 7 days). The solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate to give a residue which was purified by flash column chromatography on silica using ethyl acetate/methanol (50:50) as the mobile phase to remove starting material and then a mixture of ethyl acetate/methanol/triethylamine (5:5:1) as the mobile phase to elute the product. Appropriate fractions were combined and evaporated to give a solid which was triturated with ether and filtered to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-8-methyl-8-azabicyclo[3.2.1]octane, m.p. 238-250° C.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[C:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16])(=[O:11])[CH3:10]>C1(C)C=CC=CC=1>[C:15]([C:14]1[CH:13]=[C:12]([C:9](=[O:11])[CH2:10][C:3]([O:6][CH3:7])=[O:8])[CH:19]=[CH:18][CH:17]=1)#[N:16]
Reactant: COC(=O)OC
Reactant: CC(=O)c1cccc(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)c1cccc(C#N)c1
Yield: 95.4 %

Procedure:
Into a three-necked flask equipped with an argon inlet and a condenser were placed sodium hydride (60%, 689.5 mg, 17.23 mmol), dimethyl carbonate (1.55 g, 17.23 mmol) and 15 mL of toluene. The mixture was stirred under reflux and a solution of 3-acetylbenzonitrile (1.0 g, 6.19 mmol) in toluene (15 mL) was added drop wise. The reaction mixture was stirred at 100° C. for 2 h. The reaction mixture was monitored by LCMS and purified by column chromatography on silica gel eluted with 0-10% of ethyl acetate in petroleum ether to give the product (1.2 g, 86%).
Reaction SMILES: [N+](=[CH:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N-].O.O.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([OH:27])(=[O:26])=[O:25]>CCOCC>[O:12]=[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][O:27][S:24]([C:17]1[C:18]([CH3:23])=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[CH3:15])(=[O:25])=[O:26]
Reactant: CCCCCCCC(=O)C=[N+]=[N-]
Reactant: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Solvent: O
Solvent: CCOCC
Product: CCCCCCCC(=O)COS(=O)(=O)c1c(C)cc(C)cc1C
Yield: 69 %

Procedure:
A 1.0 g quantity of 1-diazo-2-nonanone is dissolved in 30 ml of ether, and 2.0 g of 2,4,6-trimethylbenzenesulfonic acid dihydrate is slowly added to the solution at room temperature. The same procedure as in Example 1 is thereafter repeated to give 1.4 g of 2-oxononanyl-2,4,6-trimethylbenzene sulfonate in the form of a colorless transparent oil (Compound 77). Yield 69.0%.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCl.[C-:12]#[N:13].[Na+].[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl.O>[N:8](=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]#[N:13])[OH:9]
Reactant: [C-]#N
Reactant: ON=Cc1ccccc1
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#CC(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 9.07 g (75 mmol) of benzaldoxime in 25 ml of carbon tetrachloride is added dropwise, at 5°, a solution of 45 ml of carbon tetrachloride saturated with 5.6 g (79 mmol) of chlorine gas. The mixture is stirred for 1 hour in an ice bath and then excess HCl is removed by vacuum. A saturated solution of 7.35 g (150 mmol) of sodium cyanide in water is added dropwise, at 0°. The mixture is stirred for 2 hours as it is allowed to warm to RT. An excess of aqueous sodium hydroxide is added and then the carbon tetrachloride layer is discarded. The aqueous layer is acidified and filtered, and the resulting solid is washed with water and dried to give α-oximinophenylacetonitrile, m.p.=120°-125°.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:24]([O:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][CH:28]=[C:18]([O:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:19]=1)[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
N-Boc-4-piperidine ethanol (15 g, 65 mmol) and ethyl 3-hydroxybenzoate (11 g, 65 mmol) were dissolved in dry THF (750 ml) under N2. To this was added tri-n-butylphosphin (24 ml, 98 mmol) and ADDP (25 g, 98 mmol) resulting in a suspension, which was stirred overnight at 20° C. The mixture was concentrated in vacuo to ˜100 ml, filtered, and the filtrate was evaporated with silica gel. Flash chromatography (EtOAc/heptane 1:4) afforded 24 g of the title compound. LC-MS (m/z): 401 (M+23).
Reaction SMILES: C(O)C.C([O:6][C:7](=O)[CH2:8][CH2:9][N:10]([C:17]1[C:22]([NH2:23])=[CH:21][N:20]=[C:19]([Cl:24])[N:18]=1)[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH3:16])C>C(O)(=O)C>[Cl:24][C:19]1[N:20]=[CH:21][C:22]2[NH:23][C:7](=[O:6])[CH2:8][CH2:9][N:10]([CH:11]3[CH2:15][CH2:14][CH2:13][CH:12]3[CH3:16])[C:17]=2[N:18]=1
Reactant: CCOC(=O)CCN(c1nc(Cl)ncc1N)C1CCCC1C
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CCCC1N1CCC(=O)Nc2cnc(Cl)nc21
Yield: 74.5 %

Procedure:
A mixture of 50 mL of ethanol, 1 mL of acetic acid and 2.5 g of the (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-(2-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (V-57) prepared in the previous step was heated at reflux overnight, and then concentrated under reduced pressure. The residue was taken up in dichloromethane and washed successively with 10% sodium bicarbonate solution, and then water and dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure. Trituration of the residue with ether, provided 1.6 g of (rac)-2-chloro-9-(2-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-57).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[Br:12].[H-].[Na+].Cl[C:16]1[N:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][N:17]=1>CN(C)C=O>[Br:12][C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=1[O:8][CH2:9][CH2:10][O:11][C:16]1[N:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][N:17]=1
Reactant: Nc1ncnc(OCCO)c1Br
Reactant: CSc1cnc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cnc(OCCOc2ncnc(N)c2Br)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
To a solution of 2-(6-amino-5-bromopyrimidin-4-yloxy)ethanol (611 mg) in dimethylformamide (20 ml) is added sodium hydride (60% dispersion-type, 125 mg), and the mixture is stirred for 20 minutes. To the mixture is added 2-chloro-5-methylthiopyrimidine (461 mg), and the mixture is stirred at room temperature for three hours. To the mixture is added ice-water, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by silica get column chromatography (solvent; chloroform/methanol=20:1), and crystallized from ethyl acetate/diisopropyl ether to give 5-bromo-6-[2-(5-methythiopyrimidin-2-yloxy)ethoxy]pyrimidine-4-amine (501 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1C(O)=O.CN(C=O)C.C(Cl)(=O)[C:19]([Cl:21])=[O:20]>CC1OCCC1>[S:1]1[CH:2]=[C:3]([C:19]([Cl:21])=[O:20])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2ccccc2s1
Solvent: CC1CCCO1
Solvent: CN(C)C=O
Product: O=C(Cl)c1csc2ccccc12
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To benzothiophene carboxylic acid (7 g) in MeTHF (6.5 Vols, 45.5 mL) is added a catalytic amount of DMF (0.01 eq.). Then, oxalyl chloride (1.1 eq.) is charged slowly to control the gaz release. After 16 h of stirring at 20° C., the end of the reaction is controlled by HPLC. MeTHF (6.5 Vols) is next added and the reaction mixture is concentrated to 5 volumes to remove the excess of oxalyl chloride. The resulting benzo[b]thiophene-3-carbonyl chloride is stored in a MeTHF solution.