Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[CH3:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O>>[CH2:9]([N:8]1[C:3]2=[N:1][N:2]([CH2:26][C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[C:17]([CH3:16])[CH:18]=4)[NH:22][CH:21]=3)[C:34]([C:30]3[N:29]([CH3:28])[CH:33]=[CH:32][N:31]=3)=[C:4]2[C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: Cn1ccnc1C=O
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3nccn3C)c(=O)n(C)c(=O)n4CC(C)C)c2c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-methyl-1H-indole-3-carbaldehyde, followed by 1-methyl-1H-imidazole-2-carbaldehyde. Mass: 446.26 (M+H).
Reaction SMILES: [NH2:1][CH:2]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([C:24]([F:27])([F:26])[F:25])[CH:16]=1.C(N(CC)CC)C>C1COCC1>[F:12][C:9]([F:10])([F:11])[CH:8]([OH:13])[CH:2]([NH:1][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([F:14])=[CH:16][C:17]=1[C:24]([F:27])([F:25])[F:26])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)C(N)C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.7 g (8.5 mmol) of ethyl 2-amino-4,4,4-trifluoro-3-hydroxybutyrate were dissolved in THF, and initially 1.8 g of 4-fluoro-2-trifluoromethylbenzoic acid and 2.6 g (25.4 mmol) of triethylamine and then, at 5° C., 1.9 g (8.5 mmol) of bis(2-oxo-3-oxazolinidylphosphoryl chloride were added. The mixture was stirred at RT for 16 h. The reaction solution was then concentrated, and the residue was diluted with water and extracted with ethyl acetate. The combined organic phases were dried and the solvent was removed. This gave 3.1 g (93% of theory) of the title compound as a colorless residue.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[NH:10]1[CH2:20][CH2:19][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11]1.O>C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([O:16][C:14]([CH:13]1[CH2:19][CH2:20][N:10]([C:2]2[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=2)[CH2:11][CH2:12]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccc(Cl)nn1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCN(c2ccc(OC)nn2)CC1
Temperature: 100 °C
Yield: 40.2 %

Procedure:
A mixture of 4.33 g (30 mmol) 3-chloro-6-methoxypyridazine, 5.66 g (36 mmol) ethyl isonipecotate, 3.46 g (36 mmol) sodium tert.-butylate, 0.56 g (0.9 mmol) BINAP amd 0.55 g (0.5 mmol) Pd2 dba3 in 60 mL toluene was heated to 100° C. for 90 min. After cooling to room temperature water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 3.2 g (34%) of the title compound as orange solid. MS m/e: 266.3 [M+H]+.
Reaction SMILES: C(O[CH2:5][CH2:6][C:7]1[N:8]([CH2:24]C2C=CC=CC=2[N+]([O-])=O)[C:9]([S:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)=[C:10]([CH:12]([CH3:14])[CH3:13])[N:11]=1)(=O)N.ClC1C=C(SC2N(CC3C=CC=CC=3[N+]([O-])=O)C(CCO)=[N:45]C=2C(C)C)C=C(Cl)C=1.C(OCCC1N(CC2C=CC([N+]([O-])=O)=CC=2)C(SC2C=C(Cl)C=C(Cl)C=2)=C(C(C)C)N=1)(=O)N>>[Cl:23][C:18]1[CH:17]=[C:16]([S:15][C:9]2[N:8]([CH3:24])[C:7]([CH2:6][C:5]#[N:45])=[N:11][C:10]=2[CH:12]([CH3:14])[CH3:13])[CH:21]=[C:20]([Cl:22])[CH:19]=1
Reactant: CC(C)c1nc(CCO)n(Cc2ccccc2[N+](=O)[O-])c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1nc(CCOC(N)=O)n(Cc2ccccc2[N+](=O)[O-])c1Sc1cc(Cl)cc(Cl)c1
Agent: CC(C)c1nc(CCOC(N)=O)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Product: CC(C)c1nc(CC#N)n(C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 87 %

Procedure:
2-(2-Carbamoyloxyethyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(o-nitrobenzyl)-1H-imidazole (128c) was obtained from (126c) by the same synthetic process as that for (128a) in Example 140 (yield 87%). mp 163-165° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.O.[C:11](OCC)(=[O:13])C.N1[CH:22]=[CH:21][CH:20]=CC=1>CC(=C)C(Cl)=O>[Cl:1][C:2]1[C:7]([NH:8][C:11](=[O:13])[C:21]([CH3:20])=[CH2:22])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1
Reactant: CCOC(C)=O
Reactant: c1ccncc1
Reactant: Nc1cc(F)cnc1Cl
Agent: C=C(C)C(=O)Cl
Solvent: O
Product: C=C(C)C(=O)Nc1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.2 g of 2-chloro-5-fluoropyridin-3-amine in 5 mL of pyridine, 0.86 mL of 2-methylacryloyl chloride was added under cooling with ice, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, water and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=100:0 to 50:50 to obtain 1.1 g of N-(2-chloro-5-fluoropyridin-3-yl)-2-methylacrylamide as a colorless oily substance.
Reaction SMILES: C([NH:4][C@@H:5]([C:17]([O:19]C)=[O:18])[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)(=O)C>Cl>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[CH2:6][C@H:5]([C:17]([OH:19])=[O:18])[NH2:4]
Reactant: COC(=O)[C@@H](Cc1ccc2ccccc2c1)NC(C)=O
Agent: Cl
Product: N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A solution of 2.5 g of methyl N-acetyl-3-(2-naphthyl)-D-alaninate in 60 ml of 6N HCl was heated at 120°-130° for 3 hours and cooled to room temperature. The white precipitate which formed was collected and recrystallized from 50 ml of H2O containing 1 ml of 12N HCl by neutralization with NH4OH to pH 6, and dried in vacuo to yield 1.2 g of 3-(2-naphthyl)-D-alanine, m.p. 242°-244°, [α]D25 26.6° (c 0.5, CH3CO2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.[C:23]1(=O)CCCCC1.C=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:15]([N:16]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH3:23])=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1)c1n[nH]cc1NC1CCCCC1
Reactant: O=C1CCCCC1
Agent: C=O
Product: CN(c1c[nH]nc1C(=O)Nc1ccc(F)cc1)C1CCCCC1

Procedure:
This compound was prepared in a manner analogous to the compound of Example 19 by successive reductive alkylations using firstly cyclohexanone and then formaldehyde. (LC/MS: Rt 2.77 [MH]+ 316.71).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.C([Li])CCC.[CH3:16][O:17][CH2:18][N:19]=[C:20]=[S:21]>C1COCC1>[CH3:16][O:17][CH2:18][NH:19][C:20]([C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:8]=1)=[S:21]
Reactant: Clc1ccnc2ccsc12
Reactant: COCN=C=S
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCNC(=S)c1cc2nccc(Cl)c2s1
Temperature: -78 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
Solid 7-chloro-thieno[3,2-b]pyridine (60 g, 360 mmol) was added with stirring to 600 mL dry THF. Nitrogen was bubbled through the solution for ten minutes then cooled to −78° C. n-Butyl lithium (170 mL, 432 mmol) (2.5 M solution in hexanes) was added drop-wise at a rate such that the temperature is maintained below −65° C. The reaction mixture was stirred at −78° C. for three hours. Methoxymethyl isothiocyanate (43.2 mL, 468 mmol) in 400 mL THF was slowly added. Complete solution was noted after the addition was complete. The reaction mixture was then allowed to stir at −78° C. for three hours. The reaction mixture was removed from the cooling bath and 150 mL saturated NH4Cl solution was added. The reaction mixture turned a bright yellow color. THF was removed under reduced pressure, and 7-Chloro-thieno[3,2-b]pyridine-2-carbothioic acid methoxymethyl amide was filtered, washed with ethyl acetate and dried giving 93.7 g, a 95% yield as a yellow-orange solid. C10H9ClN2OS2: APCI m/z 273.0/274.9 (MH+).); 1H NMR (d6-DMSO): δ 8.60 (d, 1H, J=5.0 Hz ), 8.13 (s, 1H), 7.55 (d, 1H, J=5.0 Hz ), 4.97 (s, 2H), 2.46 (s, 3H) ppm.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[N:10]=[C:11](SC)SC.Cl.Cl.[NH2:18][CH2:19][C@@:20]1([OH:28])[CH:25]2[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]2)[CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[NH:10][C:11]1[O:28][C@:20]2([CH2:19][N:18]=1)[CH:25]1[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]1)[CH2:21]2
Reactant: CSC(=Nc1nc2cccnc2s1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cnc2sc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc2c1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
A mixture of dimethyl thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (90 mg, 0.35 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (97 mg, 0.42 mmol) and cesium carbonate (230 mg, 0.71 mmol) in DMF (1 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-40% 9:1 methanol:ammonium hydroxide-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (84 mg, 76% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.30 (br. s., 1 H) 8.37 (dd, J=4.77, 1.51 Hz, 1 H) 7.82 (dd, J=8.03, 1.51 Hz, 1 H) 7.28 (dd, J=8.03, 4.77 Hz, 1 H) 4.05 (d, J=9.54 Hz, 1 H) 3.70 (d, J=9.54 Hz, 1 H) 3.42 (dd, J=15.06, 1.76 Hz, 1 H) 2.75-3.07 (m, 5 H) 2.14-2.26 (m, 2 H) 1.71-1.84 (m, J=13.99, 9.79, 4.17, 4.17 Hz, 1 H) 1.48-1.68 (m, 2 H). MS (LC/MS) R.T.=0.64; [M+H]+=316.15.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@:21]12[CH2:29][C@@H:28](O)[CH2:27][C@H:26]1[CH2:25][S:24][C:23]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[N:22]2.O>ClCCl>[C:34]([O:33][C:32](=[O:38])[NH:31][C:23]1[S:24][CH2:25][C@@H:26]2[CH2:27][C@@H:28]([F:11])[CH2:29][C@:21]2([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[F:14])[N:22]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)C[C@@H](O)C[C@H]2CS1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)C[C@H](F)C[C@H]2CS1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
[Bis(2-methoxyethyl)amino]sulfur trifluoride (0.0564 mL) was added to a solution of tert-butyl [(4aR*,6S*,7aS*)-7a-(2-fluorophenyl)-6-hydroxy-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl]carbamate (51 mg) in dichloromethane (2 mL) at 0° C., and the mixture was stirred at 0° C. for 1.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate. The title compound (51 mg) was obtained by removal of the drying agent and concentration under reduced pressure.
Reaction SMILES: [C:1]([NH2:4])(=[NH:3])[CH3:2].[N+:5]([C:8]1[CH:19]=[CH:18][C:11]([CH:12]=[CH:13][S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1)([O-:7])=[O:6]>>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:13][S:14]([NH:3][C:1](=[NH:4])[CH3:2])(=[O:16])=[O:15])=[CH:18][CH:19]=1)([O-:7])=[O:6]
Reactant: CC(=N)N
Reactant: O=[N+]([O-])c1ccc(C=CS(=O)(=O)Cl)cc1
Product: CC(=N)NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1

Procedure:
Reaction of acetamidine with 4-nitrostyrylsulfonyl chloride according to the above procedure provides N-(4-NITROSTYRYLSULFONYL)ACETAMIDINE, m.p. 203.0°-203.5° C. (dec.)(corr.), crystallized from acetonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[N:7]=1)=[O:5])[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH:30]([CH3:32])[CH3:31])[CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:25]3[CH:26]=[N:27][N:28]([CH:30]([CH3:32])[CH3:31])[CH:29]=3)[C:14]=2[CH3:23])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)n1
Reactant: CC(C)n1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(C(C)C)c3)c3cc(Cl)ccc23)n1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: 6-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and 4-bromo-1-isopropyl-1H-pyrazole.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[C:19]([OH:21])=O)=[O:7])(C)(C)C.[O:22]=[C:23]1[C:28](C(Cl)=O)=[CH:27][CH:26]=[C:25]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:24]1.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[C:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:28]2[C:23](=[O:22])[O:24][C:25]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:26][CH:27]=2)=[O:7])[C@H:9]([C:19]([NH:40][CH:37]2[CH2:39][CH2:38]2)=[O:21])[CH2:10]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: NC1CC1
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: CC(C)(C)ON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCCCCc1ccc(C(=O)N2CC(=NOC(C)(C)C)C[C@H]2C(=O)NC2CC2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and cyclopropylamine the title compound was obtained in 75% purity by LC/MS. MS(ESI+): m/z=432.2.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C@@H:11]([OH:28])[C@@H:12]([OH:27])[C@H:13]([CH3:26])[C@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@@H:15]([CH3:17])[CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.[Si:37](OS(C(F)(F)F)(=O)=O)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].CO>C(Cl)Cl>[C:1]1([S:7]([C:10]2[C@@H:11]([OH:28])[C@@H:12]([O:27][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C@H:13]([CH3:26])[C@H:14]([O:18][Si:19]([C:22]([CH3:23])([CH3:25])[CH3:24])([CH3:20])[CH3:21])[C@@H:15]([CH3:17])[CH:16]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C[C@H]1[C@H](O)[C@H](O)C(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: C[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@H](O)C(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Compound 39 (77 mg, 0.18 mmol) was dissolved in dry methylene chloride (2.0 mL), and cooled to −78° C. To this cold solution were added 2,6-lutidine (32 μL, 0.27 mmol), followed by TBSOTf (50 μL, 0.22 mmol) under nitrogen. After stirring for 2 h at −78° C. (the reaction was monitored by TLC until completionusing a mixture of 1:1 EA/hexanes), 0.2 mL of methyl alcohol was then added to quench the excess of TBSOTf. The resulting solution was concentrated via rotary evaporation and the residue was purified by flash column chromatography (ethyl acetate/hexane, 1:5) to afford 97 mg (99% yield) of 52 as a white solid. mp 81.0-83.0° C.; [α]20D=+38.8 (c=1.3, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.83-7.86 (m, 2H), 7.50-7.71 (m, 3H), 7.37 (d, J=7.8 Hz, 1H), 4.29 (br s, 1H), 3.81 (d, J=4.5 Hz, 1H), 3.56 (dd, J=2.1 Hz, 8.7 Hz, 1H), 2.79 (m, 1H), 2.53 (br s, 1H), 2.45 (m, 1H), 1.22 (d, J=7.2 Hz, 3H), 0.99 (d, J=7.2 Hz, 3H), 0.88 (s, 9H), 0.81 (s, 9H), 0.077 (s, 3H), 0.052 (s, 3H), −0.14 (s, 3H), −0.35 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ 148.8, 139.6, 139.5, 133.5, 129.4, 128.1, 77.7, 73.3, 70.6, 40.3, 36.3, 26.1, 18.3, 18.1, 17.6, 17.5, −4.11, −4.54, −4.61, −4.90. LRMS (CI): m/z 541 [M+H]+; HRMS (CI) calculated for C27H48O5SSi2, 541.2839; found, 541.2834.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6](=[O:10])[C@@H:7]([CH3:9])[NH2:8])[CH2:3][CH3:4].[NH:11](C(OCC1C=CC=CC=1)=O)[C@H:12]([C:24](O)=[O:25])[CH2:13][C:14](=[O:23])[O:15]CC1C=CC=CC=1>>[CH2:2]([O:5][C:6](=[O:10])[C@@H:7]([CH3:9])[NH:8][C:24](=[O:25])[C@H:12]([CH2:13][C:14](=[O:15])[OH:23])[NH2:11])[CH2:3][CH3:4]
Reactant: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCCOC(=O)[C@@H](C)N
Agent: Cl
Product: CCCOC(=O)[C@@H](C)NC(=O)[C@@H](N)CC(=O)O

Procedure:
This compound was prepared from 1.8 g D-alanine n-propyl ester hydrochloride and 3.6 g Z-Asp(OBzl) in a manner similar to Example 16 (A). Yield: 1.9 g.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:19])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=[CH:15][C:7]1=[N:6]2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>CN(C)C=O>[CH3:1][C:2]1[S:3][C:4]([CH3:19])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]([NH:33][C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[O:18])[CH:14]=[CH:15][C:7]1=[N:6]2
Reactant: Cc1sc(C)c2c(=O)n3cc(C(=O)O)ccc3nc12
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1sc(C)c2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc12
Temperature: 105 °C
Yield: 62.6 %

Procedure:
A mixture of 0.6 g (0.0022 mol) of 1,3-dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (Example 48) and 0.84 g (0.005 mol) of 1,1' carbonyldiimidazole (Aldrich Chemical Company) in 90 ml of dimethylformamide is stirred and heated in a wax bath at 105° C. for eighty five minutes under nitrogen. The mixture is allowed to stand at room temperature for thirty minutes and then 0.225 g (0.0022 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) is added and the mixture heated at 105° C. for three and one-half hours. The solvent is evaporated and the residue suspended in hot methanol, cooled and 0.71 g of crude product is collected. This material is dissolved in hot pyridine, activated charcoal (Darco G60, Matheson, Coleman and Bell) is added and the hot suspension is filtered through Supercell Hyflo® (Johns-Manville). The filtrate is cooled to give 0.47 g of 1,3-dimethyl-10-oxo-N-1H-tetrazol-5-yl-10 H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide with pyridine (1:0.2); mp >300° C. (dec).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[N+:20]([C:23]1[C:30]([NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:29]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])([O-:22])=[O:21].C(O)(=O)C>O1CCCC1>[OH:26][CH:25]([C:24]1[CH:27]=[CH:28][C:29]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:30]([NH:31][C:32](=[O:39])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:23]=1[N+:20]([O-:22])=[O:21])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=Cc1ccc(OCCCCc2ccccc2)c(NC(=O)c2ccccc2)c1[N+](=O)[O-]
Reactant: C#CC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C#CC(O)c1ccc(OCCCCc2ccccc2)c(NC(=O)c2ccccc2)c1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 105 %

Procedure:
To a solution of diisopropylamine (0.6 ml, 4.26 mmol) in tetrahydrofuran (12 ml) was added, at -78° C. under an argon atmosphere, 1.5 N butyllithium (2.66 ml, 3.99 mmol). The mixture was stirred for 30 min. Ethyl propiolate (0.49 ml, 4.79 mmol) and a solution of 2-nitro-4-phenylbutoxybenzoylaminobenzaldehyde (1.1 g, 2.66 mmol) in tetrahydrofuran (3 ml) were added in that order, and the mixture was stirred at -78° C. for additional one hr. A solution of acetic acid (0.47 ml, 8.25 mmol) in tetrahydrofuran (3 ml) was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution, and saturated brine in that order. It was then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(2-nitro-4-phenylbutoxybenzoylaminophenyl)-2-butynoate as an oil (1.443 g). Ethyl 4-hydroxy-4-(2-nitro-4-phenylbutoxybenzoylaminophenyl)-2-butynoate thus prepared was dissolved in toluene (10 ml), 4-methoxybenzylazide (1.3 g, 7.98 mmol) was added to the solution, and the mixture was stirred at 100° C. for 5 hr. The reaction mixture was cooled to room temperature, and the resultant crystal was collected by filtration to give ethyl 4-hydroxy-1-(4-methoxybenzyl)-(2-nitro-4-phenylbutoxybenzoylaminophenyl)methyl-1,2,3-triazole-5-carboxylate (a-1) (550.4 mg, 26%). Further, the filtrate was concentrated, and the resultant powder was washed with hexane:ethyl acetate (1:1) and dried to give ethyl 5-hydroxy-1-(4-methoxybenzyl)-(2-nitro-4-phenylbutoxybenzoylaminophenyl)methyl-1,2,3-triazole-4-carboxylate (a-2) (466.3 mg, 30%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:43]1[S:44][CH:45]=[CH:46][N:47]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[C:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH:31]=1)=[N:15][CH:14]=[CH:13]2)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:33]1[CH2:32][CH:31]=[C:30]([C:21]2[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:20]=2[C:16]2[C:17]3[C:12](=[CH:11][C:10]([S:7]([NH:6][C:43]4[S:44][CH:45]=[CH:46][N:47]=4)(=[O:9])=[O:8])=[CH:19][CH:18]=3)[CH:13]=[CH:14][N:15]=2)[CH2:35][CH2:34]1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4C4=CCN(C(=O)OC(C)(C)C)CC4)nccc3c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3C3=CCNCC3)nccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl 4-(2-(6-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.073 g, 0.095 mmol) was dissolved in 1 mL of DCM and TFA (0.073 ml, 0.948 mmol) was added. The reaction was stirred overnight at room temperature. The solution was concentrated and concentrated from DCM two more times. The resulting yellow solid was triturated with diethyl ether and stirred for 15 minutes. The solution was filtered and the solids were washed with diethyl ether. The material was dissolved in methanol and loaded onto an SCX ion exchange column (pre-wetted with methanol) (Biotage AB, Uppsala, SE). The column was washed several times with methanol, then the product was liberated with 2.0 M ammonia/methanol solution. The filtrate was concentrated to afford 1-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.60 (d, J=5.7 Hz, 1H), 8.44 (d, J=1.5 Hz, 1H), 8.05 (d, J=5.4 Hz, 1H), 7.93-7.79 (m, 2H), 7.72 (s, 1H), 7.61 (dd, J=8.4, 16.3 Hz, 2H), 6.96 (d, J=3.9 Hz, 1H), 6.52 (d, J=3.9 Hz, 1H), 5.49 (br. s., 1H), 3.24 (br. s., 2H), 2.72 (t, J=5.8 Hz, 2H), 2.04 (br. s., 2H). m/z (ESI) 517.2 (M+H)+.