Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][NH:58][C:59](=[O:73])[CH2:60][CH2:61][CH2:62][CH2:63][CH:64]1[CH:71]2[CH:67]([NH:68][C:69](=[O:72])[NH:70]2)[CH2:66][S:65]1)[NH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:43]=[CH:42][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][NH:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]([C:11]2[CH:42]=[CH:43][C:8]([O:7][CH2:6][CH2:5][CH2:4][NH:3][C:2](=[O:1])[CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][NH:58][C:59](=[O:73])[CH2:60][CH2:61][CH2:62][CH2:63][CH:64]3[CH:71]4[CH:67]([NH:68][C:69](=[O:72])[NH:70]4)[CH2:66][S:65]3)=[CH:9][CH:10]=2)=[O:13])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCCCC3SCC4NC(=O)NC43)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCOCCOCCOCCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCCCC3SCC4NC(=O)NC43)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
tert-butyl (3-(2-(2-(3-((4-(4-((5,21-dioxo-25-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-8,11,14,17-tetraoxa-4,20-diazapentacosyl)oxy)benzoyl)phenyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamate (16.1 g, 15.92 mmol) was dissolved in a solution of DCM:TFA (2:1, 96 ml) and the reaction mixture was stirred for ca. 1 h at r.t. Upon completion, reaction was then concentrated under reduced pressure, co-evaporated with toluene, and dried on pump for 5 hs to yield 14.13 g (98% yield) of crude N-(3-(4-(4-((3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)amino)benzoyl)phenoxy)propyl)-1-(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3,6,9,12-tetraoxapentadecan-15-amide as yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[Br:1][C:2]1[C:3]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ncccc2Br)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Bromo-2-chloropyridine (10.3 g, 53.4 mmol), 4-aminophenol (7.00 g, 64.1 mmol), cesium carbonate (34.8 g, 107 mmol), and DMSO (53 ml, 53.4 mmol) were added into a pressure tube. The tube was capped and placed in a preheated oil bath at 130° C. After 16 h, the reaction mixture was stirred and cooled in ice-water. Water was added slowly to the mixture and the product precipitated out as a gray solid. The solids were washed with water, dried under vacuum at RT to afford 4-(3-bromopyridin-2-yloxy)benzenamine. MS Calcd for C11H9BrN2O: [M]+=264. Found [M+H]+=265.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28])[CH3:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:33]=[CH:34][C:29]([C:27](=[O:28])[NH:26][CH2:24][CH3:25])=[CH:30][CH:31]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Product: CCNC(=O)c1ccc(-c2cc3cc(C4CCN(C(=O)OC(C)(C)C)CC4)oc3cn2)cc1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-ethylcarbamoyl-phenylboronic acid following a procedure analogous to that described for Example 1; the reaction is conducted at 150° C. LC (method 4): tR=1.68 min; Mass spectrum (ESI+): m/z=450 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](C)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:25]([O:27][CH2:28]C)=[O:26])=[CH:19][CH:18]=1.[F:39]C1C=C(F)C=CC=1C=O>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C@H:24]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][C:37]=2[F:39])[C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccc(C)cc3)oc2C)cc1)NCc1ccc(F)cc1
Product: COC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)NCc1ccc(F)cc1F

Procedure:
In the same manner as in Example 7, 243.9 mg of the title compound was obtained as colorless amorphous compound from 421.3 mg of Referential Compound 3 and 240 μL of 2,4-difluorobenzaldehyde.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH:13]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[C:14]([OH:16])=O)=[O:11])[CH2:3][CH2:2]1.[NH2:28][C@@H:29]([CH2:50][C:51]1[N:52]=[CH:53][NH:54][CH:55]=1)[C:30]([NH:32][C@@H:33]([CH2:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)[C@@H:34]([OH:42])[CH2:35][C@@H:36]([CH:39]([CH3:41])[CH3:40])[CH:37]=[CH2:38])=[O:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH:44]1([CH2:43][C@H:33]([NH:32][C:30](=[O:31])[CH:29]([NH:28][C:14](=[O:16])[CH:13]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH2:12][C:10](=[O:11])[NH:9][CH2:8][CH2:7][N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:50][C:51]2[N:52]=[CH:53][NH:54][CH:55]=2)[C@@H:34]([OH:42])[CH2:35][C@@H:36]([CH:39]([CH3:41])[CH3:40])[CH:37]=[CH2:38])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: O=C(CC(Cc1cccc2ccccc12)C(=O)O)NCCN1CCOCC1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)C(Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCN1CCOCC1)Cc1cccc2ccccc12)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 31.5 %

Procedure:
A mixture of 95 mg of (RS)-α-[(2-morpholinoethyl)carbamoylmethyl]-1-naphthalenepropionic acid, 100 mg of (S)-α-amino-N-[(1S,2S.4S)-1-(cyclohexylmethyl) 2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide and 97 mg of HBTU in acetonitrile was stirred at room temperature for 3.5 hours and then worked-up in the usual manner. The residue was chromatographed on silica gel with a 4: mixture of methylene chloride and methanol as the eluting agent, to obtain 60 mg of N-[(1S,2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-α-[3-[(2-morpholinoethyl)carbamoyl]-2-(1-naphthylmethyl)propionamido]imidazole-4-propionamide as a foam. MS: 743 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH2:17]([O:16][C:14]([NH:13][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:15])[CH3:18]
Reactant: CCOC(N)=O
Reactant: CCOC(=O)C1CCCCC1=O
Product: CCOC(=O)NC1=C(C(=O)OCC)CCCC1

Procedure:
Using the method of Example 1 Part A, ethyl 2-oxocyclohexanecarboxylate (201 g, 1.18 mole) was reacted with urethane to provide 135 g of ethyl 2-[ (ethoxycarbonyl)amino]-1-cyclohexene-1-carboxylate as a white solid.
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C:17](=[CH2:28])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.[OH2:40].C([O-])(O)=O.[Na+]>CC(C)=O>[CH2:28]=[C:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:40])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]1
Reactant: O
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 87 %

Procedure:
A solution of 3,3:17,17-bis(ethylendioxy)-6-methyleneandrostane (1.05 g) and pTSA.H2O (2.46 g) in acetone (105 mL) was stirred at room temperature for 3 h. The solution was neutralized by addition of 5% aqueous NaHCO3 and acetone was evaporated. The aqueous suspension was extracted with CH2Cl2 (3×). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness to give the title compound II-ac in 87% yield. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.85 (1H, m), 4.50 (1H, m), 2.63-1.02 (20H, m), 0.92 (3H, s), 0.86 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:8]=[CH:14][N:15]([CH3:17])[CH3:16])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(Br)ccc1C(N)=O
Product: Cc1cc(Br)ccc1C(=O)N=CN(C)C
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.84 g of 4-bromo-2-methyl benzoic acid amide and 18 mL of N,N-dimethylformamide dimethylacetal was stirred at 70° C. for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was washed with 5 mL of hexane to obtain 0.67 g of the aimed product as white crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30]
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
A suspension of the {9-[(2,6-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (85 mg, 0.2 mM) and 0.22 mL (0.22 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 18 hours at 25° C. A small volume of diethyl ether/hexanes was added, then cooled in the refrigerator. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH/diethyl ether/hexanes, then dried in vacuo to afford 82 mg (95%) of the {9-[(2,6-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.55 (br s, 1H), 7.45-7.3 (m, 3H), 7.25 (t, 1H, J=8 Hz), 7.1-7.0 (m, 4H), 6.5 (d, 1H, J=8 Hz), 5.65 (s, 2H), and 4.3 (s, 2H). IR (KBr, cm−1) 3470, 3360, 1658, and 1606. MS (ES) m/e 409, 411, 433.
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]1[CH2:10][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]1=[O:21])=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:5][C@H:6]1[CH2:10][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:7]1=[O:21]
Reactant: CC(C)CN1C(=O)[C@@H](NC(=O)C(F)(F)F)C[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)CN1C(=O)[C@@H](N)C[C@H]1c1ccccc1
Reaction time: 27 h
Yield: 92.6 %

Procedure:
To a solution of cis-2,2,2-trifluoro-N-(1-isobutyl-2-oxo-5-phenylpyrrolidin-3-yl)acetamide (50.0 mg, 0.152 mmol) in methanol (3 mL) and water (1 mL) was added potassium carbonate (63.1 mg, 0.447 mmol). After 27 hours, the reaction solution was concentrated, and worked up with methylene chloride and water. The organic extracts were dried over sodium sulfate, filtered and concentrated to produce the title compound (32.7 mg). MS 233 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([NH2:23])=[C:18]([NH2:24])[CH:17]=1.C(N(CC)CC)C>ClCCl>[NH2:24][C:18]1[CH:17]=[C:16]([Cl:15])[C:21]([Cl:22])=[CH:20][C:19]=1[NH:23][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([C:13]#[N:14])=[CH:12][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CCOc1cc(C#N)ccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(C#N)ccc1C(=O)Nc1cc(Cl)c(Cl)cc1N
Reaction time: 2 h
Yield: 104.3 %

Procedure:
A solution of 2-ethoxy-4-cyanobenzoyl chloride (10.9 g, 52 mmol), prepared as in Preparation 11, in dichloromethane (109 ml) was added dropwise in 5 h to a solution of 4,5-dichlorophenylendiamine (18.5 g, 104.5 mmol) and triethylamine (53 g=72.6 ml, 523 mmol) in dichloromethane (550 ml). Stirring was continued for additional 2 h. The solvent was removed under vacuum and the residue was triturated with water (100 ml), filtered and dried at 50° C. under vacuum. The solid was suspended in diethyl ether (200 ml), stirred for 1 h, filtered and dried under vacuum to give 19 g of N-(2-amino-4,5-dichlorophenyl)-2-ethoxy-4-cyanobenzamide (yield 51%), mp=195–198° C.
Reaction SMILES: II.[F:3][C:4]([F:37])([F:36])[CH2:5][CH2:6][CH:7]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:8][O:9][C:10]1[C:11]([CH:26]=O)=[CH:12][C:13]2[C:22]3[C:17](=[CH:18][N:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([CH3:24])[C:14]=2[CH:25]=1.[NH3:38].[O-]S([O-])(=S)=O.[Na+].[Na+]>O1CCCC1>[C:26]([C:11]1[C:10]([O:9][CH2:8][CH:7]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:6][CH2:5][C:4]([F:36])([F:37])[F:3])=[CH:25][C:14]2[N:15]([CH3:24])[C:16](=[O:23])[C:17]3[C:22]([C:13]=2[CH:12]=1)=[CH:21][CH:20]=[N:19][CH:18]=3)#[N:38]
Reactant: N
Reactant: Cn1c(=O)c2cnccc2c2cc(C=O)c(OCC(CCC(F)(F)F)NC(=O)OC(C)(C)C)cc21
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)c2cnccc2c2cc(C#N)c(OCC(CCC(F)(F)F)NC(=O)OC(C)(C)C)cc21
Reaction time: 3 h
Yield: 85.6 %

Procedure:
Iodine (0.047 g, 0.184 mmol) was added to a stirred solution of tert-butyl (5,5,5-trifluoro-1-((9-formyl-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.165 g, 0.167 mmol) in aqueous ammonia (4 mL, 48.1 mmol) and tetrahydrofuran (6 mL) at room temperature. The dark solution became light gray after stirring for 3 h, an indication that the reaction was complete. The reaction mixture was charged with aqueous Na2S2O3 (25 mL of 5% solution) and extracted with ethyl acetate (3×30 mL). The combined the organic layers were dried over sodium sulphate and concentrated under reduced pressure to afford tert-butyl (1-((9-cyano-6-methyl-5-oxo-5,6 dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-5,5,5-trifluoropentan-2-yl)carbamate (0.14 g, 0.143 mmol, 85% crude yield) as a pale yellow solid. The material was carried forward without further purification. LC/MS (ESI) m/e 491.5 (M+H)+, calcd for C24H26F3N4O4, 491.2]; LC/MS retention time (method D): tR=0.87 min.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(O)C>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:27]([NH:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[S:28])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNc1ccc(NCc2ccccc2)cc1
Reactant: S=C=Nc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(=O)NNc1ccc(N(Cc2ccccc2)C(=S)Nc2ccccc2)cc1

Procedure:
1-Acetyl-2-(4-benzylaminophenyl)hydrazine (2.80 g, 0.011 mole) and phenylisothiocyanate (1.35 g, 0.01mole) were mixed in ethanol (25 ml) and the resulting mixture was refluxed for 5 minutes. The mixture was chilled in ice and water was added to precipitate the product. The product oiled out of solution, but became crystalline upon standing and scratching. The solid was filtered off and washed with water, then ether. After drying the product was a pale yellow crystalline powder. Yield 3.0 g (77%), m.p. 114°-117° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH:5]=[CH2:6])[CH3:2].[CH2:10]([O:12][SiH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH3:11]>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][CH2:6][Si:13]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[O:12][CH2:10][CH3:11])[CH3:2]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CC(OCC)OCC
Product: CCOC(CC[Si](OCC)(OCC)OCC)OCC

Procedure:
A round-bottomed flask is introduced with 2 g (1.1 equivalent) of 3,3-diethoxy-1-propene produced in Example 1, and 2 ml (1 equivalent) of triethoxysilane commercially available from Aldrich, Co. Then, hydrogen hexachloroplatinate (H2PtCl6), a metal catalyst, is added in the amount of 1 ppm to the solution. After that, the resulting mixture is allowed to react at 100° C. under atmospheric pressure for 48 hours. Next, the resulting material is fractionally distilled under a vacuum, thereby giving 4.2 g of colorless 3,3-diethoxyprophyltriethoxysilane. The product is dissolved in CDCl3 and measured for 1NMR and infrared-absorbing spectrum. Results are shown in FIGS. 1 and 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[OH:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][O:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[CH:22][CH:23]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:9])=[O:10]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Reactant: Oc1ccc2ccccc2c1
Product: O=S(=O)(Nc1nccnc1-c1ccc(COc2ccc3ccccc3c2)cc1)c1ccccc1Cl
Yield: 72 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and 2-hydroxy naphthalene, the title compound was isolated as a yellow solid in 72% yield (99% purity by HPLC).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:44])=[C:9]([CH2:11][O:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[P:26](=[O:33])([O:30]CC)[O:27]CC)=[CH:22][N:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:20]=3)=[CH:15][C:14]=2[O:42][CH3:43])[N:10]=1.C(#N)C.C[Si](Br)(C)C>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:44])=[C:9]([CH2:11][O:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[P:26](=[O:27])([OH:33])[OH:30])=[CH:22][N:21]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:20]=3)=[CH:15][C:14]=2[O:42][CH3:43])[N:10]=1
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: CC#N
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/P(=O)(O)O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a mixture of diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate (0.40 g) and acetonitrile (20 mL) was added trimethylsilyl bromide (0.40 g) at room temperature. After stirring the reaction mixture at room temperature for 1 hr, trimethylsilyl bromide (0.30 g) was added again, and the mixture was further stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonic acid as pale-yellow crystals (0.28 g, yield 76%). Recrystallization from tetrahydrofuran-hexane gave pale-yellow prism crystals. melting point: 138-140° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:36])=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[CH2:9][N:10]2[CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([N:24](COC)[C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[N:23]=1)[C:18]([OH:20])=[O:19])=[O:6].O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([F:36])=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[CH2:9][N:10]2[CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[N:23]=1)[C:18]([OH:20])=[O:19])=[O:6]
Reactant: COCN(c1cc(C(=O)O)cc(CN2C[C@@H]3C[C@H]2CN3C(=O)c2cccc(Cl)c2F)n1)c1nccs1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(CN2C[C@@H]3C[C@H]2CN3C(=O)c2cccc(Cl)c2F)nc(Nc2nccs2)c1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
33 mg of 2-(((1S,4S)-5-(3-chloro-2-fluorobenzoyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl) -6-((methoxymethyl)(1,3-thiazol-2-yl)amino)isonicotinic acid was dissolved in 0.9 ml of trifluoroacetic acid and 0.1 ml of water followed by stirring 2 hours at 75° C. The reaction mixture was concentrated in vacuo to give the title compound. (15) Synthesis of 2-(((1S,4S)-5-(3-chloro-2-fluorobenzoyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl)-N,N-dimethyl-6-(1,3-thiazol-2-ylamino)isonicotinamide trifluoroacetate
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[C:35]=2[Cl:44])[CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:48]I.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:45])[N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[C:35]=2[Cl:44])[CH2:19][CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1)[CH3:48])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-carbamic acid tert-butyl ester (1.05 g, 1.64 mmol) was dissolved in anhydrous DMF (10 mL) and cooled to 0° C. under argon. NaH (78.8 mg, 1.97 mmol, 60% dispersion in mineral oil) was added and the mixture stirred at 0° C. for 30 minutes. Methyl iodide (164 uL, 2.63 mmol) was added and the reaction was allowed to warm to room temperature at which point the solution was maintained for 18 hours. The reaction mixture was then poured into H2O and extracted twice with EtOAc. The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated to a yellow oil which was further purified by silica gel chromatography (10 g Redisep column, silica, 40 um, 60 Å, 35 mL/min, A: hexanes, B: EtOAc, B: 0% for 5 min, B: 0% to 10% over 10 min; B: 10% for 10 min; B: 10% to 30% over 15 min; B: 30% for 10 min; detection at 214 nm) to give 1.05 g (1.63 mmol, 99%) of the title compound as a yellow oil. MS (ESI) 653.2