Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[O:7]=[C:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH3:16])=[O:14].S(=O)(=O)(O)O>>[C:1]([O:5][O:6][C:8]1([O:7][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH3:16])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: COC(=O)C1CCCC1=O
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCCC1(OOC(C)(C)C)OOC(C)(C)C
Temperature: -5 °C

Procedure:
Methyl 2,2-di(tertiary-butylperoxy)-1-cyclopentanecarboxylate was prepared by the addition of 92.28% TBHP (tertiary butyl hydroperoxide) (36.62 g, 0.3750 mol) to 97% methyl 2-oxo-1-cyclopentanecarboxylate (14.65 g, 0.1000 mol) at room temperature in a three necked 250-mL round bottomed flask equipped with a thermometer and mechanical stirrer. The solution was then cooled via a dry ice-acetone bath to −5° C. and 78% sulfuric acid (15.09 g, 0.1200 mol) was added dropwise to the solution with temperature at −5° C. Upon completion of the addition of sulfuric acid, the solution was allowed to reach 5° C. where it was maintained by an ice-water bath for three hours with mechanical stirring. The reaction was transferred to a separatory funnel and the lower acidic aqueous layer separated and discarded. The organic layer was then washed with saturated NaCl solution until the aqueous washings had a pH of 4.0 to 4.5. The organic layer was then dried over MgSO4, filtered through a Buchner funnel and analyzed for purity by gas chromatography (88% by area): 1H NMR (300 MHz, CDCl3) δ 3.7 (s, 3H, CH3), 3.3-3.4 (m, 1H, cyclic H), 1.9-2.2 (m, 6H, cyclic H), 1.3 (s, 9H, CH3), 1.2 (s, 9H, CH3); 13C NMR (75 MHz, CDCl3) δ 172.4 (C═O). 116.9 (O—C—O, cyclic), 79.7 (CCH3)3), 79.4 (C(CH3)3), 51.1 (CH, cyclic), 49.1 (CH3—O), 32.9 (CH2, cyclic), 27.7 (CH2, cyclic), 26.2 (C(CH3)3, (2x)), 22.1 (CH2, cyclic); IR (neat) 1740, 1364, 1198, 878 cm−1.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=1.O.[OH-].[Li+].C(OC1C=CC(C(O)=O)=CC=1)CCCCCCCCCCCCCCCCC>CO>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:21])=[O:2])=[CH:9][CH:8]=1)[CH2:12]/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC/C=C/CCOc1ccc(C(=O)OC)cc1
Agent: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCC/C=C/CCOc1ccc(C(=O)O)cc1

Procedure:
Ester 35h (600 mg, 2.07 mmol), and lithium hydroxide monohydrate (867 mg, 20.7 mmol) in 20 ml methanol were reacted according to the procedure for compound 36a. The yield was 500 mg (87%) of a white powder which was not quite pure (95%). The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][S:8]([CH3:11])(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:16][C:17]1[C:21]2[CH:22]=[C:23]([N:26]3[C:31](=[O:32])[CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N:28]([CH3:37])[C:27]3=[O:38])[CH:24]=[CH:25][C:20]=2[S:19][N:18]=1.Cl>CS(C)=O.O1CCCC1>[CH3:37][N:28]1[C:29]([C:33]([F:34])([F:35])[F:36])=[CH:30][C:31](=[O:32])[N:26]([C:23]2[CH:24]=[CH:25][C:20]3[S:19][N:18]=[C:17]([CH2:16][N:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:6](=[O:12])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:21]=3[CH:22]=2)[C:27]1=[O:38]
Reactant: CC(C)(C)OC(=O)NS(C)(=O)=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CBr)c3c2)c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CN(C(=O)OC(C)(C)C)S(C)(=O)=O)c3c2)c1=O
Yield: 78.6 %

Procedure:
tert-Butyl(methylsulfonyl)carbamate (1.52 g, 0.00780 mol) is added to a mixture of sodium hydride (60%, 0.312 g, 0.00780 mol) and tetrahydrofuran at 0° C. The mixture is allowed to come to room temperature. A solution of 3-[3-(bromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (3.00 g, 0.00714 mol) in dimethyl sulfoxide is added dropwise. The resultant mixture is stirred overnight at room temperature, poured into dilute hydrochloric acid, and extracted with methylene chloride. The combined organic layers are washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resultant residue is chromatographed on silica gel with ether:methylene chloride to give the title compound as a white solid (3.00 g, 78.7%, mp 109-111° C.) which is identified by NMR spectral analysis.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([OH:30])([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1cccc2ccccc12
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: OC1(c2cccc3ccccc23)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.4 %

Procedure:
A solution of 10.0 gm (42.2 mMol) 1-bromonaphthalene in 180 mL tetrahydrofuran was cooled to −78° C. and then to this solution were added 48.7 mL (63.3 mMol) sec-butyllithium (1.3 M in cyclohexane). After stirring for about 1.5 hours, a solution of 8.2 mL (44.3 mMol) 1-benzylpiperidin-4-one in 60 mL tetrahydrofuran was added dropwise and the resulting mixture was allowed to warm gradually to room temperature. The reaction was then quenched by the addition of 2 N sodium hydroxide. The resulting mixture was extracted with diethyl ether. The organic extracts were combined, washed with saturated aqueous sodium chloride, and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing from 0 to 2% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 4.34 gm (32%) of the desired compound as a white foam.
Reaction SMILES: O=[C:2]([CH3:21])[CH2:3][O:4][C:5]([CH:7]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:8]1)=O.C([NH2:25])(=O)C.B(F)(F)F.CCOCC>C1(C)C(C)=CC=CC=1>[CH2:14]([O:13][C:11]([N:9]1[CH2:10][CH:7]([C:5]2[O:4][CH:3]=[C:2]([CH3:21])[N:25]=2)[CH2:8]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)COC(=O)C1CN(C(=O)OCc2ccccc2)C1
Reactant: CC(N)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: Cc1coc(C2CN(C(=O)OCc3ccccc3)C2)n1
Temperature: 130 °C

Procedure:
To 130 mg (0.45 mmol) azetidine-1,3-dicarboxylic acid 1-benzyl ester 3-(2-oxo-propyl)ester in 4 mL xylene were added 132 mg (2.25 mmol) acetamide, 39 μL (0.31 mmol) boron trifluoride etherate and the mixture was heated at 130° C. for 24 hours. After cooling to room temperature and evaporation of the solvent the product was purified by chromatography (silica, hexane-EtOAc 6:4).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([O-])=O.[O:25]1[C:30]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[CH:34][C:29]=2[O:28][CH2:27][CH2:26]1>>[O:25]1[CH2:26][CH2:27][O:28][C:29]2[CH:34]=[C:33]([C:35]3[NH:22][C:21]4[CH:20]=[CH:19][C:6]([NH:7][C:8](=[O:18])[C:9]5[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)[CH:32]=[CH:31][C:30]1=2
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc5c(c4)OCCO5)nc3c2)cc1

Procedure:
Compound 184 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-dimethylaminobenzoyl)aniline and benzo[1,4]dioxane-6-carboxaldehyde. [M+H]+ calcd for C24H22N4O3: 415.17; found: 415.47.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:31]C)=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2/[CH:23]=[CH:24]\[CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CN(C)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[C:3]([OH:31])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2/[CH:23]=[CH:24]\[CH2:25][N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])(=[O:14])=[O:15])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(Br)c(OC)c1C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(Br)c(O)c1C(=O)OC
Yield: 66.4 %

Procedure:
A solution of methyl 3-bromo-6-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylmethyl]-2-methoxybenzoate (Intermediate 69, 3.9 g) and N,N-dimethylaniline (9.00 g) in DCM (150 mL) was cooled to 0° C. and aluminium chloride (3.00 g) was added in three portions. The resultant mixture was stirred at room temperature for 2 hours. The mixture was cooled in an ice bath and quenched with brine. The layers were separated and the organic phase was dried (MgSO4), filtered and the filtrate was concentrated in vacuo. Cyclohexane was added to the residual gum and then decanted off. The residual oil was dissolved in DCM and concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-15% to give methyl 3-bromo-6-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylmethyl]-2-hydroxybenzoate (2.52 g) as a blue glass.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH2:6][N+:7]([O-:9])=[O:8].[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].Cl>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH:6]([N+:7]([O-:9])=[O:8])[CH2:21][CH2:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(Cl)c(Cl)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 350 g of 4-nitro-3-(3,4-dichlorophenyl)butanoic acid methyl ester, 118 g of methyl acrylate and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-(3,4-dichlorophenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (6.51 g, 32.3 mmol) and triethylamine (6.8 ml, 1.5 mol eq) in dichloromethane (70 ml) at 0° C. was added a solution of methanesulphonyl chloride (3.73 ml, 1.5 mol) in dichloromethane (30 ml) over 30 minutes. The reaction was stirred at 0° C. for 2 hours. Saturated sodium hydrogen carbonate (100 ml) was added slowly. The organic phase was separated, washed with brine and dried over magnesium sulphate. Evaporation under reduced pressure yielded (R)-3-methanesulphonyloxypiperidine-1-carboxylic acid tert-butyl ester, 9.03 g (100%). NMR (CDCl3 7.27d) m 4.73(1H), m 3.63d(2H), m 3.44d(1H), m 3.32d (1H), s 3.05d(3H), m 1.95d(2H), m 1.83d(1 H), m 1.54d(1H), s 1.46d(9H)
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[CH:8]=O.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)(=[O:17])[CH3:16]>O.CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[CH:8]=[C:23]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]1[C:15](=[O:17])[CH3:16]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: CC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C=C2C=CC=NC2C(C)=O)cc(OC)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a well stirred solution of NaOH (12 g, 0.3 mmole) in H2O (125 ml) and methanol (250 ml) at 0° C. was added 3,5-dimethoxy benzaldehyde (19 g, 0.11 mmole) followed by a solution of 2-acetylpyridine (14.4 g, 0.12 mmole) in MeOH. The reaction was stirred at 0° C. for 1 hour and at room temperature for 16 hours. The precipitate was filtered and recrystallized from MeOH (Yield: 18 mg, 57%). The preparation scheme is shown below:
Reaction SMILES: [F:1][C:2]([F:11])([CH:8](F)F)/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:19][C:20]1[O:24][N:23]=[C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[N:21]=1>ClCCl.CN(C=O)C>[F:11][C:2]([F:1])([CH3:8])/[CH:3]=[CH:4]/[C:5]([N:28]1[CH2:29][CH2:30][N:25]([C:22]2[N:21]=[C:20]([CH3:19])[O:24][N:23]=2)[CH2:26][CH2:27]1)=[O:7]
Reactant: Cc1nc(N2CCNCC2)no1
Reactant: O=C(O)/C=C/C(F)(F)C(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(N2CCN(C(=O)/C=C/C(C)(F)F)CC2)no1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
(E)-4,4,5,5-Tetrafluoropent-2-enoic acid (31 mg, 0.23 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (20 μl, 0.23 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 5-methyl-3-piperazin-1-yl-1,2,4-oxadiazole hydrochloride (25 mg, 0.122 mmol) in dichloromethane (2 ml) and the resulting mixture was stirred at room temperature for three hours. The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 24.3 mg of a solid (0.083 mmol, 69%).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)C.C([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[SH:4][CH2:5][CH:6]([CH2:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(CC)CSC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C(CC)CS
Temperature: 0 °C

Procedure:
To a solution of the thioester of Step 1 (5 g, 24.5 mmol) in MeOH (15 mL) at 0° C., under nitrogen, was added K2CO3 (9.67 g, 73.5 mmol). The resulting mixture was stirred at 0° C. for a half hour and then HOAc (8.82 g, 147 mmol) and 25% aq NH4OAc were added. The title thiol was extracted with EtOAc, dried over Na2SO4 and purified by distillation on a Kugelrohr apparatus (200° C./760 mm Hg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[C:21]([NH2:27])=[N:22][CH:23]=[C:24](Br)[CH:25]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[C:21]([NH2:27])=[N:22][CH:23]=[C:24]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:28])[CH:34]=3)[CH:25]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(-c2cc(Br)cnc2N)cc1OC(C)c1ccccc1Cl
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2cc(-c3cccc(Cl)c3)cnc2N)cc1OC(C)c1ccccc1Cl
Yield: 42.3 %

Procedure:
5-(2-Amino-5-bromo-pyridin-3-yl)-3-[1-(2-chloro-phenyl)-ethoxy]-thiophene-2-carboxylic acid methyl ester (120 mg, 0.26 mmol, 1.0 Eq.), 3-chlorophenyl boronic acid (44 mg, 0.28 mmol, 1.1 Eq.) and Pd(PPh3)4 (30 mg, 0.03 mmol, 0.1 Eq.) were dissolved in toluene (1.6 mL) and EtOH (0.4 mL). 2M K2CO3 (0.5 mL, 1.0 mmol, 3.0 Eq) and the reaction heated under microwave conditions at 140° C. for 15 minutes. The reaction was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (40% EtOAc/petroleum Ether) to give the sub-title compound as an off-white solid (57 mg, 0.11 mmol, 45%); 1H NMR (400 MHz, CDCl3) δ 1.75 (3H, d), 3.94 (3H, s), 5.24 (2H, br s), 5.84 (1H, q), 6.86 (1H, s), 7.01-7.41 (6H, m), 7.48 (1H, s), 7.65 (1H, s), 7.68 (1H, d), 8.24 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[OH:30][C:31]([CH3:36])([CH3:35])[C:32](O)=[O:33].OCC(O)=O>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][N:25]([C:32](=[O:33])[C:31]([OH:30])([CH3:36])[CH3:35])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCNC2)c2cnccc12
Reactant: CC(C)(O)C(=O)O
Agent: O=C(O)CO
Product: CC(C)(O)C(=O)N1CC[C@@H](n2c(Cn3nc(S(C)(=O)=O)c4ccncc43)nc3cc(Cl)ccc32)C1

Procedure:
The title compound was prepared in analogy to Example 2-17 by using 1-({5-chloro-1-[(3R)-(pyrrolidin-3-yl)]-1H-benzo[d]imidazol-2-yl}methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and 2-hydroxy-2-methylpropanoic acid instead of 1-{[5-chloro-1-(pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl]methyl}-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and 2-hydroxyacetic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1)=[N+:21]=[N-:22]
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Temperature: 60 °C

Procedure:
To 4-(6-(bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.5 g) in DMF (11 mL) was added sodium azide (2 eq). The reaction was heated at 60° C. for 1 hour and then extracted with ethyl acetate and brine. The organic layer was dried (Mg2SO4), filtered and concentrated to afford 0.437 g of crude 4-(6-(azidomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine. This intermediate was then suspended in THF (4 mL), triphenylphosphine (2 eq) was added and the reaction was stirred at room temperature for 1.5 hours. Water (0.1 mL) was added to the reaction mixture which was then loaded onto a 10 g biotage isolute scx-2 cartridge then eluted with 2M ammonia in methanol then purified by flash column chromatography to yield 0.27 g (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methanamine.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]1[CH:6]=[N:7][N:8]([CH3:10])[CH:9]=1)[CH3:2].C([Li])CCC.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C>O1CCCC1.CCCCCC>[CH2:1]([S:3][CH2:4][C:5]1[CH:6]=[N:7][N:8]([CH3:10])[C:9]=1[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)[CH3:2]
Reactant: CCSCc1cnn(C)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCSCc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution of 4-[(ethylthio)methyl]-1-methyl-1H-pyrazole (0.81 g, 5.2 mmol) in tetrahydrofuran (3.0 mL) at 0° C. was added 1.6 M n-butyllithium in hexane (6.3 mL, 10. mmol). The solution was stirred at room temperature for 1 h and then cooled down to −78° C. To the solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.06 mL, 10.1 mmol). The reaction was continued at −78° C. for 0.5 h, then warmed up to 0° C. (taking about 0.5 h). The reaction mixture was quenched with brine, adjusted to PH=6-7 with 1 N HCl aqueous solution, extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give one oil residue which was purified by combi-flash chromatography eluted with EtOAc/hexane (20-100%). The purification gave 1.2 g (86% yield) of the desired product as yellowish oil. LC-MS found: 283.1 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:27][NH:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:28]([CH3:29])[CH3:27])=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CNC
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CN(C)C)cc2C)ncn1
Reaction time: 18 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with dimethylamine (Aldrich, 0.25 ml, 2M in THF; 0.5 mmol) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 18 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][C:13]1([CH3:19])[O:18][CH2:17][CH2:16][NH:15][CH2:14]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:15]2[CH2:16][CH2:17][O:18][C:13]([CH3:19])([CH3:12])[CH2:14]2)=[N:6][CH:7]=1
Reactant: CC1(C)CNCCO1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CN(c2ncc(Br)cc2[N+](=O)[O-])CCO1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a 100 mL round bottom flask containing 5-bromo-2-chloro-3-nitropyridine (2.00 g, 8.43 mmol) in DMSO (10 mL) was added 2,2-dimethylmorpholine (commercially available from ChemBridge Corporation) (1.9 mL, 16.9 mmol) dropwise. The reaction was heated to 60° C. and monitored with TLC and LC-MS. After 2.5 h, LC-MS showed that the reaction was complete. The mixture was cooled to rt then diluted with water. After extracting three times with EtOAc, the organic layers were combined then washed with brine and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure to afford an orange oil as 4-(5-bromo-3-nitropyridin-2-yl)-2,2-dimethylmorpholine. 1H NMR (400 MHz, CDCl3) δ ppm 8.34 (1H, d, J=2.2 Hz), 8.25 (1H, d, J=2.2 Hz), 3.87 (2H, m), 3.36 (4H, m), 1.26 (6H, s).