Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[N:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>CC#N>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([C:36]#[N:37])[N:35]=2)[C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccc(CBr)n1
Reactant: COc1ccc(NC2CCN([C@H](C)CCNC(=O)OC(C)(C)C)CC2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(Cc2cccc(C#N)n2)C2CCN([C@H](C)CCNC(=O)OC(C)(C)C)CC2)cc1
Yield: 77.9 %

Procedure:
Using General Procedure E, (R)-{3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyl}-carbamic acid tert-butyl ester (0.681 g, 1.81 mmol), 6-bromomethyl-pyridine-2-carbonitrile (0.535 g, 2.71 mmol) and DIPEA (630 μL, 3.62 mmol) in CH3CN (20 mL) at 55° C. for 16 h gave the crude product as a pale brown oil. Purification by column chromatography on silica gel (CH2Cl2:MeOH:, 95:5, v/v) afforded (R)-(3-{4-[(6-cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.696 g, 78%) as a yellow crystalline solid. 1H NMR (CDCl3) δ 0.95 (d, 3H, J=6.0 Hz), 1.40 (s+m, 11H), 1.65 (m, 4H), 1.86 (m, 2H), 2.13 (br t, 1H), 2.54 (br t, 1H), 2.73-2.86 (m, 3H), 3.06 (m, 1H), 3.31 (m, 1H), 3.54 (m, 1H), 3.73 (s, 3H), 4.50 (s, 2H), 6.06 (br s, 1H), 6.68 (d, 2H, J=9.0 Hz), 6.76 (d, 2H, J=9.0 Hz), 7.52 (d, 1H, J=6.0 Hz), 7.54 (d, 1H, J=6.0 Hz), 7.70 (t, 1H, J=6.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[F:32][C:33]([C:36]1[CH:41]=[CH:40][C:39]([C:42](=[N:44]O)[NH2:43])=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>CN(C=O)C>[F:32][C:33]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:43]=[C:7]([C:4]3[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=3)[O:9][N:44]=2)=[CH:38][CH:37]=1)([CH3:35])[CH3:34]
Reactant: CC(C)(F)c1ccc(C(N)=NO)cc1
Reactant: Cc1cc(C(=O)O)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(-c3ccc(C(C)(C)F)cc3)no2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a mechanically stirred solution of 5-methyl-1H-pyrazole-3-carboxylic acid (1.59 g, 12.64 mmol) in dry DMF (64 mL) was added EDCl (2.42 g, 12.64 mmol), HOBT (1.71 g, 12.64 mmol) and 4-(2-fluoropropan-2-yl)-N′-hydroxybenzenecarboximidamide (Intermediate Q, 2.48 g, 12.64 mmol). The mixture was stirred at rt for 2 h, and then heated to 140° C. and stirred for additional 1 h. After being cooled to it, the solvent was removed under reduced pressure. Ethyl acetate (150 mL) and 2% aqueous citric acid solution (150 mL) were added, and the organic phase was separated and washed with saturated aqueous sodium bicarbonate solution (150 mL) and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate and filtration, the solvent was removed in vacuo and the residue was purified by MPLC (silica, cyclohexane/ethyl acetate 3:1) to afford the title compound (2.48 g, 64%): 1H NMR (400 MHz, DMSO-d6) δ 13.54 (broad s, 1H), 8.08 (d, 2H), 7.62 (d, 2H), 6.81 (s, 1H), 2.33 (s, 3H), 1.72 (s, 3H), 1.68 (s, 3H); ES-MS m/z 287 (MH)+; HPLC RT (Method F) 2.19 min.
Reaction SMILES: CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[CH:21]1([CH2:27]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O>[CH:21]1([CH2:27][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrCC1CCCCC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCC2CCCCC2)cc1
Yield: 63 %

Procedure:
To 250 ml of DMF containing about 200 g of anhydrous potassium carbonate (1.5M) was added 122 g of 4-hydroxybenzaldehyde and 177 g of cyclohexylmethylbromide. The mixture was heated to reflux temperature and maintained overnight, after which was poured into cold water and extracted with ethyl acetate. The extracts were dried and evaporated under reduced pressure to yield the desired subtitled intermediate (63% yield), b.p. 133°-138° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:33](=[O:34])[C@@H:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:46])([CH3:47])[CH3:45])=[O:42])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (S)-2,6-bis-tert-butoxycarbonylamino-hexanoic acid to yield (3aR,4S,7aR)-4-((S)-2,6-bis-tert-butoxycarbonylamino-hexanoyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. This NBoc-protected product was then stirred in hydrochloric acid dioxane solution (4M, 10 equiv.) at room temperature for 6 hrs. Subsequently the solvent was removed the residue dissolved in dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was tried with sodium sulfate, filtrated and evaporated. The crude product was subjected to silica gel flash chromatography (ISCO CombiFlash; dichloromethane/methanol; 100/0 to 95/5) to yield (3aR,4S,7aR)-methyl 4-((S)-2,6-diaminohexanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H] 442; RT=3.992 min; LCMS Method III
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9])[C:3]#[CH:4].[H][H]>CO.[Pd].[Zn]>[CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9])[CH:3]=[CH2:4]
Reactant: [H][H]
Reactant: C#CC(C)(O)CCC(C)CC
Agent: [Pd]
Agent: [Zn]
Solvent: CO
Product: C=CC(C)(O)CCC(C)CC
Reaction time: 6 h

Procedure:
154 g (1 mole) of 3,6-dimethyl-oct-1-yn-3ol are dissolved in 100 ml of methanol, 1 g of an 0.1% strength palladium/calcium carbonate catalyst, which has been poisoned with zinc ions, is added, and hydrogen is passed in at 20° C. under atmospheric pressure. The hydrogenation is complete in 6 hours, when about 24 liters of hydrogen have been absorbed.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[NH:9]1[CH2:15][CH:14]([OH:16])[CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:15][CH:14]([OH:16])[CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)n1
Reactant: OC1CNCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: OC1CNCCN(c2cccc(Br)n2)C1
Temperature: 100 °C
Yield: 54.4 %

Procedure:
A mixture of 2-bromo-6-fluoropyridine (477 mg, 2.7 mmol), 1,4-diazepan-6-ol (350 mg, 3 mmol), and DIPEA (1.94 g, 15 mmol) in ethanol (10 mL) was heated at 100° C. for 16 hours. After it was cooled, the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 1-(6-bromopyridin-2-yl)-1,4-diazepan-6-ol as a colorless oil (400 mg, 48.9%). MS (ESI) m/z: 272 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>C(#N)C>[O:13]1[C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[O:4][CH2:3][CH2:2][NH:30][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[C:26]([F:25])([F:35])[F:36])=[N:12]1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1ccccc1CNCCOc1cccc(-c2noc3ccsc23)c1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole (0.250 g, 0.771 mmol), potassium carbonate (0.205 g, 1.48 mmol), 2-(trifluoromethyl)benzylamine (0.676 mg, 3.86 mmol) and acetonitrile (4 mL) essentially as described above in example 18 except that the reaction is run overnight and the compound is purified by column using a solvent gradient of 5% ethyl acetate in dichloromethane to 10% methanol in ethyl acetate to give the title compound (0.311 g, 96% Yield). Purity by LC/MS (APCI)=99%, [M+H]+=419.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]=[C:11]([Cl:17])[N:12]=[C:13](Cl)[C:14]=2[N:15]=1)(=[O:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(O)C>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]=[C:11]([Cl:17])[N:12]=[C:13]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]=2[N:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc2nc(Cl)nc(Cl)c2n1
Reactant: C1COCCN1
Solvent: CCO
Product: CC(=O)OCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Yield: 96.6 %

Procedure:
A mixture of (2,4-dichloropyrido[3,2-d]pyrimidin-6-yl)methyl acetate (1.92 g, 7.06 mmol) according to Srinivasan and Broom (1981) J. Org. Chem. 46:1777-1781, and morpholine (1.3 mL, 14.9 mmol) in ethanol (100 mL) was stirred at room temperature for 2 hours. The reaction mixture was then evaporated to dryness. The crude product was purified by flash chromatography (DCM) to give (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl acetate 5 (2.2 g, 96%). 1H-NMR (CDCl3): δ 8.05 (d, 1H), 7.66 (d, 1H), 5.29 (s, 2H), 4.5 (s, br, 4H), 3.87 (m, 4H), 2.19 (s, 3H)
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(=O)C.[Na+]>CN(C=O)C>[C:9]([S:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[NH2:2])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
L-Cysteine hydro-chloride (100 g, 0.634 mol) and trityl chloride (270 g, 0.969 mol) were stirred in DMF (400 mL) for 2 days at room temperature. A 10% sodium acetate solution (3.5 L) was then added dropwise and the white precipitate which formed was filtered and washed with distilled water. Afterward, the residue was stirred in acetone at 50° C. for 30 min after which it was cooled to 0° C. and filtered. The precipitate was washed with a little acetone and diethyl ether and dried in vacuo. S-Trityl-L-cysteine 1c (205 g, 89%) was obtained as a white powder. 1c: m.p. 192° C. (decomp); 1H NMR (300 MHz, DMSO-d6) δ 2.45 (dd, 1H, J=9 Hz, 12 Hz), 2.58 (dd, 1H, J=4.4 Hz, 12 Hz), 2.91 (m, 1H), 7.22-7.36 (m, 15H); 13C NMR (75.5 MHz, DMSO-d6): δ 33.8, 53.7, 66.4, 127.1, 127.8, 128.1, 128.4, 129.5, 144.5, 168.4. This material was directly used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[O:26][CH2:27][C:28](O)=[O:29].C(Cl)(=O)C([Cl:37])=O>C(Cl)(Cl)Cl.CN(C)C=O>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[O:26][CH2:27][C:28]([Cl:37])=[O:29]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetic acid (0.22 g, 0.5 mmol) in dry chloroform (5 mL) was added at ambient temperature oxalyl chloride (0.43 mL, 5.0 mmol) followed by 1 drop of N,N-dimethylformamide. The mixture was stirred at ambient temperature for 2 h and evaporated to dryness in vacuo to afford crude {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetyl chloride. The crude product was dissolved in dry dichloromethane (5 mL), and used in the next step. To a solution of methylamine hydrochloride (0.07 mg, 1.0 mmol) in dry dichloromethane (5 mL) containing triethylamine (0.35 mL, 2.5 mmol) was added at 0° C. 5.0 mL (0.50 mmol) of the stock solution of {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetyl chloride. The mixture was stirred at ambient temperature for 16 h, diluted with dichloromethane (20 mL), washed with 7% aqueous solution of citric acid (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate 1:3) to afford N-methyl-2-{3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetamide (0.09 g, 40%) as a colorless solid: mp 175-176° C.; 1H NMR (300 MHz, CDCl3) δ 7.34-7.17 (m, 3H), 7.09-6.98 (m, 2H), 6.90 (s, 1H), 6.87-6.76 (m, 2H), 6.55 (br s, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 5.09-4.96 (m, 2H), 4.88-4.79 (m, 1H), 4.75-4.69 (m, 1H), 4.60-4.51 (m, 2H), 4.47 (s, 2H), 3.11-2.92 (m, 2H), 2.92-2.88 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 177.9, 168.4, 161.9, 161.3, 157.6, 142.0, 137.9, 132.7, 130.3, 128.7, 123.9, 123.5, 121.0, 120.1, 120.0, 118.8, 113.9, 113.6, 109.1, 93.3, 80.6, 72.4, 67.2, 57.7, 43.9, 29.0, 25.7; MS (ES+) m/z 457.0 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.[OH-].[Na+].[NH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([NH:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:23][CH:24]=2)=[O:11])[CH:2]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(C=Cc1cccnc1)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a suspension of 0.33 g (2.01 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of 3-pyridineacrylic acid at 0° C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 5. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give the title compound (0.46 g, 82%). HRMS calcd for C16H14N2O3: 282.2988. Found: 282.2990. MA calcd for: C16H14N2O3: C, 68.07%; H, 5.00%; N, 9.92%. Found: C, 68.21%; H, 5.03%; N, 9.90%.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[OH-].[Na+]>CN(C=O)C>[CH3:6][N:5]([CH3:7])[CH2:4][CH2:3][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][CH:11]=1
Reactant: CN(C)CCCl
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 90.9 %

Procedure:
1-Chloro-2-dimethylaminoethane hydrochloride (2 g, 21.9 mmol, 1.2 equiv) was added in one portion to a mixture of 4-aminophenol (2 g, 18.3 mmol) and finely powdered sodium hydroxide (1.8 g, 45.8 mmol, 2.5 equiv) in DMF (27 mL), under an argon atmosphere. The reaction mixture was stirred for 17 h at rt. The resulting dark suspension was filtered. The filtrate was diluted with DCM (200 ml) and washed with brine (2×50 mL). The organic phase was dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 7:3) provided 3 g of the title compound as a brown solid: API-MS: 181.2 [M+H]+; TLC: Rf=0.18 (DCM/MeOH, 7:3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10](O)=[O:11])=[CH:9][C:5]=2[CH:4]=1.C1(C)C=CC=CC=1.S(Cl)(Cl)=O.[N:28]1C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10]([NH2:28])=[O:11])=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1cc2cc(C(=O)O)sc2cc1OC
Reactant: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2cc(C(N)=O)sc2cc1OC

Procedure:
A mixture of 5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (68.8 g), dry toluene (350 ml), thionyl chloride (126 ml) and pyridine (1.75 ml) was stirred and heated at reflux for 4 hours. The resultant mixture was cooled, evaporated to dryness under vacuum and the residue was purged with dry toluene (3×250 ml). The resulting crude acid chloride was suspended in dioxan (160 ml) then cooled in an ice bath and treated in one portion with concentrated ammonium hydroxide solution (33% w/w, 900 ml). This gave a suspension of brown solid which was stirred for two hours then filtered, washed with water and dried under vacuum over calcium chloride at 60° C. to give 5,6-dimethoxybenzo[b]thiophene-2-carboxamide (62.5 g), m.p. 211°-213° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([CH3:28])([S:19]([C:22]1[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=1)(=[O:21])=[O:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[C:10]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:28])([S:19]([C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)(=[O:21])=[O:20])[C:4]([OH:29])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(-c2ccccc2)cc1)S(=O)(=O)c1nccn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1ccnc1S(=O)(=O)C(C)(Cc1ccc(-c2ccccc2)cc1)C(=O)O

Procedure:
3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionic acid was prepared according to the general method as outlined in example 9. Starting from 3-biphenyl-4-yl-2-methyl2-(1-methyl-1H-imidazole-2-sulfonyl)-propionic acid ethyl ester (5.0 g, 11.9 mmol), ethanol (15 mL) and 10 N sodium hydroxide (10 mL). Yield 2.8 g (61%); brown solid mp 119-122° C.; MS 385.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)=[CH:15][CH:14]=1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1CCc2cc(OCc3ccc(F)cc3)ccc21
Reaction time: 12 h

Procedure:
The 5-hydroxy-1-indanone (20 g, 134.9 mmol) was solved in dry in N,N′-dimethylformamide (120 mL) and the 4-fluorobenzyl bromide (18.2 mL, 148.4 mmol) was added followed by potassium carbonate anhydrous (24.2 g, 175.4 mmol) and the mixture was stirred for 12 h to 110 IC. Water was added and the resulting precipitate was filtrated and dried (34.6 g, 100%). MS: m/e=256.1 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[C:7]([NH:9][C:10](=[N:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23])SC)#[N:8]>>[C:7]([NH:9][C:10]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[N:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23])#[N:8]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: CN(C)CCN
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCN(C)C

Procedure:
By the procedure of Example 4, 2-(dimethylamino)ethylamine is reacted with N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[O:21]3)=[CH:16][CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:26][N:27]([CH3:32])[S:28](=[O:31])(=[O:30])[NH2:29].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.Cl>[Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[O:21]3)=[CH:16][CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:29][S:28](=[O:31])(=[O:30])[N:27]([CH3:32])[CH3:26])=[O:8]
Reactant: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)O)cc3Cl)cc2O1
Reactant: CN(C)S(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(COc2ccc3c(c2)OC(C)(C)CC3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
A mixture of 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid (50 mg, 0.14 mmol), dimethyl(sulfamoyl)amine (26 mg, 0.21 mmol), N,N-Diisopropylethylamine (54 mg, 0.42 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) in DMF (2.5 mL) was stirred at room temperature for 16 hrs. The mixture was diluted with HCl (2.0 N, 20 mL) and extracted with EtOAc (50×3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase combiflash (15%-25% MeCN in 0.5% NH4HCO3) to give target product (11.8 mg, 18%) as a white solid. LCMS (ESI) Method A: RT=5.57 min, m/z: 471.2 [M+H]; 1H-NMR (500 MHz, MeOH-d4,): δ 7.62 (d, J=6.0 Hz, 1H), 7.31 (d, J=10.5 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.40 (dd, J=8.0, 2.5 Hz, 1H), 6.24 (d, J=2.5 Hz, 1H), 5.02 (s, 2H), 2.86 (s, 6H), 2.61 (t, J=7.0 Hz, 2H), 1.68 (t, J=7.0 Hz, 2H), 1.20 (s, 6H).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10]O)[N:8]=1)([CH3:3])[CH3:2].CS(Cl)(=O)=O.[CH2:17]([N:19](CC)CC)C.C(N)C>O1CCCC1.C(OCC)(=O)C>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][NH:19][CH3:17])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)c1nc(CCO)cs1
Agent: CCN
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNCCc1csc(C(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.0 g (12 mmol) of 2-isopropyl-4-(hydroxyethyl)thiazole in 50 ml of tetrahydrofuran was treated with 1.34 g (12 mmol) of methanesulfonyl chloride. The resulting solution was treated dropwise with 3.4 ml (24 mmol) of triethylamine and stirred at ambient temperature for 1 h. A portion (25 ml) of the resulting solution was added to 50 ml of aqueous ethylamine (70% in H2O) with rapid stirring. After addition, the mixture was heated to reflux for 2 h, allowed to cool, diluted with ethyl acetate, washed with aqueous NaHCO3 and saturated brine, dried over Na2SO4, and concentrated in vacuo to provide the crude desired compound. Purification of the residue by silica gel chromatography using 5% methanol in chloroform, 0.52 g (48%) of the desired compound. 1H NMR (CDCl3) δ1.38 (d, J=7 Hz, 3H), 2.46 (s, 3H), 2.93 (s, 4H), 3.30 (heptet, J=7 Hz, 1H), 6.79 (s, 1H). Mass spectrum: (M+H)+ =185.