Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])([CH3:16])[CH2:7][C:8](=O)[N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[CH3:18].S(C)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:17])[CH2:7][CH2:8][N:9]2[CH:12]([CH3:13])[CH3:14])=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc2c(cc1Br)N(C(C)C)C(=O)CC2(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1Br)N(C(C)C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
7-Bromo-1-isopropyl-4,4,6-trimethyl-3,4-dihydro-1H-quinolin-2-one (Compound 43, 50 g, 161.2 mmol) was dissolved in toluene (300 mL) and the solution was cooled to 0° C. and treated with 2.0 M of BH3.SMe2 (20 mL, 193.44 mmol) in THF. The solution was stirred at 0° C. for 1 hour and at room temperature over night, and at 60° C. for 1 day. Thereafter the reaction mixture was treated with 10% aqueous Na2CO3. The solution was stirred at room temperature for 1 hour, the layers were separated and the aqueous layer extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (2% ethyl acetate in hexane, Rf=0.35) to give the title compound (37.8 g, 79% over 4 steps) as an oil:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCOCC3)nc(Cl)nc21
Reactant: OB(O)c1ccncc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(OC3CCOCC3)nc(Cl)nc21
Temperature: 75 °C
Reaction time: 3 h
Yield: 50.5 %

Procedure:
To a solution of 2-chloro-5-iodo-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), pyridin-4-ylboronic acid (1.1 equiv), tetrakis(triphenylphosphine)-palladium(0) (0.1 equiv) in a 5:1 mixture of 1,4-dioxane and water (0.17 M) was added sodium carbonate (2.1 equiv). The reaction was stirred at 75° C. for 3 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (magnesium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-90%) ethyl acetate (with 10% 1N ammonia in MeOH) in hexane) to give the title compound (50.5% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.06 (s, 9H) 0.82-0.91 (m, 2H) 1.74 (dtd, J=12.74, 8.37, 8.37, 3.71 Hz, 2H) 2.01-2.16 (m, 2H) 3.50-3.63 (m, 4H) 3.69-3.83 (m, 2H) 5.50 (tt, J=7.91, 3.81 Hz, 1H) 5.59 (s, 2H) 7.72 (d, J=6.25 Hz, 2H) 8.12 (s, 1H) 8.60 (d, J=6.25 Hz, 2H); MS (ESI) m/z 461.0 [M+1]+.
Reaction SMILES: [I-].[Na+].[C:3](OC(=O)C)(=[O:5])[CH3:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]2[C:26]3[C:25](=[N:27]O)[CH2:24][CH2:23][CH2:22][C:21]=3[N:20]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:19]=2[CH3:35])=[CH:13][CH:12]=1>C1(C)C(C)=CC=CC=1.C(O)(=O)C>[C:3]([NH:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:18]([S:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)=[C:19]([CH3:35])[N:20]2[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:5])[CH3:4]
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c1CCCC2=NO
Reactant: CC(=O)OC(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(NC(C)=O)cccc21
Temperature: 97 °C
Reaction time: 2 h

Procedure:
In flask 1, a mixture of sodium iodide (171.6 mg, 1.14 mmol) in xylene (12.5 mL), acetic acid (12.5 ml) and acetic anhydride (4.2 mL, 44.54 mmoles) was heated to 97° C. In flask 2, acetic anhydride (4.2 mL, 44.5 mmol) was added to a stirred slurry of ethyl [3-(4-chlorophenylsulfanyl)-4-(hydroxyimino)-2-methyl-4,5,6,7-tetrahydro-1H-indol-1-yl]acetate (10 g, 22.3 mmol corrected for assay) in xylene (12.5 mL) and acetic acid (12.5 ml) at ambient temperature. The mixture in flask 2 was added to the mixture in flask 1 over 2-3 hours maintaining the temperature at 97° C. The reaction was held at this temperature for a further 2 hours following the end of the addition. The reaction was cooled to 60° C. and split into 2 equal size portions. One of these portions was cooled to r.t. and propan-1-ol (25 mL) was added, following by water (25 mL), added over 15 minutes, effecting a precipitation. After stirring for 1 h, the solid product was collected by filtration, washed with propan-1-ol (2×10 mL) and dried in vacuo at 40° C. to afford crude ethyl [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetate as a solid; 4.32 g (91% based on work up of half of the reaction mixture). Purity by HPLC 97.15 area %.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([NH:15][CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:22]([NH2:24])=[O:23])=[N:3]1.[Si](Cl)(C(C)(C)C)(C)C.C(N(CC)CC)C.CN(C)[CH:42]=[O:43]>CN(C)C1C=CN=CC=1>[CH:42]([N:19]1[CH2:18][CH2:17][CH:16]([NH:15][C:11]2[N:10]=[CH:9][C:8]3[CH2:7][CH2:6][C:5]4[C:4]([C:22]([NH2:24])=[O:23])=[N:3][N:2]([CH3:1])[C:14]=4[C:13]=3[N:12]=2)[CH2:21][CH2:20]1)=[O:43]
Reactant: CN(C)C=O
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(NC3CCNCC3)ncc1CC2
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: Cn1nc(C(N)=O)c2c1-c1nc(NC3CCN(C=O)CC3)ncc1CC2
Temperature: 37.5 °C
Reaction time: 25 h
Yield: 80 %

Procedure:
500 mg (1.53 mmol) of 1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide were dissolved in 10 mL of dimethylformamide, containing 253 mg (1.68 mmol) of tert-butyldimethylsilyl chloride, 0.26 mL of triethylamine and 7 mg of 4-dimethylaminopyridine (0.06 mmol), and the mixture stirred at 35-40° C. for 25 hours under nitrogen. The mixture was then partitioned between dichloromethane and water, the organic layer was separated, washed with brine and dried over sodium sulfate. Evaporation of the volatiles in vacuo afforded 435 mg (80% yield) of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[CH2:7])[CH2:5][OH:6].Cl[CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14].O>O1CCCC1>[CH3:7][C:4](=[CH2:3])[CH2:5][O:6][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: C=C(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)COCc1cccc(C(=O)O)c1
Yield: 85.9 %

Procedure:
To the suspension of Sodium Hydride (1.516 g, 95%, 60 mmol) in tetrahydrofuran (150 ml), 2-Methyl-prop-2-en-1-ol (4.323 g, 4.1 ml, 60 mmol) was added. After the reaction mixture was refluxed for 30 min, 3-Chloromethyl-benzoic acid (4.10 g, 24 mmol) was added and the reaction was kept to reflux for additional 10 h. After cooling down, water (100 ml) was added and the tetrahydrofuran was removed under vacuum. This resulting aqueous solution was adjusted with 6N HCl to pH 2 at 5° C., and the mixture was extracted with Et2O (50 ml×3). The organic phase was combined and washed with water (10 ml×2) respectively. The ether extract was dried with anhydrous sodium sulfate and then concentrated to give 3-(2-Methyl-allyloxymethyl)-benzoic acid as colorless oil (4.25 g, 85.9%). 1H-NMR (400 MHz, d6-DMSO): 7.90 (m, 1 arom.H); 7.85 (m, 1 arom.H); 7.55 (m, 1 arom.H); 7.45 (m, 1 arom.H); 4.96, 4.88 (2 s-like; C═CH2); 4.50 (s, —OCH2—C6H4); 3.90 (s, CH2O); 1.69 (s, CH3). 13C-NMR (100 MHz, d6-DMSO): 167.22 (—C═O); 142.03; 139.00; 131.72; 130.78; 128.56; 128.31; 128.07; 111.71; 73.41; 70.58; 19.30.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[N:11]=[CH:10][N:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[C:19](=[CH:24]\[O:25][CH3:26])/[C:20]([O:22][CH3:23])=[O:21])[CH:7]=1.O>CN(C=O)C>[N:1]([C:6]1[N:11]=[CH:10][N:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[C:19](=[CH:24]\[O:25][CH3:26])/[C:20]([O:22][CH3:23])=[O:21])[CH:7]=1)=[N+:2]=[N-:3]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(N=[N+]=[N-])ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Sodium azide (0.25 g) was added to a solution of (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (1.0 g) in DMF (30 ml). The reaction mixture was stirred for 2 hours at room temperature, then for 6 hours at 50° C. After cooling, the reaction mixture was poured into water and extracted with ether (3×100 ml). The combined extracts were washed with brine, dried and concentrated to give (E)-methyl 2-[2-(6-azidopyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (1.02 g, 99%) as an oil; 1H NHR: δ 3.51 (3H, s), 3.65 (3H, s), 6.12 (1H, s), 7.0-7.35 (4H, m), 7.37 (1H, s), mass 8.47 (1H, s) ppm; IR maxima (film): 2135, 1711, 1635 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[NH2:10])[CH3:2]
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Reaction time: 8 h
Yield: 86.1 %

Procedure:
1-[3-(ethyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperazine (0.565 g, 1.58 mmol) was placed in a 40 mL high vial and dissolved in 10 mL of 1 to 1 EtOAc/MeOA. 5 wt % Platinum(sulfided)/carbon (0.308 g, 0.079 mmol) was added followed quickly by a screw cap septum. The vial was evacuated and filled with N2 six times to remove any oxygen. The vial was then pressurized with H2 (balloon). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound (0.445 g, 1.36 mmol, 86%). 1H NMR (400 MHz, CDCl3) δ ppm 6.63 (d, J=8.42 Hz, 1H), 6.51 (d, J=2.38 Hz, 1H), 6.40 (dd, J=8.33, 2.11 Hz, 1H), 4.03 (q, J=7.02 Hz, 2H), 3.19 (t, J=6.41 Hz, 2H), 3.04-3.07 (m, 4H), 3.03 (S, 3H), 2.95 (t, J=6.41 Hz, 2H), 2.64-2.72 (m, 4H), 1.41 (t, J=6.96 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 95.3 %

Procedure:
To a solution of tert-butyl (3-nitrophenyl)methylcarbamate (40.5 g, 0.161 mol) in ethanol (810 mL) was added 10% palladium-carbon (4.1 g), and the mixture was stirred at room temperature for 19 hr under a hydrogen atmosphere. The insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The precipitate was collected by filtration to give the title compound (34.1 g, 96%) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[O:8][C:9]3[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][CH2:19][CH3:20])=[C:13]([OH:21])[C:10]=3[C:11]=2[CH3:12])=[CH:4][CH:3]=1>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:2]([O:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[O:8][C:9]3[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][CH2:19][CH3:20])=[C:13]([O:21][C:7](=[O:8])[CH3:6])[C:10]=3[C:11]=2[CH3:12])=[CH:4][CH:3]=1)(=[O:1])[CH3:3]
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(O)cc3)c(C)c2c1O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCCc1cc(Cl)c2oc(Cc3ccc(OC(C)=O)cc3)c(C)c2c1OC(C)=O
Yield: 176.8 %

Procedure:
A solution of 2-(p-hydroxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (1 gm; 3 mmoles) in pyridine (15 mL) and acetic anhydride (3 mL) was stirred at 50° C. for 15 minutes. The volatiles were removed in vacuo leaving a residue that crystallised on cooling. It was slurred with hexane, filtered, washed with hexane, and air-dried to yield 1.1 gm (87%) of 2-(p-acetoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran, mp. 119°-120° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH2:6][CH2:5]2.[CH3:16][N:17]1[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[C:18]1B(O)O.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:14]([S:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:18]3[N:17]([CH3:16])[C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)(=[O:13])=[O:12])[CH3:15]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CCS(=O)(=O)N1CCc2cc(Br)ccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Product: CCS(=O)(=O)N1CCc2cc(-c3ccc(C#N)n3C)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.6 %

Procedure:
5-Bromo-1-(ethylsulfonyl)indoline (1.85 g, 6.38 mmol), 1-methyl-5-cyano-2-pyrroleboronic acid (1.14 g, 7.7 mmol), KF (1.22 g, 21 mmol), and Pd2(dba)3 (154 mg, 0.16 mmol) were added to a round bottom flask under nitrogen. The flask was sealed and purged with nitrogen for 5 minutes. THF (16 mL) was added followed by a solution of tri-t-butylphosphine (10% wt in hexanes) (0.95 mL, 0.32 mmol) via syringe and the mixture was stirred vigorously at 25° C. for 5 hours. The mixture was diluted with ethyl acetate, filtered through a plug of silica gel, washed through with additional ethyl acetate and concentrated to give a crude brown/black semi-solid. Purification was performed using Isco chromatography (the Redisep® column, silica, gradient 10-60% ethyl acetate in hexane). Further purification via Isco chromatography (the Redisep® column, silica, gradient 50% hexane:45% methylene chloride:5% ethyl acetate) afforded 5-[1-(ethylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile (1.2 g) as a colorless oil. MS (EI) m/z 315.8; HPLC purity 99.4% at 210-370 nm, 9.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:6]([CH:14]=1)[C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8].C(N)(N)=[O:24].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[C:17]([F:22])=[N+:18]([O-:24])[CH:19]=[CH:20][CH:21]=2)=[C:6]([C:7](=[O:8])[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:14]=1
Reactant: NC(N)=O
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1Oc1cccnc1F
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc[n+]([O-])c1F
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-N,N-diethyl-2-(2-fluoropyridin-3-yloxy)benzamide (1.4 g, 3.81 mmol) and urea peroxide (1.076 g, 11.44 mmol) in 10 mL of DCM at 0 C was added dropwise trifluoroacetic anhydride (1.601 mL, 11.44 mmol) and the resulting reaction was stirred overnight. LCMS showed only less than 50% of desired conversion. The mixture was evaporated to dryness, quenched with Sat. NaHCO3, extracted with EA, dried over Na2SO4, filtered and evaporated to dryness. CC (DCM to DCM/EA=3:1 to DCM/MeOH=100:2 to 100:5 to 100:10) gave 3-(4-bromo-2-(diethylcarbamoyl)phenoxy)-2-fluoropyridine 1-oxide as an offwhite solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[C:17]([N+:25]([O-:27])=[O:26])[CH:16]=1.[H-].[Na+]>C1COCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:12]#[N:13])=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:23])=[O:22])=[C:17]([N+:25]([O-:27])=[O:26])[CH:16]=1
Reactant: N#Cc1ccc(N)c2ncccc12
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2[N+](=O)[O-])c2ncccc12
Yield: 30.9 %

Procedure:
In a similar fashion using route 14 general procedure 58, 8-aminoquinoline-5-carbonitrile (Intermediate 472) (100 mg, 0.5 mmol), 4-chloro-2-nitrobenzenesulfonyl chloride (Intermediate 454) (166 mg, 0.65 mmol), NaH (60% dispersion in mineral oil, 26 mg, 0.65 mmol) and THF (2 ml) gave the title compound (60 mg, 26%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([S:20][CH3:21])[N:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[Cl:12][C:13]1[CH:18]=[C:17]([C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:16]=[C:15]([S:20][CH3:21])[N:14]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(B(O)O)cn1
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc(Cl)nc(SC)n2)cn1
Reaction time: 3 h

Procedure:
A mixture of 2-methoxy-5-pyridyl-boronic acid (600 mg, 2.04 mmol, Intermediate (37), prepared according to the procedure described in J. Org. Chem., 67, 7541, 2002), 4,6-dichloro-2-methylsulfanyl-pyrimidine [700 mg, 3.59 mmol, Intermediate (29)], and Cs2CO3 (2.9 g, 8.97 mmol) in ethylene glycol dimethyl ether (8 mL) and water (2 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium (0) (207 mg, 0.18 mmol) at room temperature. After 3 hours at 85° C., the mixture is diluted with water (50 mL), and extracted twice with EtOAc (50 mL). The extracts are dried over magnesium sulfate, filtered, and concentrated to afford 4-chloro-6-(6-methoxy-pyridin-3-yl)-2-methylsulfanyl-pyrimidine [1.1 g, Intermediate (38)] as an oil. LCMS: RT=3.72 minutes, MS: 268 (M+H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[CH:11][C:10]=1[S:22]([CH3:25])(=[O:24])=[O:23])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH3:21][N:16]([CH2:15][C:13]1[CH:12]=[CH:11][C:10]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=1)[S:17]([CH3:20])(=[O:18])=[O:19]
Reactant: CN(Cc1ccc(S(C)(=O)=O)c(S(=O)(=O)NC(C)(C)C)c1)S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccc(S(C)(=O)=O)c(S(N)(=O)=O)c1)S(C)(=O)=O
Yield: 82.3 %

Procedure:
A solution of 1.85 g (4.5 mmol) of N-tert-butyl-5-(N-methyl-N-methanesulfonylaminomethyl)-2-methanesulfonylbenzenesulfonamide in 20 ml of trifluoroacetic acid is stirred at room temperature for 8 h. The mixture is evaporated to dryness and then coevaporated with toluene, and the residue obtained is crystallized from ethyl acetate/diisopropyl ether. 1.32 g (83%) of 5-(N-methyl-N-methanesulfonylaminomethyl)-2-methanesulfonylbenzenesulfonamide of melting point 165-169° C. are obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].O=[C:15]([CH2:21][CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[CH2:19]([O:18][C:16]([CH:15]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:21][CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)=[O:17])[CH3:20]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1cccs1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCc1cccs1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4 g of type 4 A molecular sieves (powdered) are added to a mixture of L-alanyl-L-proline (0.93 g) and ethyl 2-oxo-4-(2-thienyl)-butyrate (3.18 g) in 25 ml of anhydrous ethyl alcohol. The mixture is stirred for 45 minutes at room temperature, followed by slow addition (3.5 hours) of a solution of sodium cyanoborohydride (0.785 g) in 15 ml of anhydrous ethyl alcohol and stirring overnight at room temperature. The reaction mixture is made just slightly acidic with glacial acetic acid, filtered and the filtrate conc. in vacuo to an orange oil. Extraction of a chloroform solution of this oil with 10% potassium bicarbonate, followed by re-extraction of the acidified (pH 3) bicarbonate extracts with chloroform provide, after drying and evaporation of solvent, 400 mg of the desired substituted dipeptide. The nmr spectrum (CDCl3) shows the thienyl proton as multiplet at 7.0 ppm, two active protons in broad singlet at 6.2 ppm, six methyl protons as broad multiplet 1.22-1.43 ppm range, and a series of ill-defined multiplets ranging 1.8-4.4 ppm.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([OH:22])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27]1CCN2C(=NCCC2)CC1.P(OC)(OC)(OC)=O>O1CCOCC1>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]([CH3:27])[C:18](=[O:22])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccnc(O)c3)nc2N1C1CCCC1
Reactant: C1CCC2=NCCCN2CC1
Solvent: COP(=O)(OC)OC
Solvent: C1COCCO1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccn(C)c(=O)c3)nc2N1C1CCCC1
Yield: 45.4 %

Procedure:
To a solution of (R)-8-cyclopentyl-7-ethyl-2-(2-hydroxypyridin-4-yl)-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 14, 200 mg, 0.6 mmol) in 5 mL of 1,4-dioxane, DBU (26 mg, 3 mmol) and PO(OMe)3 (42 mg, 3 mmol) were added, and the mixture was heated to reflux for 18 h, then concentrated under reduced pressure, and extracted with EtOAc. The combined organic phase was dried with Na2SO4, concentrated under reduced pressure and the residue was chromatographed (PE:EA=1:1) to give the title compound as a yellow solid (100 mg, 50% yield). 1H NMR (CDCl3) δ: 7.95 (s, 1H), 7.53 (s, 1H) 7.35 (d, 1H), 7.11 (m, 1H), 4.54 (m, 1H), 4.29 (m, 1H), 3.6 (s, 3H), 3.38 (s, 3H), 2.2-1.6 (m, 10H) and 0.87 ppm (t, 3H); LCMS: 368.2 m/z (M+H)+; ret. Time: 1.53 min (Analytical Method E).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:15]1>>[CH3:19][C:18]1([CH3:20])[C:14]([CH3:13])([CH3:28])[O:15][B:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=3)=[CH:23][CH:22]=2)[O:17]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: BrCc1ccc2ccccc2c1
Product: CC1(C)OB(c2ccc(OCc3ccc4ccccc4c3)cc2)OC1(C)C
Yield: 85 %

Procedure:
Alkylation of 2-Bromomethyl-naphthalene with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to procedures in Step 5A in Example 3.32 to give 4,4,5,5-Tetramethyl-2-[4-(naphthalen-2-ylmethoxy)-phenyl]-[1,3,2]dioxaborolane in 85% yield. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (s, 12 H) 5.3 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.5 (m, 2 H) 7.5 (dd, J=8.3, 1.8 Hz, 1H) 7.8 (d, J=8.6 Hz,2H)7.9(m,4H).