Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12](O)=[C:11]([Cl:16])[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:6][CH3:7])=[C:11]([Cl:16])[CH:10]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 95.9 %

Procedure:
Under nitrogen, 7.3 mL (77 mmol) of dimethylsulfate was added to a stirred suspension of 10 g (48 mmol) of 4-bromo-2-chlorophenol and 5.4 g (38 mmol) of powered K2CO3 in 75 mL of fresh acetone. After 2 hours at reflux, the reaction was cooled to ambient temperature, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate; the resulting solution was washed with water and dried over MgSO4. Concentration in vacuo gave 10.2 g (96%) of 4-bromo-2-chloroanisole as a colorless solid: mp 68.5°-70.5° C.; NHR (CDCl3) δ 3.88 (s, 3H), 6.80 (d, J=9 Hz, 1H), 7.33 (dd, J=2, 9 Hz, 1H), 7.50 (d, J=2 Hz, 1H).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH:9]2[CH:21]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([NH2:25])[CH3:24]>ClCCl>[CH2:7]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH:21]=[N:25][CH2:23][CH3:24])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN
Reactant: O=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: ClCCl
Product: CCN=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.5 g (1,4-bis(phenylmethyl)-2-piperazin-carboxaldehyde in 5 ml of dichloromethane was added 0.54 ml ethylamine and 0.5 g molecular sieves. The reaction mixture was stirred for 30 min at rt then filtered. The filtrate was evaporated to dryness.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[NH:15]1[C:19]([C:20]2[CH:21]=[C:22]([C:26]3[CH:27]=[CH:28][C:29]4[O:33][C:32]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)=[C:31]([C:41]([NH:43][CH3:44])=[O:42])[C:30]=4[CH:45]=3)[CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:17]=[N:16]1>CN(C=O)C>[CH2:2]([N:15]1[C:19]([C:20]2[CH:21]=[C:22]([C:26]3[CH:27]=[CH:28][C:29]4[O:33][C:32]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)=[C:31]([C:41]([NH:43][CH3:44])=[O:42])[C:30]=4[CH:45]=3)[CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:17]=[N:16]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4ccn[nH]4)c3)cc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4ccnn4Cc4ccccc4)c3)cc12
Reaction time: 8 h
Yield: 35 %

Procedure:
(Bromomethyl)benzene (17 mg, 0.097 mmol) was added to a stirring solution of Na2CO3 (11 mg, 0.097 mmol) and 5-(3-(1H-pyrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (20 mg, 0.049 mmol) in DMF (486 μL) at 100° C. It was allowed to stir overnight, filtered and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (8.6 mg, 35%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.49-8.57 (1 H, m), 8.06-8.11 (1H, m), 7.98-8.04 (2 H, m), 7.92 (1 H, d, J=2.44 Hz), 7.86-7.89 (1 H, m), 7.75-7.83 (2 H, m), 7.69-7.75 (1 H, m), 7.63 (1 H, d, J=8.24 Hz), 7.51 (1 H, t, J=7.63 Hz), 7.34-7.43 (4 H, m), 7.27-7.32 (3 H, m), 6.89 (1 H, d, J=2.44 Hz), 5.41 (2 H, s), 2.86 (3 H, d, J=4.58 Hz). LC-MS retention time: 2.00 min; m/z (MH+): 502. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=15.47 min, purity=99%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, Rt=13.77 min, purity=100%.
Reaction SMILES: O[CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1.S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1
Reactant: COC(=O)c1csc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1csc(CCl)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixed liquid of 4.86 g of methyl 5-(hydroxymethyl)thiophene-3-carboxylate and 50 ml of dichloromethane was added 4.12 ml of thionyl chloride under ice-cooling, followed by stirring at room temperature for 15 hours. The reaction solution was concentrated, added with ethyl acetate, and then washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was then evaporated to obtain 4.90 g of methyl 5-(chloromethyl)thiophene-3-carboxylate as a pale yellow oily substance.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Br[CH2:9][CH:10]([CH3:13])[CH2:11][Cl:12]>CC(C)=O>[Cl:12][CH2:11][CH:10]([CH3:13])[CH2:9][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CCl)CBr
Reactant: C1CCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(CCl)CN1CCCC1
Yield: 57.4 %

Procedure:
Pyrrolidine (3.0 g, 42 mmol), acetone (60 ml), 5M NaOH solution (10 ml) and 1-bromo-3-chloro-2-methyl-propane (21.7 g, 0.13 mol) were reacted together according to general procedure A to give the title compound (3.9 g, 58%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>O1CCCC1>[OH:2][CH2:1][CH2:3][NH:4][S:20]([C:14]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[CH3:12])(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)c(C)c1
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NCCO)c(C)c1
Reaction time: 0.5 h

Procedure:
To 40 parts of tetrahydrofuran are added 1.5 parts of ethanolamine and 2.5 parts of triethylamine. Into this solution, 10 parts of tetrahydrofuran containing 5 parts of 2,4-dimethylbenzenesulfonyl chloride is dropped with stirring. After the dropping, the resultant mixture is stirred as it is for 30 minutes. Subsequently, the salt is removed by filtration, and the filtrate is freed from the solvent to form a solid. This solid is recrystallized from isopropyl ether to obtain 3.6 parts of N-2-hydroxyethyl-2,4-dimethylbenzenesulfonamide, m.p. 70°-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2(OCC[O:35]2)[CH2:28][S:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[CH:23][CH:22]=1.Cl>ClCCl.O1CCOCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH2:28][S:29][CH2:30][C:31]([F:34])([F:32])[F:33])=[O:35])=[CH:23][CH:22]=1
Reactant: O=C(N1CCc2ccc(Cl)c(NCc3ccc(C4(CSCC(F)(F)F)OCCO4)cc3)c2CC1)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(CSCC(F)(F)F)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 42.9 %

Procedure:
To a solution of 7-chloro-3-(2,2,2-trifluoroacetyl)-6-{4-[2-(2,2,2-trifluoroethylthio)-1,1-(ethylenedioxy)ethyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (97 mg, 0.16 mmol) in anhydrous dichloromethane (0.5 mL), add a solution of 4M hydrogen chloride in dioxane (1.2 mL) and reflux overnight. Dilute with dichloromethane and wash with saturated aqueous NaHCO3. Dry the organics extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain 7-chloro-3-(2,2,2-trifluoroacetyl)-6-[4-(2,2,2-trifluoroethylthio-methylcarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (37 mg, 41%). MS (ES+) m/z: 539 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:21][CH:20]=[C:19]([CH3:22])[N:7]2[C:8](=[O:18])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH3:3].[NH2:23][C:24]1[N:32]=[C:31]2[C:27]([NH:28][CH:29]=[N:30]2)=[C:26](Br)[N:25]=1.C(N(CC)C(C)C)(C)C>C(O)C>[NH2:23][C:24]1[N:32]=[C:31]2[C:27]([N:28]=[CH:29][NH:30]2)=[C:26]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[S:21][CH:20]=[C:19]([CH3:22])[N:7]3[C:8](=[O:18])[C:9]=2[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[CH3:3])[N:25]=1
Reactant: Cc1csc2nc(C(C)N)c(-c3cc(F)cc(F)c3)c(=O)n12
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1csc2nc(C(C)Nc3nc(N)nc4[nH]cnc34)c(-c3cc(F)cc(F)c3)c(=O)n12
Temperature: 110 °C
Yield: 52.3 %

Procedure:
A mixture of optical pure 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.13 g, 0.40 mmol) made from above, 2-amino-6-bromopurine (0.10 g, 0.47 mmol), and N,N-diisopropylethylamine (0.085 mL, 0.49 mmol) in ethanol (1 mL) was heated at 110° C. overnight. LCMS showed incomplete conversion. An additional 0.5 equivalent of 2-amino-6-bromopurine and 1.0 equivalent of N,N-diisopropylethylamine was added, and the mixture was stirred at 110° C. for another day. The solid was shown to be 2-amino-6-bromopurine by LCMS. The mixture was filtered, and the filtrates were purified on preparative-LCMS ((XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product (0.095 g, 52%). LCMS calculated for C20H17F2N8OS (M+H)+: m/z=455.1. Found: 455.1 1H NMR (DMSO-d6, 400 MHz) δ 7.67 (1H, s), 7.27 (1H, m), 7.17 (3H, m), 7.07 (1H, s), 6.89 (1H, br s), 5.45 (2H, br s), 5.03 (1H, m), 2.63 (3H, s), 1.30 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −111 ppm.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][C@H:25]([OH:31])[CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:22])[CH2:12][C@@H:11]([O:39][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][C@H:25]([OH:31])[CH:26]([CH2:27][CH3:28])[CH2:29][CH3:30])[CH3:22])[CH2:12][C@@H:11]([OH:39])[CH2:10]1
Reactant: CCC(CC)[C@@H](O)CS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)[C@@H](O)CS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 103.2 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{3-ethyl-2(R)-hydroxypentyl-thio}pregna-5,7,16-triene (54.9 mg, 0.0797 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethanol=9:1, developed once) to give the title compound as a colorless oil (37.9 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([C:17]([OH:19])=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:24]O>>[CH3:24][O:18][C:17]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=1)=[O:19]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc([N+](=O)[O-])c2)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 4′-Methyl-5-nitro-biphenyl-3-carboxylic acid (10.00 g, 0.039 mol) in methanol was added SOCl2 (5.09 g, 0.043 mol) at 0° C. The reaction mixture was allowed to warm to room temperature and was then heated to reflux for 2 hours. The solvent was removed in vacuo to afford 4′-Methyl-5-nitro-biphenyl-3-carboxylic acid methyl ester (9.72 g, 92%) as light yellow solid. MS (M+H)=273.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH3:2].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH3:2][CH2:1][O:3][C:4]([CH:5]1[C:9]([OH:11])([CH3:10])[CH2:8][CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:19]
Reactant: CCOC(=O)CN(CCC(C)=O)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1N(C(=O)OC(C)(C)C)CCC1(C)O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 10.6 %

Procedure:
To a solution of 27A (5 g, 18.29 mmol) in toluene (100 mL) cooled at 0° C. was added solid potassium tert-butoxide (2.05 g, 18.29 mmol) in small portions to maintain the solution temperature <5° C. The reaction was stirred at 0° C. for 45 min, then quenched by addition of ice-cooled 10% aqueous KHSO4 solution and extracted with CH2Cl2 (3×). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a brown oily residue, which was chromatographed (silica gel) eluting with EtOAc/hexane (1:3) to give 530 mg of the title compound (racemate).
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[C:17]#[N:18]>C1COCC1>[F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][N:11]([C:15]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][C:16]=3[C:17]#[N:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: Fc1cccc2c1OCCN2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2c(F)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
To a flask charged with 8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (AAT Pharmaceuticals) (0.237 g, 1.547 mmol) was added THF (6.19 ml). The solution was cooled in an ice water bath prior to the addition of sodium hydride (60% in mineral oil) (0.068 g, 1.702 mmol). The resulting suspension was stirred for 30 min at 0° C., the 30 min at rt. The resulting pale yellow suspension was cooled in an ice water bath prior to the addition of 2-fluoro-5-(trifluoromethyl)benzonitrile (0.322 g, 1.702 mmol). The resulting mixture was stirred for 30 min at 0° C., then 1 hr at room temperature. The mixture was heated to 60° C. overnight then at reflux for 2 hr. The mixture was cooled to room temperature and added carefully to ice water and extracted with EtOAc (2×). The combined organics were dried with Na2SO4, filtered and dried under reduced pressure. The crude material was purified with a 25 g SNAP column ramping EtOAc in heptane (0-25%, 10% DCM throughout) yielding product, obtained as a yellow oil, 2-(8-fluoro-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-5-(trifluoromethyl)benzonitrile (0.168 g, 0.521 mmol, 33.7% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.89-3.97 (m, 2 H) 4.36 (dd, J=4.94, 3.86 Hz, 2 H) 6.61 (dt, J=7.78, 1.79 Hz, 1 H) 6.70-6.80 (m, 2 H) 7.50 (d, J=8.80 Hz, 1 H) 7.71-7.77 (m, 1 H) 7.92-7.95 (m, 1 H). m/z (ESI) 323.1 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[SH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17]>>[CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([SH:12])[CH:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: O=C(O)c1cccc(S)c1
Product: CC(C)Oc1ccc(NC(=O)c2cccc(S)c2)cc1

Procedure:
The entitled compound was obtained according to the method of Example 92 but using 4-isopropoxyaniline and 3-mercaptobenzoic acid as the starting materials.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[CH:10]([NH:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:11][CH2:12][C:13]([O:15]CC=C)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:31])[CH:10]([NH:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=O)CCC(NC(=O)CCCCCCCCC)C(=O)OCc1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)NC(CCC(=O)O)C(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Pd(O)-catalyzed deprotection of the allyl ester proceeded as follows to yield 2-Decanoylamino-pentanedioic acid 1-benzyl ester (8). To a solution of 752 mg (1.74 mmol) of 2-decanoylamino-pentanedioic acid 7 in 10 mL of CH2Cl2 was added 100 mg (0.087 mmol) of tetrakistri-phenylphosphine Pd(O) followed by 0.52 mL (1.9 mmol) of tributyltin hydride. After 15 min, the reaction mixture was quenched with 10 mL of a 10% HCl solution. The aqueous layer was reextracted with 15 mL of CH2Cl2 and the organic layer dried (Na2SO4), concentrated in vacuo, and chromatographed on SiO2 (Hexanes/EtOAc, 9:1) to provide 545 mg (79.9%) of 8 as a thick oil: [α]D +2.8° (c 1.2, CHCl3, 21° C.); IR (neat) 3351, 3064, 2995, 2852, 1738, 1712, 1657, 1536, 1454, 1380, 1364, 1265, 1209, 1183, 1121, 739 cm-1 ; 1H NMR δ 10.9-10.7 (bs, 1 H), 7.22 (s, 5 H), 6.58 (d, 1 H, J=7.8 Hz), 5.09 (s, 2 H), 4.63 (dd, 1 H, J=8.1, 12.9 Hz), 2.4-2.25 (m, 2 H), 2.2-2.1 (m, 3 H), 2.0-1.9 (m, 1 H), (m, 6 H), 1.53 (t, 2 H, J=6.6 Hz), 1.19 (bs, 12 H), 0.81 (t. 3 H, J=6.0 Hz); 13C NMR δ 176.9, 174.0, 171.8, 134.9, 128.5, 128.4, 128.1, 67.3, 51.4, 36.2, 31.7, 29.9, 29.3, 29.2, 29.1, 27.0, 25.5, 22.5, 14.0; MS (El) m/z (relative intensity) 391 (54), 373 (62), 279 (13), 256 (19), 178 (27), 178 (23), 155 (13), 146 (6), 130 (7), 102 (100); HRMS (El) m/z calculated for C22H33NO5 :391.2358, found: 391.2350.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][CH:37]([NH:39][CH2:40][CH2:41][NH2:42])[CH3:38]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:42][CH2:41][CH2:40][NH:39][CH:37]([CH3:38])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CC(C)NCCN
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCNC(C)C)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 46.5 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (30 mg, 0.06 mmol) in DCM (5 mL) was added N-(1-methylethyl)-1,2-ethanediamine (0.037 mL, 0.30 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (15 mg, 46%). LC-MS m/z 538 (M+H)+; 1H-NMR (MeOD) δ 1.00 (m, 9H), 1.65 (m, 2H), 2.31 (s, 3H), 2.61 (m, 2H), 2.73 (m, 2H), 3.20 (m, 2H), 3.40 (m, 1H), 4.11 (s, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=[C:4](N)[CH:3]=1.[I:22]CI.C(ON=O)(C)(C)C>CCOC(C)=O>[I:22][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=1
Reactant: Cc1cc(N)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Reactant: ICI
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Product: Cc1cc(I)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
A suspension of Example A2 (0.62 g, 2.2 mmol), KI (3.7 g, 22.3 mmol), and diiodomethane (5 mL, 62 mmol) was treated with t-butylnitrite (1.4 mL, 11.7 mmol) and stirred at RT for 12 h. The mixture was treated with EtOAc, washed successively with satd. NaHCO3 (3×), 10% Na2S2O3 (2×), and brine (2×) and the combined aqueous washes were back-extracted with EtOAc (2×). The combined organics were dried over MgSO4, concentrated to dryness and purified by silica gel chromatography (EtOAc/DCM) to afford 2-iodo-4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.51 g, 59%). MS (ESI) m/z: 393.0 (M+H+).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl.[CH3:29][NH:30][O:31][CH3:32]>ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([C:25](=[O:27])[N:30]([O:31][CH3:32])[CH3:29])[CH2:21]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
Add portionwise 1,1′-carbonyldiimidazole (4.14 g, 25.6 mmol) to a solution of pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (5.0 g, 23.2 mmol) in dichloromethane (77 mL) at RT. Allow the mixture to stir for 15 min. Add slowly N,O-dimethylhydroxylamine hydrochloride (2.7 g, 27.9 mmol). Stir the reaction mixture at RT overnight. Dilute the mixture with dichloromethane (200 mL), wash with water (2×300 mL), brine (200 mL), dry over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatograph, eluting with 50-100% ethylacetate/hexane to give 5.36 g (89%) of the title compound. LC-MS/ES m/z 203.0 [M−tertBu+H]+.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][N:6]=1)=[O:3].[OH-].[Na+].N1C=CC=CC=1.C([O:25][C:26]1C(=[CH:31][CH:32]=[CH:33][CH:34]=1)C(Cl)=O)(=O)C>Cl.C(#N)C>[NH2:13][S:10]([C:8]1[S:9][C:5]([NH:4][C:2](=[O:3])[C:1]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[OH:25])=[N:6][N:7]=1)(=[O:12])=[O:11]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CC(=O)Nc1nnc(S(N)(=O)=O)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC#N
Product: NS(=O)(=O)c1nnc(NC(=O)c2ccccc2O)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetazolamide (50 g) was stirred and heated at reflux in 500 ml 3N hydrochloric acid for half an hour. The cooled solution was made basic with 50% sodium hydroxide. The precipitated white solid 5-amino-1,3,4-thiadiazole-2-sulfonamide was collected (Compound 1, 28 g). It was dried further at 70° C. in a vacuum oven overnight. To a mixture of Compound 1 (4.5 g, 0.025 mole) and pyridine (2.42 ml, 0.03 mole) in 70 ml acetonitrile was added acetylsalicyloyl chloride (98%, 5 g, 0.025 mole). The reaction mixture warmed and became a clear solution. Solid deposits occurred slowly after stirring at room temperature for 1/2 hour. After two hours the solvent was evaporated; the residue was triturated with isopropyl alcohol/water for two hours and then filtered, rinsed in succession with isopropyl alcohol/water, isopropyl alcohol/isopropyl ether, 2×isopropyl ether. From the combined mother liquor and rinsings, a second crop was collected. Both the first and second crops were combined and dissolved in 50 ml N-methyl-2-pyrrolidone. The solution was filtered and the filtrate was treated with 15 ml 3N hydrochloric acid at 70° C. for half an hour. Upon dilution with 200 ml water, a white solid precipitated. The solid was collected, rinsed with water, and dried in a vacuum over at 80° C. overnight to 4.4 g of title compound, mp>250° C.