Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[O:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[N:25]=3)[CH2:20][CH2:19]2)=[CH:12][N:11]=1.[OH:32]O>FC(F)(F)C(O)C(F)(F)F>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:9])=[O:32])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[O:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[N:25]=3)[CH2:20][CH2:19]2)=[CH:12][N:11]=1
Reactant: CSc1ccc(-c2ccc(OCC3CCN(c4nc(C(C)C)no4)CC3)cn2)c(F)c1
Reactant: OO
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(C)=O)cc4F)nc3)CC2)n1
Yield: 76.2 %

Procedure:
The title compound (109 g, 76%) was prepared as a white solid from 2-[2-fluoro-4-(methylthio)phenyl]-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (prepared as in Step 2, 138 g, 312 mmol), 30% H2O2 (aq) (41 mL, 410 mmol) and 1,1,1,3,3,3-hexafluoro-2-propanol (400 mL) in a manner similar to Example 171, Step 3. 1H NMR (400 MHz, CDCl3): δ 8.39 (d, 1H, J=2.8 Hz), 8.13 (t, 1H, J=7.8 Hz), 7.77 (dd, 1H, Ja=8.7 Hz, Jb=1.9 Hz), 7.50 (dd, 1H, Ja=10.4 Hz, Jb=1.6 Hz), 7.43 (dd, 1H, Ja=8.1 Hz, Jb=1.7 Hz), 7.26 (d, 1H, J=3.0 Hz), 4.27-4.16 (m, 2H), 3.92 (d, 2H, J=6.2 Hz), 3.20-3.00 (m, 2H), 2.87 (septet, 1H, J=7.0 Hz), 2.74 (s, 3H), 2.15-2.03 (m, 1H), 2.00-1.90 (m, 2H), 1.52-1.40 (m, 2H), 1.27 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 459 (M+H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[CH2:16]Br>C([O-])C.[Na+]>[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[CH2:16][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(CBr)ccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])c(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium ethanolate [prepared from 1.35 g Na in ethanol (30 ml)] were added diethyl malonate (9.2 ml) and then dropwise 3-methyl-4-nitrobenzyl bromide (13.4 g). The mixture was stirred 30 minutes at room temperature, then 30 minutes under reflux and then concentrated. The residue is treated with water and hexane, the precipitate filtered and the filtrate extracted with diethyl ether. The organic extract was dried on sodium sulfate and concentrate to give the title compound as an oil (4 g).
Reaction SMILES: [C:1]1([CH2:9][OH:10])[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(N(CC)C(C)C)(C)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>ClCCl.C(OCC)C>[Si:20]([O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:9][OH:10])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccccc1CO
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
To a solution of 1,2-benzenedimethanol (500 mg, 3.62 mmol), N,N-diisopropylethylamine (0.76 mL, 4.4 mmol) in 3.6 mL of dichloromethane was added tert-butyldimethylsilyl chloride (573 mg, 3.80 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 1 day. The reaction mixture was diluted with diethyl ether, and the solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 85/15) to obtain 2-[(tert-butyldimethylsilyloxy)methyl]benzylalcohol as a colorless oil (520 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:12][CH:13]1[C:17](=[O:18])[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH:14]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C@H:13]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C@H:14]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C1CN(c2ccccc2)C(=O)C1N
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of 3,4-dichlorophenylisocyanate in CH2Cl2 (3 ml) was added a solution of aminopyrrolidinone of Example S (350 mg, 1.41 mmol) in CH2Cl2 (3 ml) and the resulting solution was stirred for 18 h at room temperature. Concentration in vacuo gave a solid which was triturated with CH2Cl2 and filtered to give the title compound (420 mg, 68%) as a solid. MS M+1 calcd for C20H19N3O4Cl2 437, found 437 DSC=249.1°-251.7° C. at 112.7 J/g.
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[OH:15][CH:16]1[CH2:20][C:19]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:18][CH:17]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:14][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[N:23]1[CH2:22][CH2:21][C:19]3([CH2:18][C@H:17]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])[C@H:16]([OH:15])[CH2:20]3)[CH2:25][CH2:24]1)=[N:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2
Reactant: CC(C)(C)OC(=O)NC1CC2(CCNCC2)CC1O
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(N3CCC4(CC3)C[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C4)c2n1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 10.5 %

Procedure:
In a sealed tube, 8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine (500 mg, 1.96 mmol), 1,1-dimethylethyl (3-hydroxy-8-azaspiro[4.5]dec-2-yl)carbamate (530 mg, 1.96 mmol) [prepared according to Example 1], Pd2dba3 (121 mg, 0.117 mmol), rac-Binap (73 mg, 0.117 mmol), Cs2CO3 (1.30 g, 4.11 mmol) and 18-C-6 (52 mg, 0.196 mmol) in dioxane (20 mL) were combined and flushed with N2. After 15 min, the tube was sealed and heated to 100° C. while stirring rapidly. After 12 h, the solution was filtered, concentrated and the residue purified via column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) yielding the title compound (92 mg, 11%) as an orange oil: LCMS (ES) m/e 447 (M+H)+.
Reaction SMILES: N1C2C=CC=CC=2NC=1C(O)=O.C1N=CN(C(N2C=NC=C2)=O)C=1.COC1C=CC(N2CCOCC2)=CC=1N.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:44][C:43]=1[NH:54][C:55]([C:57]1[NH:61][C:60]2[CH:62]=[CH:63][CH:64]=[CH:65][C:59]=2[N:58]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:75])=CC=1>CN(C=O)C.C1(C)C=CC=CC=1.O>[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:44][C:43]=1[NH:54][C:55]([C:57]1[NH:61][C:60]2[CH:62]=[CH:63][CH:64]=[CH:65][C:59]=2[N:58]=1)=[S:75]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(N2CCOCC2)cc1NC(=O)c1nc2ccccc2[nH]1
Agent: COc1ccc(N2CCOCC2)cc1N
Agent: O=C(O)c1nc2ccccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(N2CCOCC2)cc1NC(=S)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a suspension of 0.19 g of benzoimidazole-2-carboxylic acid (1.0 mmol) in 4 ml DMF was added 0.21 g of CDI (1.3 mmol) and stirred at ambient temperature for 1 h. Then the mixture was refluxed for 30 min. After cooling to ambient temperature, 0.25 g of 2-methoxy-5-morpholin-4-yl-phenylamine (1.2 mmol) was added and the reaction mixture was heated to reflux for 16 h. The mixture was evaporated and the residue taken up in water (40 ml) and extracted 3 times with methylene chloride. The combined organic phases were dried on sodium carbonate, evaporated and the residue was stirred in hot ethyl acetate. After filtration and trying 0.27 g 1H-benzoimidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (63%) were obtained as a yellow solid; M.p.: 236–237° C. 0.2 g of 1H-Benzoimidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (0.71 mmol) was taken up in toluene (15.0 ml) and treated with 0.28 g of Lawesson reagent (0.71 mmol). The reaction mixture was heated to reflux for 2 h. After cooling to ambient temperature, water (25 ml) was added and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were dried on sodium carbonate, evaporated and the residue subjected to column chromatography (silica gel, ethyl acetate/hexanes 1:2, then ethyl acetate). 0.22 g of 1H-Benzoimidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (86%) was obtained as a yellow solid; M.p.: 240–241° C. 0.19 g of 1H-Benzoimidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (0.52 mmol) were taken up in water (5.0 ml) and treated with 0.116 g KOH (2.0 mmol) and 0.68 g of potassium hexacyano ferrate (2.0 mmol) at reflux for 24 h. After cooling to ambient temperature water (10 ml) was added and the mixture was filtered. The residue on the filter was dissolved in methanol and subjected to column chromatography (silica gel, methylene chloride/methanol 99:1). One obtained 0.089 g of 2-(1H-benzoimidazol-2-yl)-4-methoxy-7-morpholin-4-yl-benzothiazole (39%) as a yellow solid; M.p.: 284–286° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[S:36]1(=[O:46])(=[O:45])[N:40]2[CH2:41][CH2:42][NH:43][CH2:44][CH:39]2[CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:43]3[CH2:42][CH2:41][N:40]4[S:36](=[O:46])(=[O:45])[CH2:37][CH2:38][CH:39]4[CH2:44]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=S1(=O)CCC2CNCCN21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccccc1-c1cc(N2CCN3C(CCS3(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 75.9 %

Procedure:
The title compound was prepared starting from 100 mg (0.161 mmoles) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 85 mg (0.483 mmol) of hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide (D10), 44.5 mg (0.322 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 180° C. for 36-48 hrs and then added to a saturated NH4Cl solution and back extracted with DCM; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to cyclohexane/ethyl acetate 1:1 and affording 80 mg of the title compound as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:23][Mg]Br.[Cl-].[NH4+]>CCOCC>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]([OH:22])([CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: C[Mg]Br
Reactant: COc1cc(OC)cc(C(=O)CCCCC#C[Si](C)(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cc(OC)cc(C(C)(O)CCCCC#C[Si](C)(C)C)c1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
[7-(3,5-Dimetho-xyphenyl)-7-oxo-1-heptynyl]trimethysilane (1.50 g, 4.75 mmol) was dissolved in 10 mL of anhydrous ether, the solution was cooled in an ice-bath under argon and a 3.16 mL of a 3 M solution of methylmagnesium bromide (9.48 mmol) in ether was added dropwise. The light grey solution was allowed to warm to room temperature and stirred for an additional hour. The reaction mixture was poured into saturated ammonium chloride solution, the organic phase was separated and the aqueous phase was extracted with fresh diethyl ether. The combined ether extracts were dried and ether removed to afford 1.50 g (95%) of pure [7-(3,5-dimethoxyphenyl)-7-hydroxy-1-octynyl]trimethysilane as a viscous oil after passing through a short silica gel column.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[O:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([CH3:27])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.O>[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:14]5[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=5[O:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:30])[CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Nc1nccc2occ(-c3ccc4c(c3)CCN4)c12
Reactant: Cc1cc(F)cc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)cc(CC(=O)N2CCc3cc(-c4coc5ccnc(N)c45)ccc32)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.2 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine (150 mg, 0.440 mmol), 3-fluoro-5-methylphenylacetic acid (78 mg, 0.464 mmol), HATU (184 mg, 0.484 mmol), and Hunig's base (0.31 mL, 1.775 mmol) in N,N-Dimethylformamide (DMF) (3 mL) was stirred at room temperature for 4 days. Water (10 mL) was added, the mixture was stirred for about 4 hours, and the precipitate was collected by vacuum filtration. The solid was dried in the vacuum oven overnight to give 3-{1-[(3-fluoro-5-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (164 mg, 0.388 mmol, 88% yield) as a tan solid. LC/MS (ES) m/z=402 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.32 (s, 3H), 3.24 (t, J=8.46 Hz, 2H), 3.87 (s, 2H), 4.24 (t, J=8.59 Hz, 2H), 5.53 (s, 2H), 6.90-7.00 (m, 4H), 7.30 (d, J=8.34 Hz, 1H), 7.39 (s, 1H), 7.86 (d, J=5.81 Hz, 1H), 7.92 (s, 1H), 8.17 (d, J=8.34 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][CH2:3]1.[CH3:17][Li].[NH4+].[Cl-]>O1CCCC1.CCOCC>[OH:1][C:2]1([CH3:17])[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:6][CH2:7]1
Reactant: [Li]C
Reactant: CC(C)(C)OC(=O)NCC1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1.2 h

Procedure:
To a vigorous stirring solution of tert-butyl (4-oxocyclohexyl)methylcarbamate (1.7 g) in tetrahydrofuran (40 mL) at −78° C. was dropwise added 1.6 M methyllithium (14.02 mL) in ether. After completion of the addition, the mixture was stirred at −78° C. for 1.2 hours and poured into a cold NH4Cl aqueous solution. The resulting mixture was extracted with dichloromethane (100 ml, three times) and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was dissolved in dichloromethane and loaded onto an Analogix purification system, and it was eluted with 0-50% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:15]O>>[CH3:15][O:8][C:7]([C:6]1[S:5][N:4]=[N:3][C:2]=1[CH3:1])=[O:9]
Reactant: CO
Reactant: Cc1nnsc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1snnc1C

Procedure:
4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid (1.0 g, 6.94 mmol), concentrated H2SO4 (866 μL), and methanol (12 mL) were combined and heated to reflux for 15 h. The solvent was reduced by a rotary evaporator and the residue was poured into 15 g of ice. The reaction was neutralized with saturated aqueous NaHCO3. The solution was then extracted with CH2Cl2 (4×35 mL). The combined organics were dried over MgSO4, filtered, and concentrated on the rotary evaporator. The product was preadsorbed onto silica gel and purified by flash chromatography to afford the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1.[C:18]([CH2:22][C:23](Cl)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:11][C:23](=[O:24])[CH2:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CC(C)(C)CC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (40 mg) was reacted with 41 μL of tert-butylacetyl chloride via General Procedure G to give N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-3,3-dimethylbutanamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([S:22](Cl)(=[O:24])=[O:23])[CH:13]=1>CN(C1C=CN=CC=1)C>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:22]([C:14]2[CH:13]=[N:12][C:21]3[C:16]([CH:15]=2)=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:23])=[O:24])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1cnc2ccccc2c1
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1cnc2ccccc2c1
Yield: 20.9 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (57 mg, 0.40 mmol), quinoline-3-sulfonyl chloride (10 mg, 0.44 mmol) and DMAP (cat.) gave the title compound (28 mg, 21%).
Reaction SMILES: Br[C:2]1[C:7]2[O:8][CH2:9][C@@H:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C@@H:11]3[C:6]=2[CH:5]=[C:4]([O:17][CH3:18])[CH:3]=1.[CH2:19]([Li])CCC.CI.O>C1COCC1.C(OCC)(=O)C>[CH3:18][O:17][C:4]1[CH:3]=[C:2]([CH3:19])[C:7]2[O:8][CH2:9][C@H:10]3[C@H:11]([CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]3)[C:6]=2[CH:5]=1
Reactant: [Li]CCCC
Reactant: COc1cc(Br)c2c(c1)[C@H]1CN(C)CC[C@H]1CO2
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)c2c(c1)[C@H]1CN(C)CC[C@H]1CO2
Reaction time: 1 h

Procedure:
To a solution of 1.2 g (±)-[4aR*,10bS*]-7-bromo-1,3,4,4a,5,10b-hexahydro-9-methoxy-2-methyl-2H-[1]benzopyrano[4,3-c]pyridine in 25 ml dry THF is added 2.14 ml n-butyllithium (1.98M in hexane). After 30 minutes 0.36 ml CH3I is added and the reaction is warmed to 25° and stirred 1 hour. Water (50 ml) and ethyl acetate (100 ml) is added. The organic phase is washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and flash chromatrographed with CH2Cl2 /ammonia saturated methanol (20:1) to afford the title compound; m.p. HCl salt 263° dec.
Reaction SMILES: [CH3:1][N:2]([C@@H:9]([CH3:22])[CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)C(=O)C(F)(F)F.C([O-])([O-])=O.[K+].[K+]>CO.O.O>[CH3:1][NH:2][C@@H:9]([CH3:22])[CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(OC[C@H](C)N(C)C(=O)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN[C@@H](C)COc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a stirred solution of methyl (S)-4-[2-[(N-methyl)trifluoroacetamido]-1-propoxy]benzoate (710 mg, 2.22 mmol) in MeOH—H2O (10 ml, 1:1, v/v) was added K2CO3 (460 mg, 3.33 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with H2O and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated to give methyl (S)-4-[2-(N-methylamino)-1-propoxy]benzoate (430 mg, 87%) as a colorless oil. 1H-NMR (CDCl3) δ 1.17 (d, J=6.6 Hz, 3 H), 2.48 (s, 3 H), 2.98–3.06 (m, 1 H), 3.86–3.96 (series of s and m, total 5 H), 6.92 (d, J=9.0 Hz, 2 H), 7.98 (d, J=9.0 Hz, 2 H).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][C:8]=12.C([Li])CCC.[CH2:29]([O:36][C:37]([NH:39][C@@H:40]1[C:49]2[C:44](=[CH:45][C:46]([C:50](Cl)=[O:51])=[CH:47][CH:48]=2)[S:43][CH2:42][CH2:41]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[CH2:29]([O:36][C:37]([NH:39][C@@H:40]1[C:49]2[C:44](=[CH:45][C:46]([C:50]([NH:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][C:8]=34)=[O:51])=[CH:47][CH:48]=2)[S:43][CH2:42][CH2:41]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(N)ccnc21
Reactant: O=C(N[C@H]1CCSc2cc(C(=O)Cl)ccc21)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(NC(=O)c3ccc4c(c3)SCC[C@@H]4NC(=O)OCc3ccccc3)ccnc21
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
To a tetrahydrofuran solution of 4-amino-1-[2-(trimethylsilyl)ethoxymethyl]pyrrolo[2,3-b]pyridine (1.32 g) was added dropwise n-butyllithium (1.59 M, 3.17 ml) and the mixture was stirred at the same temperature for 15 min. To this solution was added dropwise a tetrahydrofuran solution (20 ml) of (S)-4-(benzyloxycarbonylamino)thiochromane-7-carboxylic acid chloride (4.20 mmol) obtained by a similar reaction step as in Starting Material Synthetic Example 9 at 0° C. The reaction mixture was stirred at room temperature for 5 hr. Water (100 ml) was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and purified by silica gel column chromatography (hexane-ethyl acetate) to give the objective (S)-4-(benzyloxycarbonylamino)-N-{1-[2-(trimethylsilyl)ethoxymethyl]pyrrolo[2,3-b]pyridin-4-yl}thiochromane-7-carboxamide (1.06 g) as a pale-brown amorphous solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccccc1CNC1CCN(Cc2ccccc2)CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccccc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
(1-Benzyl-piperidin-4-yl)-(2-nitro-benzyl)-amine (1.2 g, 3.7 mmol) and zinc dust (1 g, excess) were combined in 75% aqueous acetic acid (16 mL) and stirred at 60° C. for 2 h. After cooling to room temperature, the solvents were removed in vacuo and the resultant crude dissolved in water (10 mL), followed by addition of ammonium hydroxide until pH 3 was attained. The solution was extracted with methylene chloride (3×). The organic layers were pooled together washed with water (2×), brine (2×), dried over sodium sulfate, filtered, and concentrated to afford 0.8 g (73%) of the desired product. 1H-NMR (CD3OD) δ 2.50 (m, 2H), 3.20 (m, 2H), 3.49 (dd, J=7.0, 7.3, 1H), 3.62 (m, 4H), 4.20 (s, 2H), 4.36 (s, 2H), 7.04 (m, 2H), 7.32 (dd, J=7.3, 7.6, 1H), 7.41 (d, J=7.9, 1H), 7.50 (m, 5H). Mass spec.: 296.40 (MH)+.