Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]([O:16]C(C)(C)C)=[O:15])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:21]([CH3:23])([CH3:22])[CH3:24])[C:14]([OH:16])=[O:15])[C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product of Example 111-5 in dichloromethane (1.5 L) was added triflouroacetic acid (810 mL). The mixture was stirred at room temperature for 3 hours and concentrated. The residue was chased with heptanes (4×500 mL). The product was partitioned between dichloromethane (1.5 L) and 5% KH2PO4 (1.1 L). The organic layer was washed with 5% KH2PO4 (900 mL) and brine (900 mL), and concentrated. A solution of the residue in dichloromethane (500 mL) was dried over MgSO4, filtered and concentrated. The residue was recrystallized twice from isopropyl alcohol/water to afford the title compound. 1H NMR (DMSO-d6): δ 7.2-7.4(m, 5H), 4.28(d, 2H), 4.21(s, 1H), 3.47-3.64(m, 2H), 3.08-3.2(m, 2H), 1.0(s, 9H).
Reaction SMILES: C(OC(N[C@@H]1C(=O)N2C[C@H](OC3C=NC4C(=CC=CC=4)N=3)C[C@H]2C(=O)N[C@]2(C(OCC)=O)C[C@H]2CC(F)(F)CCCCC1)=O)(C)(C)C.[C:48]([O:52][C:53]([NH:55][C@@H:56]1[C:70](=[O:71])[N:69]2[CH2:72][C@H:73]([O:75][C:76]3[C:85]([CH3:86])=[N:84][C:83]4[C:78](=[CH:79][CH:80]=[CH:81][CH:82]=4)[N:77]=3)[CH2:74][C@H:68]2[C:67](=[O:87])[NH:66][C@:65]2([C:89]([O:91]CC)=[O:90])[CH2:88][C@H:64]2[CH2:63][C:62]([F:95])([F:94])[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1)=[O:54])([CH3:51])([CH3:50])[CH3:49]>>[C:48]([O:52][C:53]([NH:55][C@@H:56]1[C:70](=[O:71])[N:69]2[CH2:72][C@H:73]([O:75][C:76]3[C:85]([CH3:86])=[N:84][C:83]4[C:78](=[CH:79][CH:80]=[CH:81][CH:82]=4)[N:77]=3)[CH2:74][C@H:68]2[C:67](=[O:87])[NH:66][C@:65]2([C:89]([OH:91])=[O:90])[CH2:88][C@H:64]2[CH2:63][C:62]([F:94])([F:95])[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1)=[O:54])([CH3:51])([CH3:49])[CH3:50]
Reactant: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4nc3C)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cnc4ccccc4n3)C[C@H]1C(=O)N2
Product: Cc1nc2ccccc2nc1O[C@@H]1C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1

Procedure:
Example 3b was prepared according to the procedure utilized for the preparation of Example 1 g, replacing the product of Example 1f with the product of Example 3a.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][N:39]([CH3:44])[C:40](=[O:43])[CH:41]=[CH2:42].[H-].[Na+]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:42][CH2:41][C:40]([N:39]([CH3:44])[CH3:38])=[O:43])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: C=CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)CCOCC1=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
Yield: 93.2 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (951 mg, 1.75 mmol) was treated with N,N-dimethylacrylamide (540 mg, 5.44 mmol) and sodium hydride (60% in oil, 105 mg, 2.62 mmol) in tetrahydrofuran (17.5 ml) in the same manner as shown in Example 4(1) (at 5° C. for 14 hours), followed by work up and purification using column chromatography (hexane:ethyl acetate= 2:1) to give the titled compound (1.05 g, 92.7%) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.[F:26][C:27]([F:38])([F:37])[O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>CCOC(C)=O>[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:32][CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=3[O:28][C:27]([F:26])([F:37])[F:38])[N:17]=2)[CH2:12][CH2:13]1
Reactant: NCc1ccccc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2Cl)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2Cl)CC1
Temperature: 180 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
The above {4-[(2,5-dichloro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (97 mg, 0.26 mmol) was dissolved in 2-trifluoromethoxy-benzylamine (2.5 mL) and the mixture was heated to 180° C. for 20 min. The reaction mixture was diluted with EtOAc and poured into 1N HCl solution. The aqueous layer was separated and extracted with EtOAc (×2). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 (2.5 mL) and TFA (2.5 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was then poured into 10% NaHCO3 and the aqueous layer was extracted with EtOAc (×2). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 9:1:0.1 CH2Cl2:MeOH:NH4OH as an eluent to afford 97 mg (87%) of the title compound, m/z 430.5 (M+1)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[N:29]2[C:24]([CH:25]=[N:26][C:27]([S:30][CH3:31])=[N:28]2)=[C:23]([O:32][CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:22]=1.CC1(C)C(C)(C)OB([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[NH:55][S:56]([CH3:59])(=[O:58])=[O:57])O1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:31][S:30][C:27]1[N:26]=[CH:25][C:24]2=[C:23]([O:32][CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:22]=[C:21]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[N:29]2[N:28]=1
Reactant: CSc1ncc2c(OCOCC[Si](C)(C)C)cc(Br)n2n1
Reactant: CC1(C)OB(c2ccccc2NS(C)(=O)=O)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc2c(OCOCC[Si](C)(C)C)cc(-c3ccccc3NS(C)(=O)=O)n2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
Into a 30 mL vial, Palladium Acetate (0.043 g, 0.19 mmol) and Triphenylphosphine (0.14 g, 0.54 mmol) were added. The mixture was purged under an atmosphere of Nitrogen for 10 minutes. 1,4-Dioxane (14.6 mL) was added and stirred for 10 minutes at room temperature. 7-Bromo-2-methylsulfanyl-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazine (0.750 g, 1.92 mmol), N-[2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1.14 g, 3.84 mmol), N,N-Dimethylformamide (29 mL, 380 mmol), and 1.50 M of Sodium carbonate in Water (11.5 mL, 17.3 mmol) were added. The reaction was heated at 90° C. for 3 hours. The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via column chromatography with DCM and Methanol as eluant (0 to 5% MeOH). The collected fractions afforded a solid. The solid was triturated with Et2O and filtered to give N-{2-[2-Methylsulfanyl-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-methanesulfonamide as a yellow solid (0.72 g, 78%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][O:39][CH2:40][CH2:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:48]2[CH:49]=[CH:50][C:45]([S:42]([CH2:41][CH2:40][O:39][CH3:38])(=[O:44])=[O:43])=[CH:46][CH:47]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COCCS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCCS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 63.9 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (600 mg, 1.1 mmol), 4-(2-methoxy-ethanesulfonyl)-phenylboronic acid (678 mg, 2.8 mmol) and dichlorobis(triphenylphosphine)palladium (II) (77 mg, 0.1 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 1.4 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-{2-cyclopentyl-1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-vinyl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine (400 mg, 63%) as a white solid: LC/MS m/e calcd for C29H29FN2O5S2 [M+H]+ 569.69, observed 569.1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:12]=[N:13][C:14]([S:17][CH3:18])=[CH:15][CH:16]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH:26]([C:29]1[N:33]=[C:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[O:31][N:30]=1)([CH3:28])[CH3:27].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH:26]([C:29]1[N:33]=[C:32]([CH:34]2[CH2:39][CH2:38][N:37]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]4[CH:12]=[N:13][C:14]([S:17][CH3:18])=[CH:15][CH:16]=4)[N:5]=[CH:4][N:3]=3)[CH2:36][CH2:35]2)[O:31][N:30]=1)([CH3:28])[CH3:27]
Reactant: CSc1ccc(Nc2ncnc(Cl)c2C#N)cn1
Reactant: CC(C)c1noc(C2CCNCC2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2ncnc(N3CCC(c4nc(C(C)C)no4)CC3)c2C#N)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chloro-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrile (80.00 mg, 0.29 mmol) in DMF (2 ml) was mixture with Potassium Carbonate (79.62 mg, 0.58 mmol), added 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine hydrochloride (237.4 mg, 1.08 or 1.02 mmol) in DMF (1 ml) and left stirring at room temperature for 1 hour. Reaction was worked up with ethyl acetate, sodium bicarbonate, dried with magnesium sulfate, filtered and concentrate under high vacuum. Compound was recrystallized using hexane in ethyl acetate to afford Compound B136. 1H NMR 400 MHz DMSO δ (ppm): 9.48 (s, 1H), 8.55 (d, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 7.77 (d, 1H), 7.26 (d, 1H), 4.52 (m, 2H), 3.48 (m, 1H), 3.37 (m, 2H), 3.32 (s, 3H), 3.04 (m, 1H), 2.14 (m, 2H), 1.75 (m, 2H), 1.33 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:14])=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].[I:15]N1C(=O)CCC1=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:14])=[C:7]([I:15])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1c(N)ccc2cn[nH]c12
Solvent: CC#N
Product: COC(=O)c1c(N)c(I)cc2cn[nH]c12
Temperature: 50 °C
Reaction time: 6 h
Yield: 90.6 %

Procedure:
To a solution of 500 mg (2.61 mmol) of 6-amino-1H-indazole-7-carboxylic acid methyl ester, prepared as in step a in example 10, in 5 mL of acetonitrile is added 1.29 g (5.73 mmol) of N-iodosuccinimide. The reaction mixture is stirred at ambient temperature for 1 hour and at 50° C. for 6 hours. The solvent is then evaporated and the residue is suspended in water. Filtration affords 750 mg (91%) of the product as a brown solid; LC/MS:318/319 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)[CH:3]([C:6]([O:8]CC)=O)[C:4]#[N:5].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C1(C)C(C)=CC=CC=1>[O:1]=[C:2]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)[CH:3]([C:6](=[O:8])[NH:21][C:20]1[CH:22]=[CH:23][C:17]([F:16])=[CH:18][CH:19]=1)[C:4]#[N:5]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C(C#N)C(=O)c1ccc[nH]1
Solvent: Cc1ccccc1C
Product: N#CC(C(=O)Nc1ccc(F)cc1)C(=O)c1ccc[nH]1
Temperature: 25 °C

Procedure:
A mixture of 1.1 g of β-oxo-α-ethoxycarbonyl-β-(2-pyrrolyl)-propionitrile, 1.5 g of 4-fluoroaniline and 60 ml of xylene, is refluxed for 41/2 hours. After standing and cooling to room temperature overnight, the solution is filtered, evaporated and the residue is purified to yield β-oxo-α-(4-fluorophenyl carbamoyl)-β-(2-pyrrolyl)-propionitrile of example 5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Br:12][C:13]1[CH:14]=[CH:15][C:16](I)=[N:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C=CC=CC=1C(O)=O>O1CCOCC1.[Cu].[Cu](I)I>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([C:16]1[CH:15]=[CH:14][C:13]([Br:12])=[CH:18][N:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Brc1ccc(I)nc1
Agent: I[Cu]I
Agent: [Cu]
Agent: O=C(O)c1ccccn1
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cn1

Procedure:
2-(5-Bromo-pyridin-2-yl)-malonic acid diethyl ester (XXXVI) is prepared by copper-catalyzed reaction with malonic acid diethyl ester. The reaction is typically performed by mixing XXXV with malonic acid diethyl ester, copper iodide, cesium carbonate, and pyridine-2-carboxylic acid in 1,4-dioxane and heating to 70 degrees Celsius for 24 hours under nitrogen atmosphere.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[I-].[Na+].[O:16]=[S:17]1(=[O:34])[CH2:22][CH2:21][N:20]2[CH:23]=[CH:24][CH:25]=[C:26]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[C:19]2=[N:18]1.[OH-].[Na+]>CS(C)=O>[O:11]1[CH2:12][CH2:13][CH:8]([O:33][C:30]2[CH:29]=[CH:28][C:27]([C:26]3[C:19]4=[N:18][S:17](=[O:34])(=[O:16])[CH2:22][CH2:21][N:20]4[CH:23]=[CH:24][CH:25]=3)=[CH:32][CH:31]=2)[CH2:9][CH2:10]1
Reactant: BrC1CCOCC1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OC4CCOCC4)cc3)C2=N1
Temperature: 160 °C
Reaction time: 24 h
Yield: 17 %

Procedure:
A mixture of potassium carbonate (750 mg), 4-bromotetrahydro-2H-pyran (896 mg), sodium iodide (814 mg) and 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (300 mg) in DMSO (5 mL) was stirred at 150° C. overnight and 160° C. for 24 hr. The mixture was poured into 1N NaOH aq. and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give a white solid (66.6 mg). The solid was purified by preparative HPLC (C18, eluted with H2O in acetonitrile containing 0.1% TFA). The desired fraction was neutralized with sat. NaHCO3 aq. and extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (17.0 mg) as a white solid.
Reaction SMILES: [I-].C[S:3][C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.NC1C=CN=CC=1>N1C=CC=CC=1>[CH2:6]1[C@H:7]2[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16]2)[C:4](=[S:3])[S:5]1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: Nc1ccncc1
Agent: [I-]
Solvent: c1ccncc1
Product: S=C1SC[C@@H]2Cc3ccccc3CN12
Reaction time: 24 h
Yield: 22.6 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (14.5 g.) is added, a little at a time, to a solution of 4-aminopyridine (7.5 g.) in pyridine (300 cc.). The suspension gradually passes into solution. After 24 hours at a temperature of about 20° C., the suspension is concentrated to dryness under reduced pressure (25 mm. Hg). The residue is dissolved in a mixture of methylene chloride (250 cc.) and water (200 cc.). The organic phase is decanted, dried over magnesium sulphate, filtered and then concentrated to about 100 cc. under reduced pressure. This solution is poured onto a column (column diameter: 3 cm) of silica gel (300 g.) and elution is then carried out with a 1% v/v solution of methanol in methylene chloride, eluate fractions of 500 cc. being collected. After evaporating fractions 2 and 3 to dryness, (S)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline-3-thione (2.0 g.) is obtained.
Reaction SMILES: [NH:1]1[CH2:3][CH:2]1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[Cl:15][C:16]1[S:20][C:19]([C:21](Cl)=[O:22])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[S:20][C:19]([C:21]([N:1]2[CH2:3][CH:2]2[C:4]([O:6][CH3:7])=[O:5])=[O:22])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: COC(=O)C1CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CN1C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4.40 g (43.5 mmol) methyl aziridine-2-carboxylate and 13.5 ml (97.3 mmol) triethylamine in 30 ml methylene chloride is combined with 8.80 g (48.6 mmol) 5-chlorothiophenecarboxylic acid chloride in 30 ml methylene chloride while cooling with ice and subsequently after removal of the cooling bath stirred for 3 h at room temperature. Then the mixture is diluted with water, extracted with methylene chloride, dried with sodium sulphate, concentrated and purified by chromatography (silica gel, petroleum ether/ethyl acetate 80/15->80/20) to obtain the slightly contaminated title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[ClH:12].Cl.[Cl:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][SH:29])[CH2:22][CH2:21]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:14].[ClH:12].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[SH:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:31][CH:30]=3)[CH2:21][CH2:22]2)[OH:11])[CH:6]=[CH:7][CH:8]=1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: COc1cccc(N=C=O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(NC(O)=[SH]CCCN2CCN(Cc3ccc(Cl)cc3)CC2)c1
Yield: 63.3 %

Procedure:
The procedure described in Example 2 was followed, using 1.3 g of 3-methoxyphenyl isocyanate, 3.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.9 g of triethylamine and 50 ml of methylene chloride, to give 1.35 g (32% of theory) of N-(3-methoxyphenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as an off-white crystalline solid, M.p. 238°-240° C.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=O)(C)(C)C.C([Li])(C)(C)C.[CH3:21][S:22]SC.[OH-].[Na+]>O1CCCC1.Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([S:22][CH3:21])[C:9]=1[NH2:8]
Reactant: CSSC
Reactant: CC(C)(C)OC(=O)Nc1ccccc1F
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cccc(F)c1N
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
A mixture of N-(t-butoxycarbonyl)-2-fluoroaniline (5.0 g, 24 mmoles) in anhydrous tetrahydrofuran (50 ml) was cooled to -78° C. under a nitrogen atmosphere. To this solution was added t-butyl lithium (2.0M, 57.6 mmoles, 28.8 ml) at such a rate that the temperature did not exceed -65° C. When the addition was complete, the mixture was stirred at -78° C. for an additional 15 minutes and at -20° C. for 2.5 hours. To this reaction mixture was added dimethyl disulfide (2.82 g, 30 mmoles) in 10 ml of anhydrous tetrahydrofuran while maintaining the temperature at -20° C. for an additional hour. The mixture was allowed to warm to ambient temperature and then 25 ml of 1N sodium hydroxide was added. The mixture obtained was extracted with diethyl ether (2×100 ml). The organic phase was separated and dried over magnesium sulfate and then the solvent was removed by evaporation under reduced pressure to obtain a tan solid. This was hydrolized in dilute hydrochloric acid (6N, 200 ml) by heating to reflux for three hours. The resulting solution was extracted with diethyl ether and the aqueous layer was neutralized with sodium hydroxide (6N, 200 ml), and extracted with methylene chloride, dried over magnesium sulfate and the solvent removed by evaporation under reduced pressure to obtain an amber oil. This was distilled to give 3.2 g (85% of theory) of the title compound, having a b.p. of 62°-65° C. at 0.2 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][C:10]=1[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6](=[O:42])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:33][O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1COCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1COCc1ccccc1
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A 250 mL round bottomed flask was charged with 3-[2-benzyloxymethyl-4-(tert-butyl-diphenyl-silanyloxy)-phenyl]-propionic acid tert-butyl ester (1.03 g, 1.77 mmol), anhydrous THF (60 mL), and then tetrabutylammonium fluoride (5.3 mL, 5.3 mmol, 1.0 M in THF). The reaction mixture was stirred under a nitrogen atmosphere for 1 h, concentrated, and diluted with EtOAc (100 mL). The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated to give an oil. The crude oil was purified using radial chromatography (EtOAc:hexanes 10:90 to 50:50) to give a white solid (0.52 g, 86%). MS (ES) m/e 343 (M−1).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH3:6])=[O:5].[Li+].CC([N-]C(C)C)C.[I:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.S(=O)(=O)(O)O>CCOCC>[I:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](=[O:21])[CH2:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:18][CH:17]=1
Reactant: CCOC(C)=O
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1ccc(I)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 47 %

Procedure:
A solution of EtOAc (6 mL) in Et2O (15 mL) was added to a solution of LDA (2 M in THF, 60 mL, 120 mmol) in Et2O (80 mL) at −78° C. The resulting solution was stirred at −78° C. for 45 minutes. To this solution, a solution of 4-iodobenzoyl chloride (16 g, 60.5 mmol) in Et2O (30 mL) was added at −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was poured into iced-sulfuric acid (300 g, 10%), stirred for 15 minutes, and extracted with Et2O (3×80 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound as light orange oil (9 g, 47%). Compound exists as a mixture of ketone and enol forms (3:1). 1H NMR (CDCl3, 400 MHz): (ketone form) δ 7.87 (d, 2H), 7.67 (d, 2H), 4.26 (q, 2H), 3.95 (s, 2H), 1.24 (t, 3H); (enol form) δ 12.55 (s, 1H), 7.78 (d, 2H), 7.50 (q, 2H), 5.65 (s, 1H), 4.59 (q, 2H), 1.34 (t, 3H).