Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:36])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[N:17]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])C1C=CC=CC=1.[OH-].[Na+]>CO>[CH2:29]([N:17]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:11]1[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=1[C:9]([OH:36])=[O:8])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2cc(C)ccc2C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2cc(C)ccc2C(=O)O)cc1
Yield: 79 %

Procedure:
To a solution of the product of Example 12 in 30 mL of methanol was added 7.5 mL (0.038 mol) of 5N sodium hydroxide solution and the resulting mixture was heated to reflux for 66 h. The reaction was then cooled to room tempeature and the organics were removed in vacuo. The resulting mixture was acidified with 10% HCl and extracted with EtOAc. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was triturated with ether and filtered to provide 0.984 g (79%) of the desired carboxylic acid as a white solid. Electospray Mass Spec: 427 (M+H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:2]#[C:3][CH3:4].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[CH2:1]([O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([CH:12]([OH:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1cc(C(=O)c2ccccc2)ncn1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC#CCOc1cc(C(O)c2ccccc2)ncn1
Temperature: 0 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
In 2 ml of ethanol was suspended 0.5 g of 6-(2-butynyloxy)-4-benzoylpyrimidine, to which 0.11 g of sodium borohydride was added, followed by stirring at 0° C. for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined and washed with a saturated aqueous sodium chloride solution, and the combined organic layer was then dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 0.4 g of 6-(2-butynyloxy)-4-(α-hydroxybenzyl)pyrimidine (the present compound (123)).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH2:9][C:10]1[N:11]=[C:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:13][C:14](=[O:24])[C:15]=1[N:16]=NC1C=CC=CC=1>C(O)C.[OH-].[Na+]>[NH2:9][C:10]1[N:11]=[C:12]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:13][C:14](=[O:24])[C:15]=1[NH2:16]
Reactant: Nc1nc(Cc2ccccc2)[nH]c(=O)c1N=Nc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(Cc2ccccc2)[nH]c(=O)c1N
Temperature: 0 °C
Yield: 44.4 %

Procedure:
Sodium dithionite (30 g.) was added in portions to an agitated suspension of 4-amino-2-benzyl-5-phenylazo-pyrimid-6-one (14 g.) in a mixture of ethanol (200 ml.) and 2N aqueous sodium hydroxide solution (200 ml.) maintained at a temperature near to the reflux temperature. The mixture was then heated under reflux for 20 minutes, treated with a further quantity of sodium dithionite (20 g.) and the mixture heated under reflux for a further 30 minutes. The mixture was then evaporated to dryness, the residue was dissolved in water (200 ml.), acidified to pH 6 by means of concentrated hydrochloric acid, cooled to 0° C, and filtered. The solid thus obtained was recrystallised from water to give 4,5-diamino-2-benzyl-pyrimid-6-one (4.4 g.), m.p. 243°-246° C.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:17]#[N:18])[C:10]([CH3:16])=[C:11]([CH2:14][CH3:15])[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][N:27]([CH3:33])[C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:17]#[N:18])[C:10]([CH3:16])=[C:11]([CH2:14][CH3:15])[C:12]=3[N:30]3[CH2:31][CH2:32][C@H:28]([N:27]([CH3:33])[CH3:26])[CH2:29]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCc1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCc1c(C)c(C#N)c2nc(C3CC3)oc2c1N1CC[C@H](N(C)C)C1
Temperature: 90 °C
Reaction time: 13 h
Yield: 58.4 %

Procedure:
2-Cyclopropyl-6-ethyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-181) (108 mg, 0.44 mmol) was dissolved in dimethyl sulfoxide (3 ml), then at room temperature, triethylamine (93 μl, 0.66 mmol) and (3S)-3-(dimethylamino)pyrrolidine (73 μl, 0.57 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 13 hours, then cooled to room temperature. This was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=93:7) to obtain the entitled compound (87 mg, 58%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][CH:4]=1.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].[Na+]>ClCCCl>[CH2:32]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)[CH2:21][CH2:20]3)[CH:10]=2)=[CH:7][CH:8]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3cc(-c4ccc(CN)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3cc(-c4ccc(CNCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of cis-5-[4-(aminomethyl)phenyl]-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.238 mmol), benzaldehyde (28 mg, 0.262 mmol) and acetic acid (43 mg, 0.714 mmol) in 1,2 dichloroethane (4 mL) was stirred at ambient temperature for 1 hour. Sodium triacetoxyborohydride (100 mg, 2.6 mmol) was added and the mixture was stirring continued for 2 hours. Sodium borohydride (100 mg, 2.60 mmol) was added and stirring was continued for an additional 30 minutes, the solvents were removed under reduced pressure and the residue purified by preparative reverse phase chromatography to yield cis-5-{4-[(benzylamino)methyl]phenyl}-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine: 1H NMR (DMSO-d6, 400 MHz) δ 8.13(s, 1H), 7.2-7.50(m, 1OH), 6.03(bs, 2H), 4.67 (m, 1H), 3.71(d, 2H), 1.52-2.50(m, 20H); R-P-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-50% acetonitrile over 25 min, 1 mL/min) tr 14.42 min.; MS:MH+ 510.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[OH:33]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[OH:33])=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: CC(C)COC(=O)Cl
Product: COC(=O)c1ccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c(O)c1
Yield: 44.1 %

Procedure:
Using N-(tert-butoxycarbonyl)-D,L-alanine (3.74 g, 19.7 mmol), 2-methylpropyl chlorocarbonate (2.56 mL, 19.7 mmol) and methyl 4-amino-3-hydroxybenzoate (3.00 g, 19.7 mmol), a method in the same manner as in Reference Example 105 was performed, and the obtained residue was triturated with ethyl acetate to give the title compound (2.94 g, yield 48%).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[N:5]([C:15](=[O:17])[CH3:16])[CH:4]([CH3:18])[CH2:3]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(N(CC)CC)C.[Cl-].[NH4+]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:1][C@H:2]2[C:11]3[CH:10]=[C:9]4[O:12][CH2:13][O:14][C:8]4=[CH:7][C:6]=3[N:5]([C:15](=[O:17])[CH3:16])[C@@H:4]([CH3:18])[CH2:3]2)=[CH:22][CH:21]=1
Reactant: CC(=O)N1c2cc3c(cc2C(N)CC1C)OCO3
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2cc3c(cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C)OCO3
Reaction time: 48 h
Yield: 31.4 %

Procedure:
[Step 5] 40 mg (0.16 mmol) of the 1-(8-amino-6-methyl-7,8-dihydro-[1,3]dioxolo[4.5-g]quinolin-5(6H)-yl)ethanone, 38 mg (0.24 mmol) of 4-chlorophenylboronic acid, 59 mg (0.33 mmol) of copper (II) acetate, 49 mg (0.48 mmol) of triethylamine and 2 mL of dichloromethane suspension containing 30 mg of molecular sieve (4A) were vigorously stirred for 2 days. Following completion of the reaction, aqueous ammonium chloride solution was added followed by extraction with chloroform. The extract was washed with water and the organic layer was dehydrated with anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain 18 mg of cis-1-[8-(4-chlorophenylamino)-6-methyl-7,8-dihydro[1,3]dioxolo[4,5-g]quinolin-5(6H)-yl]ethanone in the form of a yellow oil (29%, 2 steps).
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9](=[O:23])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][N:5]=[C:4]([CH2:24][OH:25])[N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:24]([C:4]1[N:3]=[C:2]([OH:1])[C:7]([NH:8][C:9](=[O:23])[CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][N:5]=1)=[O:25]
Reactant: O=C(Nc1cnc(CO)nc1O)C(c1ccccc1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ncc(NC(=O)C(c2ccccc2)c2ccccc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
To a solution of compound step E product, 3-g, (1.1 g, 3.2 mmol) in DCM was added slowly Dess-Martin reagent (1.6 g, 3.84 mmol) and stirred at room temperature for 20 min. The reaction mixture was concentrated and purified by column chromatography to afford the product, 3-h (1.0 g, 90%). LC-MS (M+H+H2O)+ 352.1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].I[CH:12]([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:12]([CH3:14])[CH3:13])[C:3]=1[CH:4]=[O:5]
Reactant: CC(C)I
Reactant: O=Cc1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(F)c1C=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of commercially available 2-fluoro-6-hydroxybenzaldehyde (3.000 g; 21.40 mmol), 2-iodopropane (10.919 g; 64.20 mmol), K2CO3 (5.918 g; 42.80 mmol), and Cs2CO3 (1.395 g; 4.28 mmol) in anh. DMF (63 ml) was stirred at rt, under nitrogen, for 16 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-fluoro-6-isopropoxybenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.74 min.; [M+H]+: 183.15 g/mol.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([CH2:22][CH:23]2[CH2:28][CH:27]([OH:29])[CH2:26][CH2:25][CH:24]2[C:30](=[O:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])[O:12][C:11]1([CH3:38])[CH3:37])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:39]I>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([CH2:22][CH:23]2[CH2:28][CH:27]([O:29][CH3:39])[CH2:26][CH2:25][CH:24]2[C:30](=[O:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])[O:12][C:11]1([CH3:38])[CH3:37])=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)NC(=O)C1CCC(O)CC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCC(C(=O)NC(C)(C)C)C(CC2OC(C)(C)N(C(=O)OC(C)(C)C)C2Cc2ccccc2)C1
Temperature: 0 °C
Yield: 60.5 %

Procedure:
Sodium hydride (60% w/w in mineral oil, 20 mg, 0.52 mmol) was added to a solution of 4-benzyl-5-(2-tert-butylcarbamoyl-5-hydroxy-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (200 mg, 0.40 mmol) in dry N,N-dimethylformamid (4 ml) stirred at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. until gas evolution had ceased. Methyl iodide (40 μl, 0.6 mmol) was then added, and the solution was allowed to warm to room temperature and stirred for 20 hours. After removal of the volatiles in vacuo, the crude product was dissolved in ethyl acetate, washed twice with water, dried (anhydrous magnesium sulfate) and concentrated in vacuo. Purification by flash chromatography on silica gel provided 4-benzyl-5-(2-tert-butylcarbamoyl-5-methoxy-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (125 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][C@H:13]2[C@@H:17]3[O:18][C:19]([CH3:22])([CH3:21])[O:20][C@@H:16]3[C@@H:15]([O:23][CH2:24][CH2:25][OH:26])[CH2:14]2)[C:3]=1[N+:27]([O-])=O.C(O)(=O)C>[Fe].O.C(O)C>[NH2:27][C:3]1[C:4]([NH:12][C@H:13]2[C@@H:17]3[O:18][C:19]([CH3:21])([CH3:22])[O:20][C@@H:16]3[C@@H:15]([O:23][CH2:24][CH2:25][OH:26])[CH2:14]2)=[N:5][C:6]([S:8][CH2:9][CH2:10][CH3:11])=[N:7][C:2]=1[Cl:1]
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 104.6 %

Procedure:
A suspension of 2-((3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-(propylthio)pyrimidin-4-ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol (800 mg, 1.78 mmol, 1.00 equiv.), iron powder (800 mg, 14.29 mmol, 8.00 equiv.), acetic acid (860 mg, 14.33 mmol, 8.00 equiv.) and water/ethanol (10 mL) was stirred at about 60° C. for about 20 minutes in an oil bath. After the solids were removed by filtration, the resulting filtrate was extracted with dichloromethane (3×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a yellow oil (780 mg; yield=93%). MS: m/z=419 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[CH3:20][N:21]=[C:22]=[S:23]>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([S:17][C:22](=[S:23])[NH:21][CH3:20])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: CN=C=S
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=S)SC1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.7 %

Procedure:
In 20 ml of dichloromethane was dissolved 3.0 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol-1-one, and 0.8 g of methyl isothiocyanate, together with one drop of triethylamine, was added to the solution, followed by stirring at room temperature for 5 hours. The dichloromethane was distilled off under reduced pressure, and the resulting crystals were washed with cold ethanol and dried, thereby producing 3.5 g (yield of 94%) of the subject compound. Recrystallization from ethanol yielded white crystals, 112°-114° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[O:38][Si](C(C)C)(C(C)C)C(C)C)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[NH4+].[Cl-]>[C:1]([O:5][C:6](=[O:49])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[OH:38])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCCc1c(O[Si](C(C)C)(C(C)C)C(C)C)ccc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCCc1c(O)ccc2ccccc12
Reaction time: 1.5 h

Procedure:
N-Methoxy-N-methyl-3-{2-[2-(2-triisopropylsilanyloxy-naphthalen-1-yl)-ethoxy]-benzenesulfonylamino}-succinamic acid tert-butyl ester (270 mg, 0.38 mmol) was stirred with TBAF (0.45 mL of 1.0 M soln in THF, 0.45 mmol) in freshly distilled THF (1.45 mL) at 0° C. for fifteen minutes and then at room temperature for 1.5 h. The reaction mix was diluted with saturated aq. NH4Cl and was extracted three times with EtOAc. The organic extracts were combined, washed with brine solution, dried over Na2SO4, filtered through celite, and concentrated. The crude product was purified by flash chromatography (SiO2, 50% EtOAc-hexanes) to give 3-{2-[2-(2-hydroxy-naphthalen-1-yl)-ethoxy]-benzenesulfonylamino}-N-methoxy-N-methyl-succinamic acid tert-butyl ester in quantitative yield. MS (APCI) m/z 557.3 (M−1).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][C@@H:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C@@H:7]([OH:24])[C:6]1=[O:25].[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>C1C=CC=CC=1>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][C@@H:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C@@H:7]([O:24][C:35](=[O:36])[NH:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)[C:6]1=[O:25]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Solvent: c1ccccc1
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)Nc2ccc(F)cc2)cc1
Reaction time: 7 h

Procedure:
10 Grams (0.268 mole) of the compound prepared under (A) were dissolved in 100 ml of anhydrous benzene and subsequently added with 3.02 ml (0.0269 mole) of 4-fluoro-phenylisocyanate, then the resulting solution was stirred on an oil bath at 30°-35° C. for 7 hours. After evaporating the solvent, the residue was taken up with anhydrous diethyl ether and the obtained white precipitate was recovered by filtration.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C[O:8][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=O>>[CH:32]1([C:21]2[N:20]=[C:19]([C:17](=[N:16][C:15]3[C:11]([C:9]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])=[O:8])=[N:12][N:13]([CH3:35])[CH:14]=3)[OH:18])[C:24]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[N:28][CH:27]=3)=[CH:23][CH:22]=2)[CH2:34][CH2:33]1
Reactant: CC1CCCN1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: CC1CCCN1C(=O)c1nn(C)cc1N=C(O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 19 %

Procedure:
According to the general method described above (step 5), reaction of 2-methylpyrrolidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (19%) as sticky yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:14](OS(C)(=O)=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:14]([N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)OCCc1ccccc1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CCn2cnc(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-phenyl-1H-imidazole (1 g, 8.75 mmoles) in DMF (8 mL) is added NaH 60% dispersion in mineral oil (455 mg, 11 mmoles). The reaction mixture is stirred at room temperature for 1 hour, then methanesulfonic acid phenethyl ester (example 4D) (1.84 g, 9.12 mmoles) is added. The reaction mixture is then heated at 60° C. for 2 hours. Water is added, and the aqueous phase is extracted three times with AcOEt. The organic phase is washed with water, brine, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) (100:0) then (98:2) to give 1-phenethyl-4-phenyl-imidazole.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@@H:2]1[CH2:3][OH:4].C(NC(C)C)(C)C.CN(C)C=O.[Br:20][C:21]1[CH:37]=[CH:36][C:24]2[C:25]3[N:26]=[C:27]([C:33](Cl)=[O:34])[S:28][C:29]=3[CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1>C(OCC)(=O)C>[Br:20][C:21]1[CH:37]=[CH:36][C:24]2[C:25]3[N:26]=[C:27]([C:33]([N:1]4[CH2:7][CH2:6][CH2:5][C@@H:2]4[CH2:3][OH:4])=[O:34])[S:28][C:29]=3[CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1
Reactant: OC[C@H]1CCCN1
Reactant: O=C(Cl)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1nc2c(s1)CCOc1cc(Br)ccc1-2)N1CCC[C@@H]1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of D-(−)-Prolinol (0.205 g, 2.03 mmol) in N,N-Diisopropylamine (0.758 mL, 4.35 mmol) and N,N-Dimethylformamide (4.49 mL, 58.0 mmol) at room temperature was added 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl chloride (0.500 g, 1.45 mmol) portionwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with brine, and concentrated in vacuo to give (8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-methanone which was not further purified.