Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][O:91][CH2:92][CH2:93][P:94](=[O:101])([O:98][CH2:99][CH3:100])[O:95][CH2:96][CH3:97]>C(Cl)Cl>[CH2:99]([O:98][P:94]([CH2:93][CH2:92][O:91][CH2:90][CH2:89][O:88][CH2:87][CH2:86][O:85][CH2:84][CH2:83][NH:82][C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:101])[O:95][CH2:96][CH3:97])[CH3:100]
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCCCC
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)NCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoic acid (15, 1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (2.4 eq), followed by diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.2 eq, from example 18, step 4). The reaction was stirred at room temperature for 4 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM to afford the title compound as a clear viscous oil.
Reaction SMILES: [Si](Cl)(Cl)(Cl)Cl.[C:6]([OH:9])(=[O:8])[CH3:7].[C:10]([O:13]CC)(=[O:12])[CH3:11].[SiH4:16]>C(O)C>[C:6]([O:9][Si:16]([O:13][C:10](=[O:12])[CH3:11])([O:9][C:6](=[O:8])[CH3:7])[O:8][C:6](=[O:9])[CH3:7])(=[O:8])[CH3:7]
Reactant: [SiH4]
Reactant: CC(=O)O
Reactant: CCOC(C)=O
Agent: Cl[Si](Cl)(Cl)Cl
Solvent: CCO
Product: CC(=O)O[Si](OC(C)=O)(OC(C)=O)OC(C)=O
Temperature: 25 °C

Procedure:
Tetraacetoxysilane was prepared by the reaction of 125 g of silicon tetrachloride and 400 g of acetic acid as blended and stirred at room temperature. When the evolution of hydrogen chloride gas had ceased with precipitation of white crystalline tetraacetoxysilane, the unreacted acetic acid was removed by stripping under a reduced pressure and the residue was dissolved in 300 g of ethyl alcohol. The reaction between the tetraacetoxysilane and ethyl alcohol was carried out by heating the above reaction mixture at 60° C. with agitation for 10 hours. The formation of large amounts of ethyl acetate and hydroxy-containing silane compounds was detected in the resultant reaction mixture which had a solid content of 5.9% by weight upon dilution by adding 120 g of ethyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([N+:22]([O-])=O)[C:3]=1[O:25][CH3:26].O>C(O)(=O)C.[Fe]>[NH2:22][C:4]1[C:3]([O:25][CH3:26])=[C:2]([Cl:1])[CH:7]=[C:6]([F:8])[C:5]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]1=[O:21]
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
3-(4-Chloro-6-fluoro-3-methoxy-2-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (7.5 g, 18.9 mmol) was dissolved in acetic acid (75 ml) and 4.2 g (75.6 mmol) of iron powder was added. The solution was stirred at ambient temperature under nitrogen atmosphere for 6 hr and water was added. Extraction was carried out with ethyl acetate. Organic layer was washed with water, brine, and dried with anhydrous sodium sulfate followed by evaporation to afford the title compound (6.8 g).
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([CH2:16][CH3:17])=[N:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:22][C@H:23]1[O:25][CH2:24]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:22]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([CH2:16][CH3:17])=[N:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:23]1[O:25][CH2:24]1
Reactant: CCc1nnc(-c2cc3c(O)cccc3o2)o1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1nnc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)o1
Yield: 98.6 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(4-hydroxybenzo(b)furan-2-yl)-5-ethyl-1,3,4-oxadiazole (3.1 g) obtained in Starting Material Synthesis Example 75, (S)-glycidyl nosylate (3.5 g) and potassium carbonate (5.6 g), the title compound (3.8 g) was obtained as pale-yellow crystals.
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][C:21]=1[O:29][CH3:30].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][C:21]=3[O:29][CH3:30])[CH2:3][CH2:2]2)=[N:8]1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 122.8 %

Procedure:
A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]-ethanone (4.3 g, 20.0 mmol), K2CO3 (3.0 g, 21.8 mmol), acetonitrile (125 ml) and a catalytic amount of KI was heated to reflux and stirred under nitrogen for 24 hours. At this point, an additional amount of K2CO3 (1.0 g, 7.2 mmol) and alkylating agent (0.4 g, 1.7 mmol) was added to the reaction mixture and heating at reflux was resumed for 24 hours. The reaction was cooled to ambient temperature and filtered. The filter cake was washed with acetonitrile and the filtrate was concentrated to afford a dark oil. The oil was extracted with methylene chloride, and the organic extract was washed with water, dried with MgSO4 and concentrated to yield 9.2 g of an oil. Purification by preparative HPLC (Waters Associates Prep LC/System 500 utilizing 2 silica gel columns and 3% methanol/methylene chloride as eluent) provided 3.8 g of a soft, beige gum, which readily solidified. The compound was recrystallized twice from ethanol to give 2.1 g (28%) of 1-[4-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethoxyl-3-methoxyphenyl]ethanone as a beige solid, m.p.=98-100° C.
Reaction SMILES: [OH-].[Na+].Br[CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[OH:6]>C(OCC)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C@H:5]2[CH2:4][O:6]2)=[CH:8][CH:9]=1
Reactant: O[C@H](CBr)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Brc1ccc([C@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.5 %

Procedure:
Aqueous sodium hydroxide (1M, 400 ml) was added to 2-bromo-(1S)-1-(4-bromophenyl)ethanol (77.0 g) in diethyl ether (400 ml) and stirred at room temperature for 5 hours. The organic layer was separated and water layer was extracted with ether. Combined organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent yielded (2S)-2-(4-bromophenyl)oxirane (55.0 g) as a pale brown oil.
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:8])[CH2:6][F:7])C.[C:9]([NH:12][CH:13]([CH2:17][C:18]#[C:19][CH2:20][NH2:21])[C:14]([OH:16])=[O:15])(=[O:11])[CH3:10].C1CCN2C(=NCCC2)CC1>C(O)C>[ClH:1].[C:9]([NH:12][CH:13]([CH2:17][C:18]#[C:19][CH2:20][NH:21][C:5](=[NH:8])[CH2:6][F:7])[C:14]([OH:16])=[O:15])(=[O:11])[CH3:10]
Reactant: CCOC(=N)CF
Reactant: CC(=O)NC(CC#CCN)C(=O)O
Agent: Cl
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)NC(CC#CCNC(=N)CF)C(=O)O
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Ex-8h) 2.86 g of ethylfluoroacetimidate hydrochloride, 1 equivalent of 2-acetylamino-6-amino-4-hexynoic acid and 6.84 g of DBU are taken up in 200 mL absolute ethanol and stirred for 16 h at 20° C. under argon. Solvent is removed under vacuum and 100 mL water is added. This reaction mixture is filtered through acidic ion exchange column and the product is eluted with 10% pyridine/water. (±)-2-Acetylamino-6-(1-imino-2-fluoroethylamino)-hex-4-ynoic acid hydrochloride is obtained by removing the solvent under vacuum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7](Cl)(=[O:9])=[O:8].[C:11]([O:15][C:16](=[O:27])[NH:17][C@@H:18]1[CH2:24][CH2:23][C@@H:22]([CH3:25])[NH:21][CH2:20][C@H:19]1[OH:26])([CH3:14])([CH3:13])[CH3:12].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CCOC(C)=O>[C:11]([O:15][C:16](=[O:27])[NH:17][C@@H:18]1[CH2:24][CH2:23][C@@H:22]([CH3:25])[N:21]([S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:9])=[O:8])[CH2:20][C@H:19]1[OH:26])([CH3:13])([CH3:12])[CH3:14]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)CN1S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
Pyridine-2-sulfonyl chloride (0.55 g, 3.1 mmol) was added to a solution ((3R,4R,7R)-3-Hydroxy-7-methyl-azepan-4-yl)-carbamic acid tert-butyl ester (0.58 g, 0.2.4 mmol), sodium bicarbonate (0.84 g, 10 mmol) in CH2Cl2 (10 ml) and H2O (3 ml) and was stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc (100 ml), washed with H2O, brine, dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 45:55 EtOAC/hexanes) to yield the title compound (0.6 g, 65%): Electrospray mass spec: M+H+=386.27.
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]\Cl.C(N)CCC.[O:10]([CH2:17][C:18]#[CH:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Cu]I.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.C1COCC1>[Cl:1]/[CH:2]=[CH:3]\[C:19]#[C:18][CH2:17][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#CCOc1ccccc1
Reactant: Cl/C=C\Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: C1CCOC1
Product: Cl/C=C\C#CCOc1ccccc1
Reaction time: 5.5 h
Yield: 67.6 %

Procedure:
To a 1 L flask under Argon was added CuI (7.86 g, 41.2 mmol) and Pd(PPh3)4 (5 g, 4.3 mmol). The catalyst was covered With 600 mL of degassed THF, cis-1,2-dichloroethylene (50 g, 516 mmol), and butylamine (68 mL, 688 mmol). Phenoxy-2-propyne (45g, 340 mmol) was added neat over 10 min and the reaction mixture stirred for 5.5 h. Air was bubbled through the reaction mixture for 15 min and the reaction filtered through a pad of celite and washed with pentane. The filtrate was washed with water and brine and the aqueous fractions extracted with ether. The organic fractions were combined, dried (MgSO4), filtered through celite and concentrated. The residue was chromatographed over silica gel (hexane) to give 44.3 g of a yellow oil (67%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21]Br)=[O:4].[N:23]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21][N:32]1[CH2:33][CH2:34][CH:29]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:30][CH2:31]1)=[O:4]
Reactant: COC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2ccccc2)nc2ccccc12
Temperature: 50 °C
Yield: 56.4 %

Procedure:
5 g (14 mmol) of 3-bromomethyl-2-phenyl-quinoline-4-carboxylic acid methyl ester (compound of Description 2), 2.9 g, (15.4 mmol) of 90% [1,4′]Bipiperidinyl (Aldrich), 2.7 ml (15.4 mmol) of ethyl-diisopropyl-amine were dissolved in 100 ml of dry THF and the mixture was stirred for one night at 50° C. The solvent was concentrated, the residue was dissolved in CH2Cl2, washed with water, and the organic phase was dried over MgSO4. After concentration of the solvent, the residue was purified by flash chromatography over 160 g of silicagel (eluting with CH2Cl2/MeOH/NH4OH:95/5/0.5) affording 3.5 g (yield 56%) of the title compound as a white solid.
Reaction SMILES: [C:1]1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=C[CH:2]=1.N[C@H](C(OCC)=O)CCC(OCC)=O.C([C:34]1[CH:55]=[CH:54][CH:53]=[CH:52][C:35]=1[C:36]([NH:38][C@H:39]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:37])#C.[K+].[Br-]>C(Cl)Cl.CO>[C:1]([C:54]1[CH:55]=[CH:34][C:35]([C:36]([NH:38][C@H:39]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:37])=[CH:52][CH:53]=1)#[CH:2]
Reactant: C#Cc1ccccc1C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC
Reactant: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Agent: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.55 g of 4-ethynylbenzoic acid (obtained from tert.-butyl 4-ethynylbenzoate in 84% yield by hydrolysis with trifluoroacetic acid) in 50 ml of anhydrous ether and 25 ml of anhydrous tetrahydrofuran is added 1.58 ml of triethylamine. This is followed by 1.00 g of phenyl N-phenylphosphoramidochloridate. After stirring the reaction mixture at room temperature under nitrogen for 0.5 hour, 0.90 g of diethyl L-glutamate is added in one portion. The mixture is allowed to stir for another 8 hrs. After a workup, the residue is subjected to column chromatography using a 1% methanol:methylene chloride mixture as the eluent. The major fraction isolated from the column contained 0.68 g (54%) of diethyl N-(ethynylbenzoyl)-L-glutamate as an oil which slowly solidified: NMR (CDCl3, 300 MHz) delta 1.25 (t, 3H, J=6.9 Hz), 1.33 (t, 3H, J=6.9 Hz), 2.11-2.60 (m, 4H), 3.23 (s, 1H), 4.09 (q, 2H, J=6.9 Hz), 4.27 (l, 2H, J=6.9 Hz), 4.80 (m, 1H), 7.12 (d, 1H, J=7.2 Hz), 7.59 (d, 2H, J=8.4 Hz), 7.81 (d, 2H, J=8.4 Hz); IR (KBr) 3330, 3280, 2990, 1735, 1640, 1520, 1380, 1200, 1105, 1020, 855, and 770 cm- 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](O)([CH3:24])[CH3:23])=[C:18]([CH3:26])[CH:17]=2)=[C:12]([CH:27]([CH3:29])[CH3:28])[N:11]=[N:10]1.[SH:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>ClCCCl.[I-].[Zn+2].[I-]>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[CH:40][C:31]([S:30][C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]3[N:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:10]=[N:11][C:12]=3[CH:27]([CH3:28])[CH3:29])=[CH:17][C:18]=2[CH3:26])([CH3:23])[CH3:24])=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1C(C)(C)O
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: COC(=O)c1ccc(SC(C)(C)c2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
To an ambient temperature solution of 2-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-propan-2-ol (100 mg, 0.230 mmol) in DCE (1 mL) is added zinc iodide (37 mg, 0.115 mmol). The reaction is stirred at room temperature for 10 min. A solution of methyl 4-mercaptobenzoate (38 mg, 0.225 mmol) in DCE (1 mL) is added and the reaction is stirred overnight at room temperature. The reaction is concentrated under reduced pressure and the residue is chromatographed (SiO2 40 g, 0% to 30% EtOAC/Hexane to yield 4-(1-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-methyl-ethylsulfanyl)-benzoic acid methyl ester (114 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 7.81 (d, 2H, J=7.9 Hz), 7.52-7.39 (m, 3H), 7.22 (s, 1H), 7.16 (d, 2H, J=7.8 Hz), 7.11 (d, 1H, J=8.4 Hz), 6.63 (d, 1H, J=8.4 Hz), 4.90 (s, 2H), 3.90 (s, 3H), 3.23 (sept, 1H, J=6.6 Hz), 2.01 (s, 3H), 1.64 (s, 6H), 1.46 (d, 6H, J=6.6 Hz).
Reaction SMILES: FC(F)(F)S(OC)(=O)=O.[F:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:14][N:15]([CH3:19])[C:16](=S)[CH3:17].[C:24]([O:28][C:29](=[O:42])[NH:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([NH2:40])[CH:38]=2)[CH2:33][CH:32]1[OH:41])([CH3:27])([CH3:26])[CH3:25].N1C=CC=CC=1>C(Cl)Cl>[C:24]([O:28][C:29](=[O:42])[NH:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([N:40]=[C:16]([N:15]([CH2:14][C:13]3[CH:20]=[CH:21][C:22]([F:23])=[C:11]([F:10])[CH:12]=3)[CH3:19])[CH3:17])[CH:38]=2)[CH2:33][CH:32]1[OH:41])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(=S)N(C)Cc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)NC1c2cc(N)ccc2CC1O
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=Nc1ccc2c(c1)C(NC(=O)OC(C)(C)C)C(O)C2)N(C)Cc1ccc(F)c(F)c1
Reaction time: 0.5 h
Yield: 298.9 %

Procedure:
Add methyl trifluoromethanesulfonate (0.750 g, 3.49 mmol) to a solution of N-(3,4-difluorobenzyl)-N-methylthioacetamide (0.145 g, 0.736 mmol) in 10 mL of CH2Cl2 at room temperature. Stir the mixture for 30 minutes and remove the solvent under reduced pressure. Then add (6-amino-2-hydroxyindan-1-yl)-carbamic acid t-butyl ester (0.78 g, 2.97 mmol) followed by 5 mL of pyridine. The resulting mixture is stirred for 12 h. After pyridine is evaporated, the residue is purified by column chromatograph (silica gel, 3% MeOH in CH2Cl2) to give 0.98 g of (6-(1-((3,4-difluorobenzyl)-methyl-amino)-ethylideneamino)-2-hydroxyindan-1-yl)-carbamic acid tert-butyl ester as a white solid: MS 446 (MH+).
Reaction SMILES: CC(O)[CH2:3][NH:4]CC(O)C.N[C:11]1[CH:22]=[CH:21][C:14]([C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:13][CH:12]=1.N[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=C[CH:25]=1>O>[CH:24]1[C:33]([CH2:32][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=[C:18]([O:17][C:15]([C@@H:14]2[CH2:21][CH2:22][C@@H:11]([CH2:3][NH2:4])[CH2:12][CH2:13]2)=[O:16])[CH:25]=1
Reactant: CCCOC(=O)c1ccc(N)cc1
Reactant: CC(O)CNCC(C)O
Reactant: COC(=O)c1ccc(N)cc1
Solvent: O
Product: NC[C@H]1CC[C@H](C(=O)Oc2ccc(CCC(=O)O)cc2)CC1
Temperature: 80 °C

Procedure:
A mixture comprising 100 grams of cetraxate hydrochloride, 10 grams of dibutyl adipate, 30 grams of propylene carbonate, 100 grams of olive oil, 30 grams of isopropyl myristate, 30 grams of isotridecyl myristate, 30 grams of behenyl alcohol, 40 grams of cetyl palmitate, 30 grams of stearic acid, 30 grams of polyoxy-ethylene (5)-glyceryl stearate, 30 grams of poly-ethylene glycol mono-stearate and 10 grams of polyoxy-ethylene (2) cetyl ether was dissolved by heating at 82° C. or higher to thereby yield a homogeneous solution (a solution A). Separately, 20 grams of di-isopropanol amine, 50 grams of isoprene glycol, 1 gram of propyl p-aminobenzoate and 1 gram of methyl p-aminobenzoate were added to ca. 450 ml of purified water, and the resulting mixture was warmed to 80° C. to thereby form a homogeneous dispersion (a dispersion B). While the dispersion B was held at 80° C., the solution A was added gradually to the dispersion B with vigorous stirring, thereby forming an emulsion. After completion of the addition of the solution A, the heating was suspended and allowed to cool to 60° to 55° C. Then, while stirring the resulting mixture at room temperature, purified water was added to the mixture cooled to 60° to 55° C. so as to make its total weight to 1 kg. The cream product was allowed to stand and bubbles were removed, followed by filling the cream in containers.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH3:5][C:6](=[C:8]([CH3:10])[CH3:9])[CH3:7].S(=O)(=O)(O)O.[OH-].[Na+]>O.C(O)(=O)C>[CH3:5][C:6]([NH:1][C:2]([NH2:4])=[O:3])([CH:8]([CH3:10])[CH3:9])[CH3:7]
Reactant: NC(N)=O
Reactant: CC(C)=C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(C)(C)NC(N)=O
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To the mixture of 288 mL glacial acetic acid, 412 g (6.86 mole) urea and 288 g (3.43 mole) 2,3-dimethyl-2-butene, the solution of 412 mL concentrated sulfuric acid and 412 mL of glacial acetic acid was added dropwise under stirring, while maintaining the reaction temperature at the range of 45° C. to 50° C., then stirred for 5 hours at the temperature of 50-55° C. The mixture stood overnight. Next day, the mixture was reacted for another 7 hours at the temperature of 50-55° C., then poured into the solution of 1200 g (30 mole) sodium hydroxide in 8 L glacial water. The resulting solid was filtered, washed with water (200 mL×5) and dried to give 404 g (yield 81.8%) N-(2,3-dimethyl-2-butyl)urea as white solid, mp 175-176° C. Elemental analysis for C7H16N2O(%): Calculated C, 58.30; H, 11.18; N, 19.42. Found C, 58.70; H, 11.54; N, 19.25. 1H-NMR(CDCl3, ppm) 0.88-0.91(d, 6H, 2×CH3), 1.26(s, 6H, 2×CH3), 2.20-2.26(m, 1H, CH), 4,45(br, 2H), 4.65(br, 1H). MS(m/z) 145.0, 144.0(M+), 143.0, 129.1, 101.0, 86.1, 69.1, 58.0(B).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([O-:17])=[O:16])[C:6](=[O:21])[C@@:5]12[CH2:23][C:22]1([CH3:25])[CH3:24].Cl>O1CCCC1.[OH-].[Na+].O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])[C:6](=[O:21])[C:5]12[CH2:23][C:22]1([CH3:25])[CH3:24]
Reactant: CC1(C)C[C@]12C(=O)N(Cc1cccc(C(=O)[O-])c1)c1ccc(F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC12C(=O)N(Cc1cccc(C(=O)O)c1)c1ccc(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
A mixture of (R) and (S)-3-((5′-fluoro-2,2-dimethyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoate (850 mg, 2.4 mmol) in tetrahydrofuran (10 mL) and 30% sodium hydroxide in water (5 mL) was stirred at 25° C. for 16 hours. The mixture was neutralized with a 2 N aqueous hydrochloric acid solution, diluted with ethyl acetate (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% trifluoro-acetic acid in water) afforded the title compound as white solid (410 mg, 50%): LC/MS m/e calcd. for C20H15FNO3 (M+H)+: 340.37, observed: 340.2; LC/MS m/e calcd. for C20H18FNO3: 339, observed (M+H)+: 340.1 1H NMR (400 MHz, DMSO-d6) δppm 1.37 (s, 3 H) 1.48 (s, 3 H) 1.76 (d, J=4.29 Hz, 1 H) 1.88 (d, J=4.29 Hz, 1 H) 5.04 (dd, 2 H) 6.91-7.08 (m, 2 H) 7.17 (dd, J=9.35, 2.53 Hz, 1 H) 7.44-7.57 (m, 2 H) 7.80-7.93 (m, 2H) 12.99 (s, 1 H).