Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12)[NH2:5].[CH3:20][N:21]1[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[C:22]1=[O:29].Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:26]([CH:23]2[CH2:24][CH2:25][N:21]([CH3:20])[C:22]2=[O:29])=[O:27])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: CN1CCC(C(=O)O)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCC(C(=O)Nc2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)C1=O
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 200.0 mg, 0.5179 mmol), 1-methyl-2-oxopyrrolidine-3-carboxylic acid (148.3 mg, 1.04 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (297.8 mg, 1.55 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (209.9 mg, 1.55 mmol), N-ethyl-N-isopropylpropan-2-amine (334.7 mg, 2.59 mmol) and THF (25 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (dichloromethane/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (213 mg, 80.4%). LRMS (APCI pos) m/e 512 (M+1). 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.42 (d, 1H), 7.79 (dd, 1H), 7.76 (s, 1H), 7.29 (m, 1H), 7.19 (t, 1H), 6.45 (dd, 1H), 3.43-3.49 (m, 3H), 2.94 (s, 3H), 2.36-2.61 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:4]=2[O:3]1.CN(C=O)C.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)Cl>[Br:27][C:10]1[C:11]([CH3:13])=[CH:12][C:4]2[O:3][C:2]([CH3:14])([CH3:1])[C:7](=[O:8])[NH:6][C:5]=2[CH:9]=1
Reactant: Cc1ccc2c(c1)OC(C)(C)C(=O)N2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1Br)NC(=O)C(C)(C)O2
Reaction time: 4 h
Yield: 58 %

Procedure:
A solution of Compound 1A (4.24 g, 22.2 mmol) in 150 mL of chloroform was treated with 5 mL of dry DMF followed by 4.4 g (24.4 mmol) of NBS at room temperature. After 4 hours, the reaction was quenched with 150 mL of a saturated sodium thiosulfate solution. The aqueous layer was extracted with chloroform and the combined organic layers were dried with magnesium sulfate, filtered, and excess solvent removed on the rotary evaporator. The crude product was purified via silica gel chromatography (5% EtOAc/Hexanes) to yield 3.48 g of brominated product (58%). MS (electrospray): mass calculated for C11H12BrNO2, 269.01; m/z found 268, [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:4][N:3]=1.[CH3:17][C:18]([O:21][C:22]([NH:24][C@@H:25]([CH2:30][C:31]#[CH:32])[C:26]([O:28][CH3:29])=[O:27])=[O:23])([CH3:20])[CH3:19].C(NCC)C>C(OCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][C:18]([O:21][C:22]([NH:24][C@@H:25]([CH2:30][C:31]#[C:32][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:4][N:3]=1)[C:26]([O:28][CH3:29])=[O:27])=[O:23])([CH3:17])[CH3:19]
Reactant: Fc1ccccc1COc1ccc(Br)nc1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Solvent: CCOCC
Product: COC(=O)[C@H](CC#Cc1ccc(OCc2ccccc2F)cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
To a solution of 2-bromo-5-{[(2-fluorophenyl)methyl]oxy}pyridine (D82, 0.60 g, 2.13 mmol), methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (D64, 1.20 g, 5.30 mmol), synthesized with an analogous procedure to the one described hereinabove, and diethylamine (1.10 ml, 10.65 mmol) in diethyl ether (20 ml) were added copper iodide (0.042 g, 0.22 mmol) and PdCl2(PPh3)2 (0.077 g, 0.11 mmol) and the mixture was stirred for three hours at room temperature. The reaction was quenched with a saturated solution of ammonium chloride diluted with water and extracted with diethyl ether. The organic layer was dried (Na2SO4) filtered and evaporated. The residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (9:1 to 8:2) to afford the title compound as a yellow solid (0.36 g, 40%). Rt (HPLC): 5.64 min; MS: (ES/+) m/z: 429 [MH]+ C23H25FN2O5 requires 428; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.28-8.39 (m, 1H); 7.44-7.53 (m, 1H); 7.32-7.41 (m, 2H); 7.16-7.25 (m, 2H); 7.08-7.16 (m, 1H); 5.37-5.55 (m, 1H); 5.19 (s, 2H); 4.46-4.66 (m, 1H); 3.81 (s, 3H); 2.91-3.07 (m, 2H); 1.47 (s, 9H).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14]O)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:12]1[O:13][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2ccc(CO)o2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2ccc(CCl)o2)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-yl]-methanol (3.52 g, 19.11 mmol) in dry CH2Cl2 (35.2 mL) was treated at 0° C. with Et3N (3.20 mL, 22.93 mmol) followed by DMAP (233 mg, 1.91 mmol) and Ms-Cl (1.63 mL, 21.02 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (35 mL), extracted with CH2Cl2 (30 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give 3.65 g of crude 2-(5-chloromethyl-furan-2-yl)-2-methyl-[1,3]dioxolane as an orange oil. The crude material in acetone (20 mL) was added, under inert atmosphere (N2) to a solution of 4-nitro-1H-pyrazole (1.57 g, 13.91 mmol) in acetone (20 mL). K2CO3 (7.69 g, 55.66 mmol) followed by TBA iodide (1.03 g, 2.73 mmol) were added and the reaction mixture was stirred at rt overnight. Water (100 mL) and EA (100 mL) were added. The aq. layer was extracted with EA (100 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as an orange oil. TLC: rf (60:40 hept-EA)=0.31. LC-MS-conditions 02: tR=0.91 min. 1H NMR (400 MHz, CDCl3) δ 1.72 (s, 3H), 3.99 (dd, J=4.5, 2.5 Hz, 2H), 4.06 (dd, J=4.4, 2.5 Hz, 2H), 5.31 (s, 2H), 6.35 (d, J=3.3 Hz, 1H), 6.42 (d, J=3.3 Hz, 1H), 8.09 (s, 1H), 8.12 (s, 1H).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6]OCC1.[CH3:8][NH:9][C:10](=[O:30])[C@@H:11]([NH:22][C:23]([O:25]C(C)(C)C)=O)[CH2:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1>>[CH3:8][NH:9][C:10](=[O:30])[C@@H:11]([NH:22][C:23](=[O:25])[C@H:11]([CH3:10])[CH2:12][S:13][C:7](=[O:2])[C:6]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1)[CH2:12][S:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1
Reactant: C1COCCO1
Reactant: CNC(=O)[C@H](CSCc1ccc(C)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CNC(=O)[C@H](CSCc1ccc(C)cc1)NC(=O)[C@H](C)CSC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 N hydrogen chloride/dioxane (1.5 ml) is added to (2R)-2-(tert-butoxycarbonylamino)-3-(4-methylbenzylthio)propionic acid methylamide (reference compound No. 4-1, 200 mg), and the mixture is stirred at room temperature for one hour. The reaction mixture is concentrated under reduced pressure, and the obtained residue is dissolved in methylene chloride (5 ml). To the solution are added N-methylmorpholine (0.119 ml), 1-hydroxybenzotriazole (109 mg), (2S)-3-(benzoylthio)-2-methylpropionic acid (182 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (135 mg) and N-methylmorpholine (0.077 ml) successively under ice-cooling, and the mixture is stirred overnight at room temperature. A 5% aqueous sodium hydrogencarbonate solution is added to the system of reaction, and the whole is extracted with ethyl acetate. The organic layer is washed with a 5% aqueous sodium hydrogencarbonate solution and a saturated sodium chloride solution successively, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give the titled compound.
Reaction SMILES: [NH3:1].[CH2:2]([NH:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1.O>[CH2:2]([NH:9][C:10]1[CH:15]=[C:14]([NH2:1])[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc(F)cc1NCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc([N+](=O)[O-])c(NCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
Ammonia (49 mmol) is purged in THF for 1 h at −70° C., benzyl-(5-fluoro-2-nitro-phenyl)-amine E-1.1″ (6.000 g; 24 mmol) is added to the reaction mixture. The reaction mixture is stirred in a steel bomb vessel at 90° C. for 16 h. The reaction is then cooled to 0° C., diluted with water and extracted with ethyl acetate. The combined organic layers are dried with Na2SO4, filtered and concentrated under reduced pressure. The residue is used in the next step without further purification (yield: 84%; 5.000 g; 20.554 mmol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:11]([O-:13])=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:14]N(C)CCCN=C=NCC.CCOCC>CC#N.CN(C1C=CN=CC=1)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])Cc1ccc2c(c1)CCN2
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)Cc1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 1-(S-[4-tert-butoxycarbonyl)-4-(tert -butoxycarbonylamino)]butanoyl)indoline-5-acetate 7. Crude 3 (327 mg, 1.9 mmol) was prepared as described above (see compound 4), dissolved in dry MeCN (30 mL) and treated with DMAP (611 mg, 5 mmol) and N-tert-BOC-L-glutamic acid α-tert-butyl ester (607 mg, 2 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (422 mg, 2.2 mmol). The mixture was stirred at rt for 18 h, then evaporated and the residue was dissolved in EtOAc and washed successively with 0.5 M aq. HCl, saturated aq. NaHCO3 and brine, dried and evaporated to give a viscous oil. Flash chromatography [EtOAc-hexanes (55:45)] and trituration with ether gave. 6 as white crystals (626 mg, 69%), mp 80-81° C. (EtOAc-hexanes); IR: νmax/cm−1; 3340, 1730, 1680, 1655, 1625; 1H NMR: δH (400 MHz) 8.15 (d, J=8 Hz, 1H), 7.07-7.11 (m, 2H), 5.23 (d, J=6.9 Hz, 1H), 4.22 (m, 1H), 4.03 (2×t, J=8.5 Hz, 2H; rotamers), 3.68 (s, 3H), 3.57 (s, 2H), 3.17 (t, J=8.5 Hz, 2H), 2.43-2.59 (m, 2H), 2.18-2.31 (m, 1H), 1.98-2.07 (m, 1H), 1.47 (s, 9H) and 1.41 (s, 9H). Anal. Calcd for C25H36N2O7: C, 63.01; H, 7.61; N, 5.88. Found: C, 63.08; H, 7.81; N, 5.64.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH:5]=[N:6][OH:7].[O:12]1[CH:16]=[CH:15][CH2:14][CH2:13]1.O>C(Cl)Cl.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH:14]3[CH2:15][CH2:16][O:12][CH:13]3[O:7][N:6]=2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: C1=COCC1
Reactant: ON=Cc1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(C2=NOC3OCCC23)cc1Cl
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a suspension of 3,4-dichlorobenzaldehyde oxime (1 eq) in DCM (10 vol) was added a 50% aqueous bleach solution (10 vol). 2,3-Dihydrofuran was then added and the resultant biphasic system was stirred vigorously at room temperature for 21 hours. Water (25 vol) and brine (25 vol) were added and the organic layer was separated. The aqueous phase was further extracted with (2×5 vol) DCM. The combined organic phases were washed with a 1:1 mixture of water and brine (50 vol), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash column chromatography (eluent: EtOAc:heptane) to yield 3-(3,4-Dichloro-phenyl)-3a,4,5,6a-tetrahydro-furo[3,2-d]isoxazole.
Reaction SMILES: [CH3:1][C@:2]1([CH2:14][OH:15])[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4][CH2:3]1.[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.[H-].[Na+]>>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:15][CH2:14][C@@:2]2([CH3:1])[O:7][C:6]3=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]3[CH2:4][CH2:3]2)=[CH:19][CH:18]=1
Reactant: C[C@@]1(CO)CCn2cc([N+](=O)[O-])nc2O1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Product: C[C@@]1(COCc2ccc(Br)cc2)CCn2cc([N+](=O)[O-])nc2O1
Yield: 61 %

Procedure:
Alkylation of (S)-alcohol 162 with 4-bromobenzyl bromide (1.35 equiv.) and NaH (1.55 equiv.) as in Example 2UU above for 3 h, followed by chromatography of the product on silica gel, eluting with CH2Cl2 (foreruns) and then with 1% EtOAc/CH2Cl2, gave (7S)-7-{[(4-bromobenzyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (163) (373 mg, 61%) as a white solid: mp (CH2Cl2/hexane) 159-161° C.; 1H NMR (CDCl3) δ 7.46 (dt, J=8.4, 2.1 Hz, 2H), 7.39 (s, 1H), 7.12 (dt, J=8.4, 2.1 Hz, 2H), 4.50 (s, 2H), 4.09 (ddd, J=12.5, 7.0, 5.8 Hz, 1H), 4.01 (ddd, J=12.5, 7.1, 5.9 Hz, 1H), 3.62 (d, J=10.2 Hz, 1H), 3.58 (d, J=10.2 Hz, 1H), 2.37 (ddd, J=14.4, 7.1, 5.9 Hz, 1H), 2.10 (ddd, J=14.5, 7.0, 5.9 Hz, 1H), 1.46 (s, 3H); [α]D27−32.0° (c 1.00, CHCl3); HRFABMS calcd for C15H17BrN3O4m/z [M+H]+ 384.0382, 382.0402. found 384.0374, 382.0393.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]([CH3:44])[N:38]=1>>[CH3:44][C:39]1[N:38]=[C:37]([C:20]2[CH:19]=[CH:18][C:17]([C@@H:15]([N:11]3[CH2:10][CH2:9][C@@:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12]3=[O:14])[CH3:16])=[CH:22][CH:21]=2)[CH:42]=[C:41]([CH3:43])[N:40]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Cc1cc(Br)nc(C)n1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)nc(C)n1

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.073, m/z=464.1; 1H NMR (CD3OD) 1.21 (m, 1H), 1.48 (d, 3H), 1.82 (m, 2H), 2.15 (m, 1H), 2.23 (m, 2H), 2.38 (m, 1H), 2.46 (s, 3H), 2.62 (s, 3H), 3.08 (m, 1H), 3.39 (m, 2H), 5.51 (m, 1H), 6.95-7.08 (m, 4H), 7.21 (m, 2H), 7.51 (s, 1H), 7.83 (d, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(C(F)(F)F)cc1

Procedure:
Reaction of 4-trifluoromethylbenzoic acid with thionyl chloride affords 4-trifluoromethylbenzoyl chloride, which, on reaction with diethylamine, affords 4-trifluoro-methyl-N,N-diethylbenzamide. Following a procedure similar to that described in Preparation 5, reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 4-trifluoromethyl-2-aminosulfonyl-N,N-diethylbenzamide, which on heating in glacial acetic acid, affords 6-trifluoro-methylsaccharin.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[NH:17][C:18]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:19])[C:8]1=[O:26].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[O:46]=[C:47](Cl)OC(Cl)(Cl)Cl.CCOCC>ClCCl>[Cl:25][C:22]1[S:21][C:20]([C:18]([NH:17][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:14]=2[C:15](=[O:16])[N:7]([CH2:6][C:5]2[CH:27]=[CH:28][CH:29]=[C:3]([CH2:2][N:1]=[C:47]=[O:46])[CH:4]=2)[C:8]3=[O:26])=[O:19])=[CH:24][CH:23]=1
Reactant: NCc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Solvent: CCOCC
Product: O=C=NCc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 430 mg (1.0 mmol) of N-{2-[3-(aminomethyl)benzyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-5-chloro-2-thiophenecarboxamide and 433 mg (2.0 mmol) of 1,8-bis-(dimethylamino)naphthalene in 222 ml of dichloromethane is added dropwise to an ice-cooled solution of 0.12 ml (0.96 mmol) of diphosgene in 7.5 ml of dichloromethane. After 5 min at 0° C., the mixture is warmed to room temperature and stirred for 35 min, and 40 ml of ether are then added. Insoluble particles are filtered off and the filtrate is concentrated and dried under high vacuum. The resulting solid is immediately reacted further, without further purification. Yield: 454 mg (99.5% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH:9]([CH3:11])[C:8]([OH:12])=[C:7]([C:13]([O:15][CH2:16][CH3:17])=O)[CH2:6]1)=[O:4].[CH2:18]([OH:21])[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:18]1[O:21][C:13]([CH:7]2[C:8](=[O:12])[CH:9]([CH3:11])[CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]2)([O:15][CH2:16][CH3:17])[O:20][CH2:19]1
Reactant: CCOC(=O)C1=C(O)C(C)CN(C(=O)OC)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC1(C2CN(C(=O)OC)CC(C)C2=O)OCCO1

Procedure:
A mixture of 1.9 g (7.8 mmol) of (RS)-ethyl 1-methoxycarbonyl-4-hydroxy-5-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate (prepared as described in Acta Chem. Scand. B32, 327 (1978)), ethylene glycol (2.2 ml), 4-toluenesulfonic acid (0.15 g), and toluene was refluxed for 20 hours using a Dean-Stark water separator. The mixture was washed with aqueous sodium bicarbonate, dried and evaporated in vacuo. The crude product was distilled at 0.5 mm Hg, B.P. 148°-152° C. Yield 1.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]([CH3:16])[C:12]([SH:15])=[N:13][CH:14]=2)[OH:9])=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[N:11]([CH3:16])[C:12]([S:15][CH2:18][CH2:19][CH3:20])=[N:13][CH:14]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: Cn1c(C(O)c2ccc(Cl)cc2)cnc1S
Reactant: CCCBr
Product: CCCSc1ncc(C(O)c2ccc(Cl)cc2)n1C
Yield: 71 %

Procedure:
The product of Example I, Step A (3.35 g) was subjected to the same conditions as described in Example I, Step B except that bromopropane (1.4 mL) was employed as the alkylating agent to provide (4-Chlorophenyl)-(3-methyl-2-propylsulfanyl-3H-imidazol-4-yl)-methanol (2.69 g, 71%). M calc=296; M+H found=297. Calculated for C14H17N2OSCl: C 56.65, H 5.77, 9.44; found C 55.88, H 5.88, N 9.84.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].[Br:16][C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH2:23][CH2:24]O)=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:24][CH2:23][CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([Br:16])=[CH:27][CH:26]=1
Reactant: OCCCOc1ccc(Br)cc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(Br)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
To a solution of 0.30 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.24 g of 3-(4-bromophenoxy)-1-propanol and 0.27 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.21 g of diisopropylazodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.34 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(4-bromophenoxy) propyloxy)benzene (65% yield), nD25.0 1.5917.
Reaction SMILES: [S:1](=[O:3])=[O:2].[S:4]([O-:7])([O-:6])=[O:5].[Mg+2:8]>>[S:4](=[O:5])([OH:7])[O-:6].[Mg+2:8].[S:1](=[O:5])([OH:3])[O-:2]
Reactant: O=S([O-])[O-]
Reactant: O=S=O
Agent: [Mg+2]
Product: O=S([O-])O

Procedure:
U.S. Pat. No. 4,388,238 to Abrams, et al. describes how sulfur dioxide is contacted with a magnesium sulfite solution in a scrubbing zone at a pH in the range of about 6 to 7.5 in order to produce magnesium bisulfite. It also teaches providing a minor regeneration stream which is subjected to oxidation to oxidize bisulfite and sulfite to sulfate. This reference also teaches the use of a type S hydrated dolomitic lime for the spray dryer at a weight percent of 3-15% suspended solids and at a stoichiometric ratio of 1.1 to 1.5 and injected at a temperature of 145° to 165° F. The product is calcium sulfite and sulfate, magnesium sulfite and sulfate, unreacted lime, and flyash. However, the presence of calcium sulfite and sulfate and magnesium sulfate is undesirable.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][C:15]([NH:19]CC4C=CC(OC)=CC=4OC)=[N:14][C:13]=3[N:12]([C:31]([CH3:42])([CH3:41])[CH2:32][O:33][Si](C(C)(C)C)(C)C)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH3:43][C:44]1[N:48]([CH2:49][C:50](O)=[O:51])[N:47]=[C:46]([C:53]([F:56])([F:55])[F:54])[CH:45]=1>>[NH2:19][C:15]1[N:16]=[CH:17][C:18]2[C:10]([C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:50](=[O:51])[CH2:49][N:48]4[C:44]([CH3:43])=[CH:45][C:46]([C:53]([F:56])([F:55])[F:54])=[N:47]4)[CH:7]=[N:6][CH:5]=3)=[O:9])=[CH:11][N:12]([C:31]([CH3:41])([CH3:42])[CH2:32][OH:33])[C:13]=2[N:14]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: COc1ccc(CNc2ncc3c(C(=O)c4cncc(N)c4)cn(C(C)(C)CO[Si](C)(C)C(C)(C)C)c3n2)c(OC)c1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)Nc1cncc(C(=O)c2cn(C(C)(C)CO)c3nc(N)ncc23)c1

Procedure:
The title compound was prepared according to the method described for Example 46 using (5-aminopyridin-3-yl){7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-[(2,4-dimethoxybenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (see Preparation 51) and (5-methyl-3-trifluoromethyl-pyrazol-1-yl)acetic acid (46.8 mg, 0.225 mmol) to afford the title compound as a brown solid in 79% yield, 82 mg.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[O:20][CH2:21][CH2:22][NH2:23].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:13])=[CH:4][C:3]=1[O:20][CH2:21][CH2:22][NH:23][C:31](=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: NCCOc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCOc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.6 %

Procedure:
2-{[6-Fluoro-1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethanamine (Intermediate 29, 2.0 g 6.0 mmol) in DCM (100 mL) was treated with triethylamine (2.5 mL, 18 mmol) and 4-dimethylaminopyridine (0.37 g, 3.0 mmol). The solution was cooled to 0° C. and treated with acetyl chloride (0.85 mL, 12 mmol). The mixture was stirred at room temperature for 1.5 hours and washed with saturated aqueous NaHCO3 (40 mL) and 0.5 M HCl (40 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (2.0 g). MS m/z 377 [M+H]+.