Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[Cl:25].[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[Cl:25][C:3]1[C:2]([C:31]2[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)=[N:7][C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(Cl)c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2Cl)cn1
Temperature: 120 °C
Yield: 51.1 %

Procedure:
N-(6-Bromo-5-chloropyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (259 mg, 0.600 mmol) was dissolved in 6 mL of 1,2-dimethoxyethane (DME) in a microwave reactor tube. 6-Methoxypyridin-3-ylboronic acid (138 mg, 0.900 mmol), 0.6 mL of an aqueous 2 M potassium carbonate solution, and tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4, 34.7 mg, 0.0300 mmol) were added and the reaction mixture was heated at 120° C. in a microwave reactor for 20 minutes. The resulting material was cooled to room temperature, filtered, and the layers were separated. The crude product was evaporated to dryness and then purified on 40 g of silica gel utilizing a gradient of 0-100% ethyl acetate in hexanes to yield N-(3-chloro-6′-methoxy-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane carboxamide (141 mg, 51%) as a colorless oil. ESI-MS m/z calc. 459.1. found; 459.9 (M+1)+ Retention time 2.26 minutes.
Reaction SMILES: [CH:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:16]>C(Cl)Cl>[CH:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][Br:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrP(Br)Br
Reactant: OCc1ccccc1C1CCCCC1
Solvent: ClCCl
Product: BrCc1ccccc1C1CCCCC1
Yield: 79 %

Procedure:
According to example 17, 3.36 g of 2-cyclohexylbenzyl alcohol was treated with 0.59 mL of PBr3 in 25 mL of anhydrous CH2Cl2 to afford 3.90 g of crude product (90% pure by 1H-NMR). This material was vacuum distilled via short path (1.0 mmHg, 117-120° C.) to afford 3.54 g (79%) of 2-cyclohexylbenzyl bromide as a clear liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([N:27]([CH3:44])[NH:28][C:29](=[O:43])[CH2:30][CH2:31][NH:32][C:33]([NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([N:27]([CH3:44])[NH:28][C:29](=[O:43])[CH2:30][CH2:31][NH:32][C:33]([NH:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(NC(=O)CCNC(=O)NCc1ccccc1)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(NC(=O)CCNC(=O)NCc1ccccc1)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-benzyl 3-(4-(benzyloxy)phenyl)-2-(2-(3-(3-benzylureido)propanoyl)-1-methylhydrazinyl)propanoate (Compound XVII-1) 149 mg (0.25 mmol) in tetrahydrofuran:methanol=1:1.5 1.5 ml, a solution of lithium hydroxide monohydrate 16 mg in water 0.3 ml was added and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was cooled to 0° C. and 1N HCl aq. 10 ml was added and the mixture was extracted with ethyl acetate 20 ml. The organic phase was washed with water 20 ml and brine 20 ml and dried over magnesium sulfate and filtered. The mother solution was concentrated in vacuo to obtain the title compound. The residue was used without further purification.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)([O-:4])=[O:3].Br[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([N:17]2[CH2:18][CH2:19][N:20]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)[CH2:21][CH2:22]2)[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)N1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)N1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 60 °C

Procedure:
A mixture of methyl(2S)-3-(4-nitrophenyl)-2-piperazin-1-ylpropanoate hydrochloride (100 mg, 0.30 mmol), 1-(2-bromoethyl)-4-nitrobenzene (77 mg, 0.33 mmol), and triethylamine (92 mg, 0.91 mmol) in DMF was heated to 60° C. for 16 hours. LC showed some product. More 1-(2-bromoethyl)-4-nitrobenzene (77 mg, 0.33 mmol) and triethylamine (92 mg, 0.91 mmol) were added to the reaction, and the mixture was allowed to heat for another 24 hours. LC showed complete reaction at that point. The reaction was diluted with EtOAc, washed with water, and purified by HPLC to deliver the desired product. LC-MS (IE, m/z): 443 [M+1]+. (0.51 μM)
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1O.[C:13]([O-:16])([O-])=O.[K+].[K+].[CH3:19]I>CC(C)=O>[Br:1][C:2]1[C:3]([O:16][CH3:13])=[CH:4][CH:5]=[C:6]2[C:7]=1[CH:8]=[CH:19][NH:9]2
Reactant: Cc1c([N+](=O)[O-])ccc(O)c1Br
Reactant: O=C([O-])[O-]
Reactant: CI
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2[nH]ccc2c1Br
Temperature: 90 °C
Reaction time: 48 h
Yield: 15 %

Procedure:
2-Bromo-3-methyl-4-nitro-phenol, (100 g, 0.43 mol, Intermediate 72) was dissolved in acetone (500 mL), grinded K2CO3, 119 g (0.86 mol) and methyl iodide, 83 g (0.59 mol) were added and the reaction mixture was heated at reflux for one hour. The suspension was filtered and the solvent was removed at reduced pressure to give a brown spontaneously crystallizing oil that was used directly in the next synthetic step. Quantitative yield. The crude methoxy ether, 106 g (0.43 mol) was dissolved in dry DMF (350 mL), dimethylformamid dimethylacetal[DMFDMA], 103 g (0.87 mol) was added and the reaction was heated and stirred at 90° C. for two days. During the next three days were each day a portion of DMFDMA, 20 g (0.17 mol) added while the mixture was continued to be heated. The solvent was removed at reduced pressure and the black/red oily residue was dissolved in HOAc (300 mL). The viscous solution was carefully added to a well stirred suspension of iron powder, 72 g (1.3 mol) in warm HOAc (700 mL) at such rate the exothermic reaction allowed. The thick reaction mixture was heated at reflux for one hour, the solids were filtered of and the solvent was removed at reduced pressure. The black residue was dissolved in warm CHCl3 (700 mL), heptane (600 mL) and 50 g of silica gel was added, the mixture was filtered through a pad of silica, washed with 50/50 CHC13/heptane and the solvent was again removed at reduced pressure. The black residue was chromatographed on a column of silica with petroleum ether/EtOAc 90/10 as eluent to give 14.9 g (15%) of the target compound as a olive green solid. MS (ESI+) for C9H8BrNO m/z 226/228 (M+H)+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][CH:11]([C:13]2[CH:14]=[C:15]([C:30]([O:32]C)=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][C:18]3=[O:29])[CH3:12])[CH:7]=[CH:8][CH:9]=1.C1COCC1>CO>[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][CH:11]([C:13]2[CH:14]=[C:15]([C:30]([OH:32])=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:19][C:18]3=[O:29])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(C(C)Nc2cccc(Cl)c2F)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Sodium hydroxide (0.217 mL, 0.43 mmol) was added to a stirred solution of methyl 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (200 mg, 0.43 mmol) dissolved in MeOH (2 mL). The resulting solution was stirred at room temperature for 16 hrs. THF was added and the resulting solution was stirred at 50° C. for 8 hrs. The pH was adjusted to 3 with HC12N, the solvent was removed under vacuum and the residue diluted with H2O. The solid was collected by filtration, washed with water and dried to give 8-(1-(3-chloro-2-fluorophenylamino) ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (171 mg, 88%) as a white solid. Mass Spectrum: M+H+ 447.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:3]=1[O:4][CH2:5][C@H:6]1[O:11][CH2:10][C@@H:9]([CH2:12][OH:13])[N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1.C(C1NC=CN=1)(C1NC=CN=1)=[O:29].[N:40]1[CH:45]=CC=CC=1>>[C:45]([O:13][CH2:12][C@H:9]1[N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:7][C@@H:6]([CH2:5][O:4][C:3]2[C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=[CH:24][C:2]=2[F:1])[O:11][CH2:10]1)(=[O:29])[NH2:40]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](COc2c(F)cccc2[N+](=O)[O-])OC[C@H]1CO
Reactant: c1ccncc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Product: CC(C)(C)OC(=O)N1C[C@@H](COc2c(F)cccc2[N+](=O)[O-])OC[C@H]1COC(N)=O
Temperature: 60 °C

Procedure:
To a solution of the product from step 3 (1.6 g, 4.1 mmol) in pyridine (12 mL) was added carbonyl diimidazole (2.0 g, 12.3 mmol) and the mixture was heated in a sealed tube at 60° C. for 2 h. The reaction mixture was cooled to ambient temperature and NH3 gas was bubbled into the solution for 5 min, and the mixture was heated in a sealed tube at 60° C. for 16 h. The reaction was cooled to ambient temperature and the solvent was concentrated under reduced pressure. The residue was purified on a 24 g SiO2 column using a gradient elution of 20-70% EtOAc in hexanes. Fractions containing product were combined and the solvents were removed under reduced pressure to provide the product (1.4 g) as a colorless oil. LC MS: RT=3.60 min, M+H=430 (6 min gradient).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)O[C:2]2=[O:3].CSC(=N)[NH:16][S:17]([CH2:20]Cl)(=[O:19])=[O:18].C(#[N:25])C>CN(C1C=CN=CC=1)C>[NH:16]1[C:5]2=[N:6][C:7]3[C:1]([C:2](=[O:3])[N:25]2[CH2:20][S:17]1(=[O:18])=[O:19])=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: CC#N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CSC(=N)NS(=O)(=O)CCl
Agent: CN(C)c1ccncc1
Product: O=c1c2ccccc2nc2n1CS(=O)(=O)N2

Procedure:
To a stirred slurry of isatoic anhydride (3.10 g, 19 mmol) and S-methyl-N-(chloromethanesulfonyl)isothiourea (3.85 g, 19 mmol) in acetonitrile (30 ml) under nitrogen is added 4-(N,N-dimethylamino)pyridine (2.32 g, 19 mmol). The mixture is refluxed under nitrogen for 16 hr, concentrated, then worked up as in Example 4 above. Recrystallization from DMF provided the title compound as a white solid, mp >300° C. (1.32 g, 29%).
Reaction SMILES: [NH:1]=[C:2]=N.[Cl:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[C:17]=1[O:29][Si](C(C)(C)C)(C)C)=S.CS(Cl)(=O)=O.C([N:44](CC)CC)C>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]([C:2]#[N:1])[C:13]([NH:12][C:6]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=2[Cl:4])=[NH:44])=[C:17]([OH:29])[C:18]=1[S:23]([N:26]([CH3:28])[CH3:27])(=[O:24])=[O:25]
Reactant: N=C=N
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccc(F)cc2Cl)c1O[Si](C)(C)C(C)(C)C
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N(C#N)C(=N)Nc2ccc(F)cc2Cl)c1O

Procedure:
Following the general procedure for carbodiimide formation outlined in example 12, N-(2-chloro4-fluorophenyl)-N′-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]thiourea (420 mg, 0.76 mmol), methanesulfonyl chloride (0.11 mL, 1.52 mmol) and triethylamine (0.22 mL, 1.52 mmol) were reacted to form the desired product (420 mg, crude). 1H NMR (CDCl3) δ 0.36 (s, 6H), 1.02 (s, 9H), 2.89 (s, 6H), 6.99 (m, 1H), 7.08 (d, 1H), 7.19 (m, 2H), 7.33 (d, 1H).
Reaction SMILES: N[C@@H:2]([CH2:9][C:10]([OH:12])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:13][C@H](CC(O)=O)C1C=CC=CC=1>>[NH2:13][C@H:9]([C:10]([OH:12])=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N[C@H](CC(=O)O)c1ccccc1
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The optical purity of (S)-β-phenylalanine was calculated from the peak area of the chromatogram obtained under analysis conditions illustrated in (1) above. Furthermore, the reaction yield of (S)-β-phenylalaninewas calculated from the peak area of the chromatogram obtained under analysis conditions illustrated in (2) above. Concretely, when the reaction solution contained a solid of β-phenylalanine or a solid of L-phenylalanine, a solution obtained by collecting a part of the reaction solution containing these solids, mixing with a 0.2 mol/l hydrochloric acid solution and dissolving these solids was analyzed. The amount (g) of (S)-β-phenylalanine synthesized was calculated from the peak area of the chromatogram using a calibration curve of (S)-β-phenylalanine standards to determine the yield from (Formula 1). Yield (%)=Amount of (S)-β-phenylalanine synthesized (g)/Amount of L-phenylalanine added (g)×100  (Formula 1)
Reaction SMILES: [C:1]([O:42]N1C(=O)CCC1=O)(=O)[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][C:31]([O:33]N1C(=O)CCC1=O)=O.[NH2:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][O:80][CH2:81][CH2:82][NH:83][S:84]([C:87]1[CH:92]=[CH:91][CH:90]=[C:89]([CH:93]2[C:102]3[C:97](=[C:98]([Cl:104])[CH:99]=[C:100]([Cl:103])[CH:101]=3)[CH2:96][N:95]([CH3:105])[CH2:94]2)[CH:88]=1)(=[O:86])=[O:85]>>[Cl:103][C:100]1[CH:101]=[C:102]2[C:97](=[C:98]([Cl:104])[CH:99]=1)[CH2:96][N:95]([CH3:105])[CH2:94][CH:93]2[C:89]1[CH:88]=[C:87]([S:84]([NH:83][CH2:82][CH2:81][O:80][CH2:79][CH2:78][O:77][CH2:76][CH2:75][O:74][CH2:73][CH2:72][O:71][CH2:70][CH2:69][O:68][CH2:67][CH2:66][O:65][CH2:64][CH2:63][O:62][CH2:61][CH2:60][O:59][CH2:58][CH2:57][O:56][CH2:55][CH2:54][O:53][CH2:52][CH2:51][NH:50][C:31](=[O:33])[CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][C:1]([NH:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][O:80][CH2:81][CH2:82][NH:83][S:84]([C:87]2[CH:92]=[CH:91][CH:90]=[C:89]([CH:93]3[C:102]4[C:97](=[C:98]([Cl:104])[CH:99]=[C:100]([Cl:103])[CH:101]=4)[CH2:96][N:95]([CH3:105])[CH2:94]3)[CH:88]=2)(=[O:86])=[O:85])=[O:42])(=[O:86])=[O:85])[CH:92]=[CH:91][CH:90]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN)c2)C1
Reactant: O=C(CCOCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Yield: 49.8 %

Procedure:
Compound 217 was prepared following the procedure outlined in Example 168 using bis(2,5-dioxopyrrolidin-1-yl) 4,7,10,13,16,19,22,25,28-nonaoxahentriacontane-1,31-dioate (69.1 mg, 0.0975 mmol) and N-(32-amino-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 214, 166.2 mg, 0.195 mmol). Purification by preparative HPLC gave the title compound (106.3 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.88 (d, 2H), 7.76 (s, 2H), 7.66 (t, 2H), 7.56 (m, 4H), 6.86 (s, 2H), 3.90 (m, 2H), 3.82 (t, 2H), 3.76 (m, 6H), 3.62-3.41 (m, 28H), 3.38 (m, 6H), 3.35-3.28 (m, 56H), 3.15 (s, 6H), 3.05 (t, 4H), 2.43 (t, 4H). MS (m/z): 1094.37 [(M+2H)/2]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:56][CH2:55][C@@:54]2([CH3:57])[C@H:4]([CH2:5][C@@H:6]([OH:60])[C@@H:7]3[C@@H:53]2[CH2:52][C@H:51]([OH:58])[C@@:50]2([CH3:59])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:49])[CH2:13][CH2:14][C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[C:30]([Cl:31])=[CH:29][C:28]([NH:32][C:33](=[O:44])[C:34]([O:36]CC4C=CC=CC=4)=[O:35])=[CH:27][C:26]=3[Cl:45])=[CH:20][C:19]=2[CH:46]([CH3:48])[CH3:47])=[O:16])[CH2:3]1.[H][H]>C(O)C>[OH:1][C@@H:2]1[CH2:56][CH2:55][C@@:54]2([CH3:57])[C@H:4]([CH2:5][C@@H:6]([OH:60])[C@@H:7]3[C@@H:53]2[CH2:52][C@H:51]([OH:58])[C@@:50]2([CH3:59])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:49])[CH2:13][CH2:14][C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[C:26]([Cl:45])=[CH:27][C:28]([NH:32][C:33](=[O:44])[C:34]([OH:36])=[O:35])=[CH:29][C:30]=3[Cl:31])=[CH:20][C:19]=2[CH:46]([CH3:48])[CH3:47])=[O:16])[CH2:3]1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(NC(=O)C(=O)OCc3ccccc3)cc2Cl)ccc1OC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: [H][H]
Solvent: CCO
Product: CC(C)c1cc(Oc2c(Cl)cc(NC(=O)C(=O)O)cc2Cl)ccc1OC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C

Procedure:
4-{4-[(2-benzyloxy-1,2-dioxoethyl)amino]-2,6-dichlorophenoxy}-2-isopropylphenyl 3,7,12(3α, 5β,7α,12α)-trihydroxycholan-24-oate (260 mg) and 26 mg of 10% carbon in 50 ml ethanol are treated with hydrogen on a Parr shaker. Catalyst is removed by filtering through Celite and the filtrate is stripped to give 4-{2,6-dichloro-4-[(2-hydroxy-1,2-dioxoethyl)amino]phenoxy}-2-isopropylphenyl 3,7,12(3α,5β,7α,12α)-trihydroxycholan-24-oate, as an amorphane monohydrate, m.p. 180°-92° (dec.).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:20][F:21])([CH3:19])[C:4](=[O:18])[CH:5](Br)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][CH2:2][C:3]([CH2:20][F:21])([CH3:19])[C:4](=[O:18])[CH:5]([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1
Reactant: c1c[nH]cn1
Reactant: CC(CF)(CF)C(=O)C(Br)Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(CF)(CF)C(=O)C(Oc1cccc(C(F)(F)F)c1)n1ccnc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 48.6 %

Procedure:
135 g (0.36 mole) of 3,3-bisfluoromethyl-1-bromo-1-(3-trifluoromethyl-phenoxy)-butan-2-one in 400 ml of acetone were added dropwise to 24.5 g (0.36 mole) of imidazole and 55.3 g (0.4 mole) of potassium carbonate in 400 ml of acetone. The mixture was stirred at 50° C. for 6 hours and was then concentrated by distilling off the solvent under a waterpump vacuum. The oily residue was taken up in 800 ml of methylene chloride, the mixture was washed twice with 2,000 ml of water each time, the organic phase was stirred with active charcoal, filtered and dried over sodium sulphate and the solvent was distilled off. The oily residue was distilled under a high vacuum. 63.4 g (48.8% of theory) of 3,3-bisfluoromethyl-1-(imidazol-1-yl)-1-(3-trifluoromethyl-phenoxy)-butan-2-one of boiling point 169°-73° C./0.1 mm Hg were obtained.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH3:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>>[CH3:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH3:13]
Reactant: BrCCCCCCCCCCCCBr
Reactant: Cc1c(O)ccc2ccccc12
Agent: [Na]
Product: Cc1c(OCCCCCCCCCCCCOc2ccc3ccccc3c2C)ccc2ccccc12

Procedure:
Using the method of Example 1, the sodium salt of 2-hydroxy 1-methylnaphthalene can react with 1,12-dibromododecane to afford 1,12-bis(1-methyl-2-naphthoxy) dodecane.
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+]>>[N:36]1([CH2:7][CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:27]4[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]5[S:29][CH:30]=[CH:31][CH:32]=5)[CH:26]=4)[NH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: C1COCCN1
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)c[nH]c12
Yield: 55.5 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indole-7-carboxamide (40 mg, 0.13 mmol) and morpholine (0.069 mL, 0.65 mmol) were allowed to react in the presence of K2CO3 (74 mg, 0.65 mmol). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (37.3 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.[C:21](OCC)(=[O:23])C.O1CCCC1>C(O)(=O)C>[Cl:1][C:2]1[N:7]2[C:8]([CH:21]=[O:23])=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: Clc1cccc2nccn12
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=Cc1cnc2cccc(Cl)n12
Yield: 37 %

Procedure:
A solution of 5-chloroimidazo[1,2-a]pyridine (997 mg) and hexamethylenetetramine (1.8 g) in acetic acid (10 ml) was stirred at 90° C. for 5 hours. After the reaction mixture was allowed to cool, ethyl acetate-tetrahydrofuran (4/1; 200 ml) was added and the mixture was washed with saturated aqueous solution of sodium chloride. The organic layer was neutralized with 2N-aqueous solution of sodium hydroxide, dried over MgSO4, and concentrated. The resulting crystals were rinsed with diethyl ether to provide the title compound (440 mg, 37%).