Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
31.4 g of 5-fluoro-2-nitrophenol (0.2 mol) and 34.3 g of benzyl bromide (0.2 mol) are dissolved in 200 ml of dry acetonitrile in a 500 ml three-neck flask fitted with reflux condenser, stirrer and nitrogen inlet. 60 g of potassium carbonate (0.43 mol) are added, and the solution is refluxed for 2 hours in a temperature-controllable oil bath. The reaction solution is then allowed to cool to room temperature, and the residue is filtered off via a fluted filter. The resultant solution is then evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the yellow-orange reaction product precipitates in crystalline form. The reaction product is then filtered off via a fluted filter, recrystallized from ethanol and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: [S:1](=[O:3])=[O:2].[S:4]([O-:7])([O-:6])=[O:5].[Na+:8].[Na+]>O>[S:4]([S:1]([O-:3])=[O:2])([O-:7])(=[O:6])=[O:5].[Na+:8].[Na+:8]
Reactant: O=S([O-])[O-]
Reactant: O=S=O
Agent: [Na+]
Solvent: O
Product: O=S([O-])S(=O)(=O)[O-]

Procedure:
In another embodiment, the invention relates to a method for producing sodium metabisulfite. In particular, the method comprises introducing a gas stream, having sulfur dioxide, and a liquid stream, having sodium sulfite and water, into a column. The method also comprises absorbing at least a portion of the sulfur dioxide into the liquid stream and reacting at least a portion of the absorbed sulfur dioxide with sodium sulfite to produce a sodium metabisulfite stream. The method further involves evaporating at least a portion of the water from the liquid stream into the gas stream. The method also comprises precipitating sodium metabisulfite from the sodium metabisulfite stream in a crystallizer and withdrawing a slurry of sodium metabisulfite from the bottom of the crystallizer.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][OH:6].[OH:11][C:12]1[CH:17]=[C:16]([CH3:18])[O:15][C:14](=O)[CH:13]=1>ClC1C=CC=CC=1Cl>[Cl:10][C:9]1[CH:8]=[CH:7][C:4]([CH2:5][OH:6])=[CH:3][C:2]=1[N:1]1[C:16]([CH3:18])=[CH:17][C:12]([OH:11])=[CH:13][C:14]1=[O:15]
Reactant: Nc1cc(CO)ccc1Cl
Reactant: Cc1cc(O)cc(=O)o1
Solvent: Clc1ccccc1Cl
Product: Cc1cc(O)cc(=O)n1-c1cc(CO)ccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
3-amino-4-chloro-benzyl alcohol (8.0 g, 51.0 mmol) and 4-hydroxy-6-methyl-2-pyrone (6.4 g, 51.0 mmol) were taken up in 1,2-dichlorobenzene (50 ml). The mixture was plunged into a 165° C. oil bath where it stirred for 20 minutes. The reaction was cooled to room temperature and the reaction was worked up by washing with saturated NaHCO3 (aq.) and extracting impurities with ethyl acetate. The product remained in the aqueous layer. The basic aqueous layer was made acidic with concentrated HCl. The product was extracted from the acidic aqueous layer with ethyl acetate. The ethyl acetate layer was dried over Na2SO4 and the solvent removed in vacuo. The product was obtained as a yellow oil in a 26% yield and was carried through to the next step with no further purification. 1H NMR (300 MHz, CD3OD) δ 7.62 (d, J=8.26 Hz, 2H), 7.51 (dd, J=8.46, 2.22 Hz, 1H), 7.36 (d, J=2.01 Hz, 1H), 6.13 (br s, 1H), 5.84 (d, J=2.42 Hz, 1H), 4.68 (s, 2H), 1.97 (s, 3H); LC/MS, tr=0.25 minutes and 1.41 minutes (tautomer), (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 266 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:1]([C:8]1[N:12]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reactant: CCOC(=O)CCCCCCCBr
Product: CCOC(=O)CCCCCCCn1c(Cc2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Yield: 52.6 %

Procedure:
2-Benzyl-4,5-diphenylimidazole (3.3 g) (Weiss, M, J. Am. Chem. Soc., 1952, 74, 5193-5) was reacted with ethyl 8-bromooctanoate as in Example 9. Column chromatography on silica gel eluted with a dichloro-methane:ethanol gradient followed by distillation at 200° C./0.1 torr to remove volatile impurities gave a yellow oil. Recrystallisation from hexane gave 2-benzyl-1-(7-ethoxycarbonylheptyl)-4,5-diphenylimidazole (2.69 g, 52.6%) as a white solid, m.p. 82°-3°. Found: C, 80.35; H, 7.58; N, 6.08%; C32H36N2O2 requires: C, 79.96; H, 7.55; N. 5.83%.
Reaction SMILES: [CH2:1]([N:7]([C:14]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)[C:8](=[O:13])C(Cl)(Cl)Cl)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+].C([N:38](CC)CC)C>C(O)(C)(C)C>[CH2:1]([N:7]1[C:14]2[C:15](=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)[C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:38][C:8]1=[O:13])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCN(CC)CC
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1N(CC1CCCO1)C(=O)C(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)(C)O
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1CC1CCCO1

Procedure:
A mixture of 2.36 g of 2-(N-tetrahydrofurfuryltrichloroacetamido)-5-nitrobenzophenone, 2.4 g of ammonium acetate, 0.5 g of triethylamine and 30 ml of tertiary butanol was stirred under reflux for 10 hours. Then the solvent was removed and water was added to the residue. The resulting mixture was extracted with chloroform and the extract was washed successively with dilute ammonia water and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was washed with ether and the insoluble product was collected by filtration and dried to give 1-tetrahydrofurfuryl-4-phenyl-6-nitro-2(1H)-quinazolinone, m.p. 150°-152° C.
Reaction SMILES: [C:1]([O:4][C@:5]1([O:28][C@H:27]([C@@H:29]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[O:30][C:31](=[O:33])[CH3:32])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[CH2:16]1)[C:6]([O:8]CC1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:4][C@:5]1([O:28][C@H:27]([C@@H:29]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[O:30][C:31](=[O:33])[CH3:32])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[CH2:16]1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@H]1O[C@@](OC(C)=O)(C(=O)OCc2ccccc2)C[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OC[C@@H](OC(C)=O)[C@H]1O[C@@](OC(C)=O)(C(=O)O)C[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
A mixture of 20b (220 mg, 0.41 mmol) and Pd-C (10%, 55 mg) in ethanol (3 mL) was vigorously stirred under H2 at room temperature for 1 h. After the catalyst was filtered off, the filtrate was concentrated in vacuo. The residue was recrystallized from diethyl ether to give 20a (177 mg, 97%) as fine needles, mp 132°-133° C.; [α]25D +374° (c 0.88, CHCl3). Its 1H NMR spectrum (C6D6) was identical with that reported previously by Unger et al. (Carbohydr. Res. 1980, 80, 191).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].[O:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[NH:20][CH:25]1[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(NC3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of 2-amino-4-(4-methyl-piperazin-1-yl)-benzoic acid tert-butyl ester (11.5 g, 39.5 mmol) in dichloromethane (340 mL) were added tetrahydro-pyran-4-one (4.5 mL, 49.3 mmol), trifluoroacetic acid (8.2 mL) and tetramethylammonium triacetoxyborohydride (15.57 g, 59.2 mmol). The mixture was stirred at room temperature for 2 hours then washed with 0.5N hydrochloric acid, with 0.5N NaOH and with a saturated solution of NaHCO3. The organic layer was dried over sodium sulfate and evaporated to dryness affording the title compound as a pale yellow solid (13.3 g, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:17]([NH:20][S:21]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])([CH3:19])[CH3:18]>>[CH:17]([NH:20][S:21]([C:24]1[NH:25][C:26]2[C:31]([C:32]=1[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])([CH3:19])[CH3:18]
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(C)NS(=O)(=O)c1cc2ccccc2[nH]1
Product: CC(C)NS(=O)(=O)c1[nH]c2ccccc2c1C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 83 %

Procedure:
Substantially the same procedure as in Example 266 was repeated using 4,4'-dichlorobenzhydrol (1.14 g, 4.50 mmol) and N-isopropylindole-2-sulfonamide (1.00 g, 4.46 mmol) to give 1.76 g (yield: 83%-) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[N:18]=[N:17]3)C=C2)=[C:4]([Cl:23])[N:3]=1.I([O-])(=O)(=O)=O.[Na+].S(S([O-])=O)([O-])(=O)=[O:31].[Na+].[Na+].CCO[C:42]([CH3:44])=[O:43]>CC#N.O.[Ru](Cl)(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[N:18]=[N:17]3)[CH:44]([OH:31])[CH:42]2[OH:43])=[C:4]([Cl:23])[N:3]=1
Reactant: CCOC(C)=O
Reactant: CCc1cn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)nn1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CCc1cn(C2CC(n3cnc4c(Cl)nc(Cl)nc43)C(O)C2O)nn1
Reaction time: 6 h

Procedure:
A solution of 2,6-dichloro-9-[(1R,4S)-4-(4-ethyl-[1,2,3]triazol-1-yl)-cyclopent-2-enyl]-9H-purine (1.442 g, 4.12 mmol) in EtOAc (15 mL) and MeCN (15 mL) is treated with a solution of ruthenium trichloride (0.120 g, 0.58 mmol) and sodium periodate (1.32 g, 6.18 mmol) in water (5 mL). The reaction mixture is stirred vigorously for 6 hours and then treated with sodium metabisulfite (saturated aqueous solution, 25 mL) and then stirred overnight. The resulting mixture is partitioned between water and EtOAc and the aqueous portion is extracted with EtOAc. The combined organic portions are washed with water, dried (MgSO4) and concentrated in vacuo. The crude product is purified by chromatography on silica eluting with 0-100% EtOAc in iso-hexane to afford the title compound as an oil orange solid. (MH+ 350).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:28])[C:5]([N:8]2[C:14]3=[N:15][C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:17]=4[N:13]3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:29][S:30]([O-:32])=[O:31].[Na+]>CN1CCCC1=O.C(OCC)(=O)C.[Cu]I>[Cl:22][C:21]1[C:16]2[N:15]=[C:14]3[N:8]([C:5]4[C:4]([CH3:28])=[CH:3][C:2]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:7][N:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[C:17]=2[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][CH:20]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Br)cc1C
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(S(C)(=O)=O)cc1C
Temperature: 180 °C
Yield: 36.2 %

Procedure:
A mixture of 1-(5-bromo-3-methylpyridin-2-yl)-10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (463 mg, 0.216 mmol), sodium methanesulfinate (66 mg, 0.648 mmol) and copper(I) iodide (123 mg, 0.648 mmol) in 1-methyl-2-pyrrolidinone (1.0 mL) was heated under microwave irradiation at 180° C. for 1 hr. After cooling, the mixture was diluted with ethyl acetate, filtered through a pad of celite, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture followed by recrystallization from ethyl acetate/n-hexane to afford the title compound (36 mg, 36%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:17])=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[N:18]([O-])=O.[Na+]>O>[ClH:16].[Cl:16][C:15]1[CH:14]=[CH:13][C:4]([CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[C:3]([F:17])[C:2]=1[NH:1][NH2:18]
Reactant: O=N[O-]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1F
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(NN)c1F
Product: Cl

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-7 by using N-(3-amino-4-chloro-2-fluorobenzyl)pivalamide (0.500 g, 1.93 mmol), sodium nitrite (0.200 g, 2.90 mmol), stannous chloride.H2O (4.84 g, 1.09 mmol), conc. HCl (20.0 g) and water (3 mL) to afford 0.300 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.12 (s, 9H), 4.23 (d, J=5.4 Hz, 2H), 4.34 (br s, 2H), 5.91 (s, 1H), 6.65 (t, J=7.8 Hz, 1H), 8.02 (m, 1H); MS (m/z): 274.08 (M+H+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](OS(C)(=O)=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([S:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:1])([F:10])[F:11])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: FC(F)(F)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2C(F)(F)F)CC1
Temperature: 80 °C
Yield: 62.6 %

Procedure:
To a stirred solution of 2-trifluoromethylbenzenethiol (0.637 g, 0.00358 mole) in DMF (5 mL) was added cesium carbonate (1.396 g, 0.00429 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 0.00358 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed brine solution, dried over sodium sulfate, filtered and concentrated. The resulting residue was washed with hexane to afford 0.81 g (99%) of 4-(2-trifluoromethyl-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 362.13 (M+1)+, 99%. A solution of 4-(2-trifluoromethyl-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (0.81 g, 0.00224 mole) in dioxane.HCl (2 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 0.604 g (90%) of 4-(2-trifluoromethyl-phenylsulfanyl)-piperidine hydrochloride which was used in the next step without further purification. LCMS: 262.08 (M+1)+, 95.07%.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:23]1[CH:24]=[N:25][NH:26][CH:27]=1.[CH3:28][N:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)[CH3:30].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C.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:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([C:23]4[CH:24]=[N:25][NH:26][CH:27]=4)=[C:2]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([N:29]([CH3:30])[CH3:28])[CH:36]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cn[nH]c3)sc2n1
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: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(N(C)C)c3)c(-c3cn[nH]c3)sc2n1
Temperature: 110 °C
Yield: 7.4 %

Procedure:
A mixture of N-[3-bromo-6-methyl-2-(1H-pyrazol-4-yl)thieno[2,3-b]pyridin-4-yl]-3-chlorobenzenesulfonamide (Example 100) (100 mg, 0.207 mmol), 3-(N,N-dimethylamino)-phenylboronic acid (68.2 mg, 0.413 mmol) and tetrakis(triphenylphosphine)palladium(0) (11.9 mg, 10.34 μmol) and potassium carbonate (86 mg, 0.620 mmol) in 1,4-dioxane (1 mL), DMF (0.5 mL) and water (0.25 mL) was heated at 110° C. overnight (ca. 22 h). After cooling to RT, the reaction mixture was filtered through celite and the filtrate concentrated and purified by chromatography on silica, eluting with a gradient of 0-100% ethyl acetate in DCM. The material was then passed through an SCX cartridge, eluting with MeOH (ca. 60 mL) and 2M NH3 in MeOH (60 mL), to give the title compound (8 mg). LCMS (A) m/z: 524 [M+1]+, Rt 1.28 min (acidic).
Reaction SMILES: [NH2:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5].O.C(=O)(O)[O-].[C:15](O)(=[O:26])[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.Cl>COCCOC.CN(C)C=O>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[C:15]([NH:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:26]
Reactant: NC(=O)[C@@H](N)CC(=O)O
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Solvent: CN(C)C=O
Product: NC(=O)[C@H](CC(=O)O)NC(=O)c1ccc2ccccc2n1
Yield: 69.1 %

Procedure:
To a solution of 0.50 g (3.78 mmol) of L-isoasparagine in 5.0 mL H2O containing ˜45 mg (1.5 eq) of solid bicarbonate. To this was added a suspension of 1.02 g (3.78 mmol) quinaldic acid, N-hydroxysuccinamide ester in ethylene glycol dimethylether, and the suspension was solubilized by the addition of 10 mL of dimethylformamide. After 3 hours the solution was acidified by the addition of 5% HCl (aqueous) and the product was filtered and washed with water, dried under vacuum to yield 750 mg (70% yield) of N-(2quinolinylcarbonyl)-L-isoasparagine.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([C:21]([O:23]C)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1.[OH-].[Li+].OS(O)(=O)=O>O1CCOCC1.O>[OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([C:21]([OH:23])=[O:22])[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:13]=1
Reactant: COC(=O)c1cc(OC2COCC2O)cc(-c2ccc(C)cc2)c1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(OC3COCC3O)cc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 5-(4-hydroxytetrahydrofuran-3-yloxy)-4′-methylbiphenyl-3-carboxylate (140 mg, 0.40 mmol) in 1,4-dioxane (2.8 mL) and water (2.8 mL) was added lithium hydroxide (50 mg, 2.1 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then acidifized with 2N aq. H2SO4 to pH 4-5 and concentrated in vacuo. The residue was treated with water and extracted with EtOAc (10 mL×2). The combined organic layers were dried (MgSO4) and concentrated to afford the title compound. 1H NMR (CD3OD, 400 MHz): 7.87 (t, J=1.6 Hz, 1H), 7.55-7.51 (m, 3H), 7.42 (t, J=2.0 Hz, 1H), 7.28 (d, J=7.6 Hz, 2H), 4.84 (d, J=4.4 Hz, 1H), 4.38 (d, J=4.0 Hz, 1H), 4.23 (dd, J=10.4, 4.4 Hz, 1H), 4.05 (dd, J=9.6, 4.4 Hz, 1H), 3.94 (dd, J=10.4, 1.6 Hz, 1H), 3.77 (dd, J=9.6, 1.6 Hz, 1H), 2.38 (s, 3H).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH2:28][N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:25]=4)[C:10]=3[N:11](COCC[Si](C)(C)C)[N:12]=2)=[CH:4][CH:3]=1.[C-:36]#[N:37].[Na+]>CN(C=O)C>[CH3:35][N:32]1[CH2:33][CH2:34][N:29]([CH2:28][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[C:10]2[NH:11][N:12]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([C:36]#[N:37])=[N:7][CH:6]=4)[C:9]=2[CH2:27]3)[CH2:30][CH2:31]1
Reactant: [C-]#N
Reactant: CN1CCN(Cc2ccc3c(c2)Cc2c(-c4ccc(F)nc4)nn(COCC[Si](C)(C)C)c2-3)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc3c(c2)Cc2c(-c4ccc(C#N)nc4)n[nH]c2-3)CC1
Temperature: 75 °C
Yield: 14.3 %

Procedure:
A mixture of Example 123D (70.6 mg, 0.142 mmol) and NaCN (9.7 mg, 0.199 mmol) in DMF (1.2 mL) in a capped vial was heated to 210° C. for 1200 seconds in a Smith Synthesizer (300W). The reaction was cooled using 40 psi pressurized air. The mixture was extracted with EtOAc and the organic layer was washed with 50% brine, NaHCO3, dried over MgSO4, filtered, concentrated. The crude product was treated with HCl (conc., 2 drops) and EtOH (3 mL) and the mixture was heated at 75° C. for 2.5 hours. The solvent was evaporated and the residue was purified using reversed-phase HPLC to give 7.5 mg of the desired product as TFA salt.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][OH:17])=[CH:10][CH:11]=2)[N:6]([CH3:18])[C:5]1=[O:19].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:17][CH2:16][C@@H:14]1[CH2:15][C@H:13]1[C:9]1[N:8]=[C:7]2[N:6]([CH3:18])[C:5](=[O:19])[N:4]([CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[C:12]2=[CH:11][CH:10]=1)(=[O:32])=[O:31]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CO)nc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3COS(C)(=O)=O)nc21
Temperature: -10 °C
Reaction time: 0.02 h

Procedure:
1-(2,2-Dimethylpropyl)-5-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (31-4, 53.2 mg, 0.18 mmol, 1.0 equiv) was added to anhydrous DCM (1.8 mL) and cooled to −10° C. Triethylamine (108 μL, 0.77 mmol, 4.2 equiv) and methanesulfonyl chloride (32 μL, 0.40 mmol, 2.2 equiv) were added sequentially and the resulting reaction mixture was stirred for 1 min. Following this duration, TLC showed complete consumption of 31-4. The reaction mixture was partitioned between ethyl acetate (5 mL) and saturated NaHCO3 (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a clear, yellow oil. The crude product was carried forward without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7]([CH2:15][C:16]#[N:17])([C:13]#N)[CH2:6][CH2:5]2.[OH2:18].CC(O)=[O:21]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7]1([CH2:15][C:16](=[O:18])[NH:17][C:13]1=[O:21])[CH2:6][CH2:5]2
Reactant: O
Reactant: CC(=O)O
Reactant: COc1cc2c(cc1Cl)CCC2(C#N)CC#N
Agent: O=S(=O)(O)O
Product: COc1cc2c(cc1Cl)CCC21CC(=O)NC1=O
Temperature: 200 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-chloro-1-(cyanomethyl)-6-methoxy-2,3-dihydro-1H-indene-1-carbonitrile (Prep17, 520 mg, 2.11 mmol) in AcOH (5.2 ml), H2SO4 (0.364 ml) was added. The mixture was stirred for 15 min at 200° C. Water was added and the mixture extracted with EA twice, solvent was evaporated, dried over Na2SO4, concentrated to give the title compound that was used in the next step without further purification. (540 mg, y=96%).