Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]([N:9]([CH3:26])[CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)[CH2:14][CH2:13]2)=[O:8])=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7](=[O:8])[N:9]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH2:14][CH2:13]2)[CH3:26])=[CH:4][CH:3]=1
Reactant: CN(CC[C@H]1CC[C@H](CCCOS(C)(=O)=O)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC[C@H]1CC[C@H](CCCn2ccnc2)CC1)C(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice-cooled solution of 200 mg (0.46 mmol) trans-methanesulfonic acid 3-(4-{2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-ethyl}-cyclohexyl)-propyl ester (example 11.16) and 126 mg (1.85 mmol) of imidazole in 3.5 ml of N,N-dimethylformamide was added at 0° C. 30.3 mg (0.69 mmol) of sodium hydride (55% in oil). The reaction mixture was then stirred for 4 hours at room temperature. After quenching with ammonium chloride solution, the reaction mixture was partitioned between water and ether. The combined ether phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 95:5 v/v mixture of ethylacetate and methanol as the eluent giving 103 mg (55%) of pure trans-{2-[4-(3-imidazol-1-yl-propyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 404 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12](=[O:13])[N:11]([C:14]3[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=3)[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12](=[O:13])[N:11]([C:14]3[CH:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:18][CH:19]=3)[N:10]([CH2:30][CH3:31])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(-c2cccc(Cl)c2)c[nH]n1-c1cccc(C(F)(F)F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCn1cc(-c2cccc(Cl)c2)c(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 4.6 grams of the pyrazolinone prepared above, 4 grams potassium carbonate, 15 ml. ethyl iodide and 50 ml. ethanol was refluxed overnight. The reaction product mixture was worked up in the customary way to yield 1.8 grams of the desired product, m.p.=113°-114° C.
Reaction SMILES: Cl.[NH2:2]O.[CH:4]1([C:7](=[O:18])[C:8](=[CH:14]OCC)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5]1>CCO>[CH:4]1([C:7]2[O:18][N:2]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5]1
Reactant: NO
Reactant: CCOC=C(C(=O)OCC)C(=O)C1CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnoc1C1CC1
Yield: 57.7 %

Procedure:
A mixture of hydroxylamine hydrochloride (105.0 g, 1.51 mole), ethyl β-cyclopropyl-α-ethoxymethylene-β-ketopropionate (320.0 g, 1.51 mole) [prepared in Step A] and 1200 ml of EtOH was heated at reflux for 2 h. The solvent was removed in vacuo and the residue was partitioned between water and ether. The organic phase was separated, washed again with water, dried and evaporated to leave a dark, greasy solid. Trituration of the crude product under Skellysolve B gave 158 g of the title compound.
Reaction SMILES: C(OC(N1[C@H](C(=O)N[C@H](C(O)=O)CC2C=CC(C3C=CN=C(C)C=3C)=CC=2)CC2C=C3OC[C@H](C4C=CC(O)=CC=4)OC3=CC=2C1)=O)(C)(C)C.FC(F)(F)C1CCC(CO)CC1.C[O:64][C:65](=[O:126])[C@@H:66]([NH:82][C:83]([C@@H:85]1[CH2:94][C:93]2[CH:92]=[C:91]3[O:95][CH2:96][C@H:97]([C:99]4[CH:104]=[CH:103][C:102]([O:105][CH2:106][CH:107]5[CH2:112][CH2:111][CH:110]([C:113]([F:116])([F:115])[F:114])[CH2:109][CH2:108]5)=[CH:101][CH:100]=4)[O:98][C:90]3=[CH:89][C:88]=2[CH2:87][N:86]1[C:117]([C:119]1[N:120]=[C:121]([CH3:125])[O:122][C:123]=1[CH3:124])=[O:118])=[O:84])[CH2:67][C:68]1[CH:73]=[CH:72][C:71]([C:74]2[CH:79]=[CH:78][N:77]=[C:76]([CH3:80])[C:75]=2[CH3:81])=[CH:70][CH:69]=1.C(Cl)CCl.CC1OC(C)=C(C(O)=O)N=1>C(Cl)Cl>[CH3:125][C:121]1[O:122][C:123]([CH3:124])=[C:119]([C:117]([N:86]2[C@H:85]([C:83]([NH:82][C@@H:66]([CH2:67][C:68]3[CH:73]=[CH:72][C:71]([C:74]4[CH:79]=[CH:78][N:77]=[C:76]([CH3:80])[C:75]=4[CH3:81])=[CH:70][CH:69]=3)[C:65]([OH:126])=[O:64])=[O:84])[CH2:94][C:93]3[CH:92]=[C:91]4[O:95][CH2:96][C@H:97]([C:99]5[CH:100]=[CH:101][C:102]([O:105][CH2:106][CH:107]6[CH2:108][CH2:109][CH:110]([C:113]([F:114])([F:116])[F:115])[CH2:111][CH2:112]6)=[CH:103][CH:104]=5)[O:98][C:90]4=[CH:89][C:88]=3[CH2:87]2)=[O:118])[N:120]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1nc(C)oc1C)O[C@@H](c1ccc(OCC2CCC(C(F)(F)F)CC2)cc1)CO3
Agent: Cc1nc(C(=O)O)c(C)o1
Agent: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)OC(C)(C)C)O[C@@H](c3ccc(O)cc3)CO5)C(=O)O)cc2)c1C
Agent: OCC1CCC(C(F)(F)F)CC1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCC3CCC(C(F)(F)F)CC3)cc2)O4)c(C)o1
Reaction time: 0.67 h

Procedure:
(3S,8S)-8-{(S)-1-Carboxy-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-ethyl-carbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester was coupled with (4-trifluoromethyl-cyclohexyl)-methanol according to the General Procedure K. The resulting product was converted to (S)-2-({(3S,8S)-7-(2,5-dimethyl-oxazole-4-carbonyl)-3-[4-(4-trifluoromethyl-cyclohexyl-methoxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester according to General Procedure C, then the residue was suspended in DCM. TEA (3 eq.) added and the mixture was concentrated. In a separate vial, EDC (3 eq.) and 2,5-dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred for 40 minutes. This solution was added to the above mixture and stirred for 16 hours. The reaction mixture was directly purified over silica (hexanes; 1:1 hexanes/EtOAc; 1:1 hexanes EtOAc+1% MeOH). This ester was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 868.
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][C:7]([CH3:11])([CH3:10])[CH2:6][CH2:5]1.[C:12](O)(C(F)(F)F)=O.CC1(C)CC(C)(C)CC(C=O)C1.C[Mg+].[Br-].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C1COCC1.CCOCC.C(Cl)Cl.CCO>[CH3:10][C:7]1([CH3:11])[CH2:8][CH2:9][CH:4]([C:3](=[O:2])[CH3:12])[CH2:5][CH2:6]1
Reactant: O=C(O)C(F)(F)F
Reactant: COC=C1CCC(C)(C)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC1(C)CC(C=O)CC(C)(C)C1
Agent: C[Mg+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1CCC(C)(C)CC1

Procedure:
The compounds listed in the Examples 54, 55 and 56 below were made starting from a common cyclohexanone precursor. For the synthesis of the compounds in Examples 54 and 55 below, 4,4-dimethylcyclohexanone was converted by a four-step process into 1-(4,4-dimethylcyclohexyl)ethanone. The 4-step process is similar to that given in Example 53: the Wittig reagent generated as in Example 53 from (methoxymethyl)triphenylphosphonium chloride and NaH in THF was used to form the corresponding enol ether product from 4,4-dimethylcyclohexanone: (4-methoxymethylene-1,1-dimethyl-cyclohexane). This enol ether was hydrolyzed using TFA:DCM to generate the corresponding aldehyde. This aldehyde was treated with MeMgBr in THF/Et2O to give a methylcarbinol derivative which was then oxidized using PCC in DCM to give the desired 1-(4,4-dimethylcyclohexyl)ethanone. Also in an analogous fashion to the process disclosed in Example 53, this ketone was then treated with pyrrolidone hydrotribromide to give the 2-bromoketone derivative, and this bromoketone intermediate was subsequently treated with the appropriate thiourea derivatives in MeOH to produce the products shown in Examples 54 and 55 after hydrolysis of the esters, purification of the acids, and generation of the sodium carboxylate salts.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N+:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[NH:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Reactant: N#Cc1cccc(N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(Nc2ccc3ccccc3c2[N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
An anhydrous toluene (40 mL) suspension of 1-nitronaphthalen-2-yl triflate (3.00 g, 8.64 mmol), 3-aminobenzonitrile (1.02 g, 8.64 mmol), potassium carbonate (1.19 g, 8.64 mmol), triphenylphosphine (227 mg, 0.864 mmol), and tetrakis(triphenylphosphine)palladium (500 mg, 0.432 mmol) was stirred at 110° C. for 18 hours. After cooling on standing, the reaction mixture was filtered, and the filtrate was diluted with ethyl acetate. The obtained organic solution was washed with a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=99/1) to obtain the titled compound as a yellow powder (1.60 g, yield 64%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[N:20]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[NH:27][CH2:26][CH2:25][C:24]=2[CH:23]=[N:22][CH:21]=1>N1C=CC=CC=1>[N:20]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[N:27]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[CH2:26][CH2:25][C:24]=2[CH:23]=[N:22][CH:21]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)NCCc1cncnc1-2
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3cncnc3-c3ccccc32)cc1

Procedure:
As described for Example 1, 5 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido[5,4-d][1]benzazepine in pyridine to give the product as a solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([CH2:12][N:13]2[C:19](=[O:20])[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:14]2)[CH2:11][CH2:10]1.[Br:34]Br>O1CCCC1>[Br:34][CH:18]1[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:14][N:13]([CH2:12][CH:9]2[CH2:10][CH2:11]2)[C:19]1=[O:20]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N(CC2CC2)CC1c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Br)C(=O)N(CC2CC2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide (1M in THF; 2.13 mL, 2.13 mmol) was added to tert-butyl 4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-diazepane-1-carboxylate (0.489 g, 1.42 mmol) in tetrahydrofuran (5 mL) at −78° C. After 30 min, the enolate solution was transferred dropwise via cannula to a solution of bromine (0.36 mL, 7.10 mmol) in tetrahydrofuran (3 mL) at −78° C. over a period of 5 min. After 15 min, the mixture was quenched with aqueous saturated sodium sulfite and allowed to warm to ambient temperature. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered, and concentrated. MS 423 (M+1).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:37][CH2:36]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1ccc(N2CCNCC2)cc1OC
Product: CCc1cc(NC(=O)N2CCN(c3ccc(OC)c(OC)c3)CC2)c(OC)nc1C
Yield: 69 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,4-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15]C(C3CC3)=O)[CH:10]=2)[C:5](=[O:21])[N:4]2[C:22]([C:27]3[CH:32]=C[CH:30]=[C:29](F)[CH:28]=3)([CH3:26])[NH:23][C:24](=[O:25])[C:3]=12.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O1CCCC1.CN(C)C1C=CN=CC=1>[NH2:15][C:11]1[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:6]2[C:5](=[O:21])[N:4]3[C:22]([CH:27]4[CH2:32][CH2:30][CH2:29][CH2:28]4)([CH3:26])[NH:23][C:24](=[O:25])[C:3]3=[CH:2][CH:7]=2)[CH:10]=1
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC1(C2CCCC2)NC(=O)c2ccc(Nc3cc(N)ncn3)c(=O)n21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5,6-dichloropyrimidin-4-amine (1, 3.0 g, 18.29 mmol) in tetrahydrofuran (30 mL), 4-dimethylaminopyridine (0.16 g, 1.31 mmol) and di-tert-butyl dicarbonate (8.77 g, 40.2 mmol) were added at room temperature. The reaction mass was stirred at room temperature for overnight. After completion, distilled out the solvent. The above residue was diluted with water and extracted with ethyl acetate (2×50 mL). The organics were then separated and dried (magnesium sulfate) and concentrated to dryness under vacuum to afford ethyl tert-butyl N-tert-butoxycarbonyl-N-(5,6-dichloropyrimidin-4-yl)carbamate (2) as white solid. Yield: 3.1 g, 47%; MS (ESI) m/z 364.3 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 1.40 (s, 18H).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[CH2:21]([O:23][C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[C:30]([C:2]2[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=2[CH2:4][N:5]2[C:13]3[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=3)[CH:7]=[CH:6]2)[CH:29]=[CH:28][CH:27]=1)=[O:25])[CH3:22]
Reactant: O=C(O)c1ccc2c(ccn2Cc2ccccc2Br)c1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Product: CCOC(=O)c1cccc(-c2ccccc2Cn2ccc3cc(C(=O)O)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 38, using 1-(2-bromobenzyl)-1H-indole-5-carboxylic acid instead of the (S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide and the (3-(ethoxycarbonyl)phenyl)boronic acid instead of the phenylboronic acid. ESI-MS (m/z): 400 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(F)ccc1Br
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 28 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a stirred solution of 2-bromo-5-fluorotoluene (1.495 g, 7.909 mmol, Aldrich, used as received) in conc. H2SO4 (10.0 mL) at 0° C., KNO3 (0.800 g, 7.91 mmol) was added in one lot. The resulting pale yellow solution was warmed to 28° C. and stirred overnight at 28° C. It was then poured into ice (50 g) and extracted with ethyl acetate (75 mL). The ethyl acetate was dried over anhydrous Na2SO4, removed under vacuum, and the resulting oil dried further under vacuum to afford 1.832 g (98%) of the title compound as an oil; 1H NMR (CDCl3): δ2.495 (s, 3H), 7.213 (d, 1H, J1 =11.4 Hz), 8.268 (d, 1H, J1 =7.2 Hz).
Reaction SMILES: [CH3:1][Si:2]([CH3:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:3]1[C@@H:7]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([CH2:17][OH:18])=[CH:5][CH2:4]1.CC([O:30]O)(C)C>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(N(C(C)C)CCC1C2C(=CC=CC=2)NC=1)C>[CH3:1][Si:2]([CH3:25])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:3]1[CH2:4][CH:5]2[C:6]([CH2:17][OH:18])([O:30]2)[CH:7]1[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OO
Reactant: C[Si](C)(c1ccccc1)[C@H]1CC=C(CO)[C@@H]1COCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)N(CCc1c[nH]c2ccccc12)C(C)C
Agent: CC(C)[O-]
Solvent: ClCCl
Product: C[Si](C)(c1ccccc1)C1CC2OC2(CO)C1COCc1ccccc1
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 162.8 %

Procedure:
To an oven dried, 1-L 3-necked round bottomed flask equipped with a mechanical stirrer, a temperature probe, and an argon line was charged activated molecular sieves (35 g) and DCM (160 mL) under an atmosphere of argon. The solution was cooled to about −30° C. DIPT (2.34 g, 0.01 moles) followed by titanium (IV) isopropoxide (2.36 mL, 0.008 moles) was added to the reaction mixture. The reaction mixture was stirred at −30° C. for about 20 minutes. Crude 76 (42 g, ˜0.1 moles) in DCM (40 mL) was added to the reaction mixture and stirred for about 30 minutes. TBHP (40 mL, 0.2 moles) was added to the reaction mixture at −30° C. After complete addition of TBHP, the reaction mixture was stirred at −30° C. for about 5 hours to complete the reaction. The excess peroxide was quenched with aqueous sodium bisulfite (20 g). The mixture was filtered through a Buchner Funnel with a pad of diatomaceous earth (Hyflo Celite®). The filtrate was washed with saturated NaHCO3, solution (100 mL) and brine (100 mL). The organic layer was concentrated in vacuo to give the crude title compound (60 g, >100% material balance) as an oil.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:8][C:7]2[C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH:5]=1)O.[Br-:17].[C:18]1([PH+:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br-:17].[CH3:13][C:12]1([CH3:14])[C:6]2[CH:5]=[C:4]([CH:2]([P+:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:1])[S:8][C:7]=2[C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11]1
Reactant: CC(O)c1cc2c(s1)C(C)(C)CCC2(C)C
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CC#N
Product: CC(c1cc2c(s1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 103.4 %

Procedure:
20.2 g of 4,5,6,7-tetrahydro-α,4,4,7,7-pentamethylbenzo[b]thiophene-methanol are dissolved in 260 ml of acetonitrile and the solution is treated with 29.2 g of triphenylphosphonium bromide. After stirring at 50° C. for 3 hours, the mixture is evaporated to dryness, the residue is taken up with 80% aqueous ethanol and extracted twice with hexane. The ethanol phase is evaporated, the residue is dissolved in methylene chloride, the solution is dried over sodium sulphate and evaporated. There are obtained 49.4 g of [1-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)ethyl]triphenylphosphonium bromide as an amorphous white powder.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:16][CH:17]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH2:18][CH2:19][CH3:20])(=[O:15])[CH2:13][CH3:14]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:16][CH:17]([O:21][C:22]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:23])[CH2:18][CH2:19][CH3:20])(=[O:15])[CH2:13][CH3:14]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCC(OC(=O)CC)OC(=O)ON1C(=O)CCC1=O
Solvent: O
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Product: CCCC(OC(=O)CC)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]butyl propanoate (686 mg, 2.38 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 34 (144 mg, 18% yield) as a brittle off-white solid after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 5H), 1.01 (t, J=7.2 Hz, 3H), 1.17-1.38 (br. m, 5H), 1.63-1.73 (br. m, 4H), 1.84-1.92 (br. m, 2H), 2.10 (tt, J=12.0, 3.6 Hz, 1H), 2.22-2.38 (m, 2H), 2.75-2.87 (m, 2H), 6.60 (t, J=6.0 Hz, 1H), 7.42 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 352.18 (M+Na)+; 328.14 (M−H)−.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([O:30]C)=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[Cl-].[NH+]1C=CC=CC=1.Cl>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([OH:30])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(OC)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1cccc(COc2cnc(O)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 8 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((6-methoxy-5-neopentylpyridin-3-yl)oxy)methyl)phenyl)propanoate (2.86 g) in DMF (20 mL) was added pyridinium chloride (7.77 g), and the mixture was stirred at 100° C. for 3 hr. To the reaction mixture was added 1N hydrochloric acid (100 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was crystallized from diisopropyl ether to give the title compound (220 mg) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1c(F)cc(F)cc1F
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2c(F)cc(F)cc2F)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,4,6-trifluorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (1.0 mg) with purity >90%. MS (pos) m/z 381.4.