Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O.O>[N:11]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN=[N+]=[N-])cc1
Temperature: 23 °C
Reaction time: 15 h
Yield: 100.2 %

Procedure:
To a stirred solution of 4-methoxybenzyl chloride (25.0 g, 156 mmol) in N,N-dimethylformamide (75 mL) was added sodium azide (11.5 g, 177 mmol). The reaction mixture was stirred at 23° C. for 15 h, then diluted with water (300 mL). The mixture was extracted with diethyl ether (3×75 mL) and the combined organic layers were washed with water (2×100 mL). The organic layer was dried (MgSO4), filtered, and evaporated under reduced pressure to afford the title compound (25.5 g) as a pale yellow oil. The title compound was used directly in the next step without further purification.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:21]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:21][C:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: c1cncc(-c2c3ccccc3cc3ccccc23)c1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2cccnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 26 h

Procedure:
In a 200 μL three-neck flask, 1.0 g (4.0 mmol) of 3-(9-anthryl)pyridine and 25 mL of carbon tetrachloride were placed. Then, 10 μL of a carbon tetrachloride solution containing 0.83 g (5.1 mmol) of bromine was dripped into the solution under nitrogen stream, and the solution was stirred for 26 hours at room temperature. After a certain period, 100 mL of a 1.0 M sodium thiosulfate solution was added into the mixture. Then, an aqueous layer of the mixture was extracted with chloroform. The obtained extracted solution and the organic layer were combined, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was condensed to give a solid. A chloroform solution of the solid was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and alumina, and the filtrate was condensed to give a solid. The solid was recrystallized with ethyl acetate/hexane, so that 0.74 g of target pale yellow powder was obtained in a yield of 53%.
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1)([CH3:3])[CH3:2].[C:9]1([OH:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[OH-].[K+]>>[C:9]1([O:19][CH2:5][CH:6]([OH:8])[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Oc1cccc2ccccc12
Reactant: CC(C)N1CC(O)C1
Agent: [K+]
Agent: [OH-]
Product: CC(C)NCC(O)COc1cccc2ccccc12
Temperature: 160 °C
Yield: 76 %

Procedure:
To a mixture of 11.5 parts of 1-(iso-propyl)-3-azetidinol and 15.8 parts of α-naphthol 0.2 part of 182°- potassium hydroxide was added, and the mixture was heated under nitrogen gas at 160° C. for 20 hours. The reaction mixture was cooled and then extracted with ether. The ether extract was washed with 2N-NaOH aqueous solution and then with water. The liquor was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was recrystallized for cyclohexane or subjected to distillation under reduced pressure. As a result 19.6 parts of 1-(α-naphthoxy)-3-(isopropylamino)-2-propanol having a melting point of 94°-96° C. and a boiling point of 158°-159° C. under 2.5 mm Hg were obtained. The yield was 76%. The residue of infra-red spectrum analysis of the product are as follows:
Reaction SMILES: [OH-].[K+:2].[CH3:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]3[N:29]=[N:28][NH:27][N:26]=3)=[CH:17][CH:18]=2)[C:10]([CH2:30][OH:31])=[C:9]([Cl:32])[N:8]=1>C(O)(C)C>[CH3:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]3[N:29]=[N:28][N-:27][N:26]=3)=[CH:15][CH:14]=2)[C:10]([CH2:30][OH:31])=[C:9]([Cl:32])[N:8]=1.[K+:2]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A solution of potassium hydroxide (0.305 g, 4.62 mmol (1 eq.)) and isopropyl alcohol (15 mL) was slowly added to a suspension of losartan (2.0 g, 4.73 mmol) in isopropyl alcohol (25 mL). The reaction mixture was stirred for about 2 hours at room temperature. The mixture was filtered, concentrated to about a 15 mL volume, heated to reflux and stirred for about 12 hours at room temperature. The precipitate was filtered, washed with isopropyl alcohol (5 mL), and dried under reduced pressure for about 2 hours at about 50° C. to give losartan potassium (1.85 g, 85% yield) as a white powder. Purity was determined to be 99.74% by HPLC. Losartan potassium (1.0 g) was then triturated with ethyl acetate (10 mL) and recovered from the triturate in a purity of 99.775% by HPLC.
Reaction SMILES: I[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.O=O.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(N(CC)CC)C.CN(C=O)C.[Pd](Cl)Cl.[Cu]I>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1)([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: O=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1c[nH]c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 5-iodouracil (8g, 30mmol) in redistilled triethylamine (500 mL) and dry DMF (10mL) was deqassed with oxygen-free nitrogen for 15 minutes. Bis(triphenylophosphine palladium (II) chloride (0.5g), copper (I) iodide (0.5g) and trimethylsilylacetylene (10g, 102mmol ) were than added and the mixture was heated with stirring at 50° C for 24 hours. The cooled reaction mixture was filtered, the filtrate evaporated to dryness and the residue dissolved in dichloromethane (500mL). The organic solution was washed with a 2% aqueous solution of disodium EDTA (3×250mL), water (3×200mL), dried (Na2SO4) and evaporated to dryness. The residue was triturated with ethanol to give the first crop of the title compound. The solid filtered from the reaction mixture was also found to contain the required product but in a more impure form and so was worked up as above in a separate batch to give a second crop.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>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.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCNC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, N-methylpropargyl amine (44.9 mg, 0.65 mmol) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P)4Pd (32 mg) and Cul (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C1(=O)O[CH2:15][CH2:14][O:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH:7]1[C:8]2[C:3](=[C:2]([O:1][CH2:15][CH2:14][OH:13])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Oc1cccc2cnccc12
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: OCCOc1cccc2cnccc12
Temperature: 155 °C
Yield: 67.5 %

Procedure:
A mixture of 5-hydroxyisoquinoline (2.05 g, 14.1 mmol), ethylene carbonate (1.43 g, 16.2 mmol), K2CO3 (0.97 g, 7.1 mmol) in DMF (6 mL) was heated at 155° C. for 1.5 h under stirring in a sealed tube. After cooling, the mixture was diluted with CHCl3 and filtered through a pad of Celite. The brownish filtrate was concentrated in vacuo, and the residue was purified by chromatography on silica gel using EtOAc as eluent to give 1.8 g (67%) of the title product as a beige oil which solidified on standing: mp 64-67° C.; HRMS m/z calcd for C11H11NO2 (M)+189.0790, found 189.0789. Anal. (C11H11NO2) C, H, N.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O1CCOCC1>[N:14]1([C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: C1COCCO1
Product: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzoic acid (4.86 g, 26.2 mmol) in dioxane (50 ml) was added morpholine (11.5 ml). The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was dissolved in water and the mixture was acidified with HCl 2N. The solid was filtered, washed with water and dried to provide the title compound (6.2 g, 93%) as a yellow solid, MS (m/e): 251.2 (M−H, 100%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)CCC>C(#N)C.[Pd](Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccs4)cc3CC[C@@H]12
Yield: 33.1 %

Procedure:
Five hundred mg of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was combined with 730 mg of 2-(tri-n-butylstannyl)thiophene and 100 mg of bis(triphenylphosphene) palladium chloride in 6 mL of acetonitrile in a screw capped sealable tube. The mixture was flushed with argon for 5 minutes, capped and heated at 90° for 20 h. Upon cooling, the mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by chromatography on a silica gel column, eluting with ethyl acetate, and the isolated product was recrystallized from ethyl acetate/hexane/chloroform to obtain 167 mg of the desired product. mp: 193°-195°; FDMS 311.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10]C)[CH:5]=[C:6]([O:8]C)[CH:7]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:10])[CH:3]=1
Reactant: COc1cc(Cl)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(O)cc(Cl)c1
Temperature: -78 °C
Reaction time: 48 h
Yield: 58.6 %

Procedure:
A solution 5-chloro-1,3-dimethoxybenzene (20.71 g) in dichloromethane (50 ml) at -78° C. was treated dropwise with a solution of boron tribromide (56 ml) in dichloromethane (250 ml), maintaining the temperature at -78° C. The mixture was slowly warmed to room temperature then left at ambient temperature for 48 hours. The reaction mixture was quenched with water (100 ml), (sodium hydroxide scrubber required) and partitioned between water (1000 ml) and dichloromethane (1000 ml). The organic layer was separated and the aqueous layer was extracted twice with a mixture of dichlioromethane and methanol (500 min, 98:2, v/v). The combined organic extracts were washed with saturated brine (200 ml), dried over magnesium sulphate and evaporated affording the title compound (10.17 g) as a yellow/orange oil which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+].CO>C1C=CC=CC=1>[CH2:6]([NH:1][C@H:2]([CH3:5])[CH2:3][OH:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@@H](N)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: C[C@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-Aminopropan-1-ol (20.00 g, 266.3 mmol) was dissolved in benzene (266 mL) before benzaldehyde (26.91 mL, 266.3 mmol) was added and the reaction refluxed under a Dean-Stark trap for 1.5 h collecting 4.2 mL of water. The reaction mixture was cooled in an ice bath before sodium borohydride (10.07 g, 266.3 mmol) was added. The mixture was warmed to RT and stirred overnight. In an ice bath, methanol was added to the reaction mixture to quench the hydride, then the reaction concentrated, filtered, washed with dichloromethane, concentrated, and purified by flash chromatography to give the title compound. MS (ES+): 166 (M+H)+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].CC#N.[F:13][C:14]([F:32])([F:31])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][NH:22][C:23]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24].[OH-].[Na+]>O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:28]2[CH2:29][CH2:30][CH:25]([C:23]([NH:22][CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]([F:13])([F:31])[F:32])=[O:24])[CH2:26][CH2:27]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C(NCc1ccccc1C(F)(F)F)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(NCc1ccccc1C(F)(F)F)C1CCN(c2nc(Cl)nc(Cl)n2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of cyanuric chloride (1.00 g, 5.42 mmol, 1.00 equiv) in 1:1 CH3CN:H2O (9.0 mL) at 0° C. was added N-{[2-(trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide (1.55 g, 5.42 mmol, 1.00 equiv). This mixture was treated with 1 N NaOH to maintain a pH of 9-10, and the resulting suspension was stirred for 10 min at 0° C. This material was used in the next step without workup or purification. MS (ES+): m/e 433.8 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:41][N:42]([C:52]([NH:54][C@H:55]([C:59](O)=[O:60])[CH:56]([CH3:58])[CH3:57])=[O:53])[CH2:43][C:44]1[N:45]=[C:46]([CH:49]([CH3:51])[CH3:50])[S:47][CH:48]=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH3:41][N:42]([C:52]([NH:54][C@H:55]([C:59]([NH:1][C@@H:2]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:60])[CH:56]([CH3:58])[CH3:57])=[O:53])[CH2:43][C:44]1[N:45]=[C:46]([CH:49]([CH3:51])[CH3:50])[S:47][CH:48]=1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product of Example 70 (9.1 g, 21.4 mmol), HOBT (3.6 g, 23.5 mmol) and N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine (7.37 g, 23.5 mmol) in THF (170 mL) was added DCC (4.85 g, 23.5 mmol). The solution was stirred at ambient temperature for 16 hours (DCU precipitates). THF was removed under vacuum and the resulting paste was stirred with cold 1N HCl (106 mL at 5° C.) for 3 hours to dissolve the the crude product. The DCU was removed by filtration and the filter cake was washed with 1N HCl (30 mL). KH2PO4 (3.2 g) was dissolved in the combined HCl filtrates. The solution was mixed with ethyl acetate (80 mL) and neutralized to pH 7 with aqueous NaOH (60.3 g of 10% w/w NaOH). The aqueous layer was extracted with another 25 mL ethyl acetate and the combined ethyl acetate extracts were washed with aqueous NaHCO3 (2×37 mL of 5% w/w NaHCO3). The organic layer was dried with Na2SO4 (13 g), filtered, and concentrated under vacuum at ≦45° C. The residue was dissolved in a 1:1 ethyl acetate/heptane mixture (200 mL) at 70° C. The solution was allowed to cool slowly and stirred overnight at room temperature to provide a thick slurry. The product was collected by filtration and washed with 1:1 ethyl acetate/heptane (20 mL). The product was dried briefly at 55° C. in a vacuum oven to obtain an approximate weight prior to the second crystallization (12.85 g, 83%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1)=[O:12].O>C(Cl)Cl>[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]([C:1](=[O:3])[CH3:2])=[CH:18][NH:19]2)=[CH:15][CH:14]=1)=[O:12]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(C(C)=O)c[nH]c2c1
Yield: 99.7 %

Procedure:
To a solution of acetyl chloride (0.23 mL, 3.3 mmole) and aluminum chloride (0.88 g, 6.6 mmol) in methylene chloride (30 mL) was added 1H-indole-6-carboxylic acid methyl ester (0.53 g, 3.0 mmol). After stirring 1 hr at room temperature water (300 mL) was added and then this was extracted with ethyl acetate (300 mL). The organic layer was dried (MgSO4), filtered and concentrated to collect 0.65 g (99% yield) of 3-acetyl-1H-indole-6-carboxylic acid methyl ester a light yellow solid. 1H NMR (300 MHz, DMSO) δ 12.27 (s, 1H), 8.52 (s, 1H), 8.24 (d, 1H, J=8.2 Hz), 8.08 (d, 1H, J=1.0 Hz), 7.78 (dd, 1H, J=8.2, 1.0 Hz), 3.86 (s, 3H), 2.47 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16][CH:17]=[CH2:18]>CN(C=O)C>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:18][CH2:17][CH:16]=[CH2:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: C=CCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCC(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
A mixture of sodium hydride (60% in mineral oil, 435 mg, 10.87 mmol, 1.1 eq) in DMF (20 mL) was treated dropwise with diethyl malonate (1.5 mL, 9.88 mmol, 1.0 eq). The reaction mixture was then cooled to 0° C. and 4-bromo-1-butene (1.0 mL, 9.88 mmol, 1 eq) was added dropwise. The reaction mixture was warmed to rt, stirred for 3 days and then partitioned between ether and water. The layers were separated, the aqueous layer was extracted with ether (2×50 mL) and the combined organic phases were washed with water (2×) and brine, dried over MgSO4 and concentrated. Column chromatography (SiO2, 5% ether/heptane) gave C8.1 (1.51 g, 71% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 5.77 (m, 1 H), 5.00 (m, 2 H), 4.13 (q, J=7.1 Hz, 4 H), 3.43 (t, J=7.4 Hz, 1 H), 2.02 (m, 2 H), 1.84 (m, 2 H), 1.17 (t, J=7.1 Hz, 6 H).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:9]([OH:11])=O)=[C:6]([CH3:8])[N:7]=1)[CH3:2].CN(C)C(=O)C.C(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[S:4][C:5]([C:9]([Cl:20])=[O:11])=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCc1nc(C)c(C(=O)O)s1
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCc1nc(C)c(C(=O)Cl)s1

Procedure:
In a similar apparatus to Example 1, 15.0 g (0.09 mole) of 2-ethyl-4-methylthiazole-5-carboxylic acid were suspended in 150 ml of toluene, followed by the addition of 0.1 g of N,N-dimethylacetamide. Under heating and reflux, phosgene was blown at a rate of 1.5 l/hr for 3.5 hours (0.23 mole). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 16.1 g of 2-ethyl-4-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 98.2% and 96.9%, respectively.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([S:6]([OH:9])(=[O:8])=[O:7])[C:3]1=[O:10].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+:25].P(=O)(O)(O)O>O.O1CCCC1>[C:11]1([CH2:17][C:18]([NH:1][CH:2]2[CH2:5][N:4]([S:6]([O-:9])(=[O:8])=[O:7])[C:3]2=[O:10])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+:25]
Reactant: NC1CN(S(=O)(=O)O)C1=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC1CN(S(=O)(=O)[O-])C1=O
Yield: 45.6 %

Procedure:
In 1 ml of water is dissolved 50 mg of the above 3-amino 2-oxoazetidine-1-sulfonic acid, followed by addition of a solution of 69 mg of phenylacetyl chloride in 1 ml tetrahydrofuran and 101 mg of sodium hydrogen carbonate in alternate portions with ice-cooling and stirring. After stirring at room temperature for 30 minutes, the mixture is adjusted to pH 5.8 with phosphoric acid. The tetrahydrofuran is then distilled off under reduced pressure. The water layer is washed with ethyl acetate and purified by XAD-II chromatography, whereby 42 mg of sodium 3-phenylactamido-2-oxoazetidine-1-sulfonate is obtained.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:3]=1[C:4]([NH:6][C@@H:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH2:28][O:29][CH2:30][CH3:31])=[CH:22][C:21]=2[O:32][CH3:33])=[CH:16][CH:15]=1)[C:8]([O:10]CC)=[O:9])=[O:5].Cl>O.O1CCOCC1>[F:1][C:2]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:3]=1[C:4]([NH:6][C@@H:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21]([O:32][CH3:33])=[CH:22][C:23]([CH2:28][O:29][CH2:30][CH3:31])=[CH:24][C:25]=2[O:26][CH3:27])=[CH:18][CH:19]=1)[C:8]([OH:10])=[O:9])=[O:5]
Reactant: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)OCC)cc2)c(OC)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)O)cc2)c(OC)c1
Temperature: 60 °C
Reaction time: 60 h
Yield: 90 %

Procedure:
To a solution of ethyl (αS)-α-[(2,6-difluorobenzoyl)amino]-4′-ethoxymethyl-2′,6′-dimethoxy(1,1′-biphenyl)-4-propionate (500 mg) in water (12.6 ml) and dioxane (50 ml) was added hydrochloric acid (12.4 g) and the mixture was stirred for 60 hours at 60° C. The organic solvent was removed in vacuo and the aqueous layer was cooled. The crystalline precipitates were collected by filtration and recrystallized from ethanol-water to yield (αS)-α-[(2,6-difluorobenzoyl)amino]-4′-ethoxymethyl-2′,6′-dimethoxy(1,1′-biphenyl)-4-propionic acid (426 mg). The physicochemical data were the same as that obtained in Example 1.