Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][OH:16])[CH3:13].Cl>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:16][CH2:15][CH:14]([CH2:12][CH3:13])[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CCCCC(CC)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(CC)COS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Yield: 87.5 %

Procedure:
In a 1-L round-bottomed flask containing 250 mL of pyridine, added was 75 g of p-toluenesulfonyl chloride. After the reaction solution was cooled to 0° C., 34 g of 2-ethylhexanol was added dropwise over 30 minutes, and the resulting mixture was left at 0° C. while cooled overnight. The reaction solution was poured into cold 1N hydrochloric acid; the product was extracted with ethyl acetate; and the organic layer was washed with 1N hydrochloric acid until the aqueous hydrochloric acid layer became acidic. The organic layer was dried over magnesium sulfate and evaporated, to give 65 g of 2-ethylhexyl p-toluenesulfonate. The fact that the product is the desirable compound was confirmed with NMR, IR, and mass spectrometry spectra.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH3:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:18])[CH2:15][C:16]#[N:17])=[CH:10][CH:9]=1.NCCC(O)=O.C(O)(=O)C>CCOC(C)=O.C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([C:15](=[C:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[C:16]#[N:17])=[O:18])=[CH:12][CH:13]=1
Reactant: N#CCC(=O)c1ccc(Cl)cc1
Reactant: CCCC(C)=O
Agent: NCCC(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCC(C)=C(C#N)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of pentan-2-one (20 mmol), 3-(4-chlorophenyl)-3-oxopropanenitrile (3.6 g, 20 mmol), β-alanine (180 mg, 2 mmol), acetic acid (2.6 mL) and toluene (60 mL) is heated to reflux in a Dean-Stark system for 18 h. The solution is cooled to RT, then diluted with EtOAc (50 mL), washed with 5% NaHCO3 (3×20 mL), water (20 mL), brine (20 mL), dried (Na2SO4) and finally concentrated in vacuo. A mixture of the two isomers is obtained as a colorless oil by chromatographic purification of the crude residue on silica gel using EtOAc:petroleum ether (0.5:9.5) as eluent.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([OH:17])=O.C(N(C(C)C)CC)(C)C.[CH2:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:28].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:28][CH2:27][N:29]([C:15]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:12])[C:11]=2[C:2]=1[OH:1])=[O:17])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCNc1ccccc1
Reactant: Cn1c(=O)c(C(=O)O)c(O)c2c(Cl)cccc21
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 12.5 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
The mixture of 1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid (1 gm) and toluene (50 ml) was cooled to 10-15° C. under nitrogen atmosphere. Diisopropylethyl amine (1.78 gm) was added to the resulting mass at 10-15° C. to form a clear solution. The solution was followed by the addition of N-ethyl aniline (0.52 gm) in one portion at 10-15° C. and then thionyl chloride (0.61 gm) was added at 0° C. The resulting mixture was stirred for 4 hours and toluene was distilled out under vacuum at below 60° C. The resulting residue was dissolved in ethyl acetate (50 ml) and washed with 5% sodium hydroxide solution (6.5 ml) at 25-30° C. The resulting aqueous layer was cooled to 10-15° C. followed by adjusting pH of the mass to 1 by using 18% aqueous hydrochloric acid solution (2.5 ml). The resulting mass was stirred for 1 hour at 10-15° C. The separated white colored solid was filtered and dried at 55-60° C. to yield 1 gm of laquinimod (HPLC Purity: 98.93%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([CH:9]1CC2O[CH:10]1C=C2)(OC)=[O:6]>>[CH2:1]([NH:4][C:5](=[O:6])[CH:9]=[CH2:10])[CH2:2][NH:3][C:5](=[O:6])[CH:9]=[CH2:10]
Reactant: NCCN
Reactant: COC(=O)C1CC2C=CC1O2
Product: C=CC(=O)NCCNC(=O)C=C
Temperature: 140 °C
Reaction time: 8 h

Procedure:
7.2 parts 30% methanolic Na-methylate solution are added to 15 parts ethylenediamine. 77 parts 2-carbomethoxy-7-oxabicyclo(2,2,1)hept-5-ene are added drop-wise at 30° C. during cooling. Recrystallisation is then allowed to proceed overnight and the crystalline mass is dissolved in 400 parts chloroform, and neutralised with 4 parts concentrated hydrochloric acid. 50 parts water are added, the organic phase separated off, and the aqueous phase extracted 5 times with 50 parts chloroform in each instance. The combined organic phases are reduced in a rotary evaporator at a bath temperature of 90° C. and under a vacuum of 20 Torr. The residue is heated in a vacuum of 10 Torr to 110° to 120° C. (bath temperature 140° C.). On conclusion of the furane separation the sedimentation temperature increases to 140° C. After cooling, the product is dissolved in hot n-butanol, filtered, and allowed to recrystallise at 0° C. 27 g N,N'-ethylenebisacrylamide with a melting point of 150° to 155° C. is obtained.
Reaction SMILES: ClC(OCC(C)C)=O.[CH3:9][O:10][CH2:11][C:12]#[C:13][C:14]([OH:16])=O.CN1CCOCC1.N#N.[NH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][C:31]([C:37]#[N:38])=[C:30]2[NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([Br:46])[CH:41]=1>N1C=CC=CC=1>[Br:46][C:42]1[CH:41]=[C:40]([NH:39][C:30]2[C:29]3[C:34](=[CH:35][CH:36]=[C:27]([NH:26][C:14](=[O:16])[C:13]#[C:12][CH2:11][O:10][CH3:9])[CH:28]=3)[N:33]=[CH:32][C:31]=2[C:37]#[N:38])[CH:45]=[CH:44][CH:43]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: COCC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: COCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
Isobutyl chloroformate (0.432 g, 3.2 mmol) was dropwise added into an ice cold solution of 4-methoxy-2-butynoic acid (0.72 g, 6.32 mmol) and N-methylmorpholine (0.959 g, 9.78 mmol) in 20 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 0.5 g (1.58 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 8 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 5% methanol in chlorform. The product was collected, and dried in vacuo to give 0.27 g (41%) of yellow solid; mass spectrum (electrospray, m/e,): 435.1, 437.0 (M+H+); mp 197° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]([CH2:8][Cl:9])=[O:7])[CH3:2].C(OCC)(OCC)O[CH2:13][CH3:14]>S(=O)(=O)(O)O>[Cl:9][CH2:8]/[C:6](/[O:7][CH2:13][CH3:14])=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:10]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C(/CCl)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl-4-chloroacetoacetate (5.0 g), triethyl orthoformate (4.5 g) and concentrated sulfuric acid (2 drops) was stirred at room temperature for 48 hours under a nitrogen atmosphere. The excess triethyl orthoformate was removed on a rotavap and the residue was dissolved in toluene (~20 mL) and a small amount of p-toluene sulfonic acid was added and refuxed for three hours. The mixture was diluted with ethyl acetate (~20 mL) and washed with aqueous sodium bicarbonate and brine; dried over anhydrous sodium sulphate and the solvent removed on a rotavap to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].CN1CCCC1=O.[F:17][C:18]1[C:23]([F:24])=[C:22](F)[CH:21]=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[F:24][C:23]1[C:18]([F:17])=[C:19]([N+:26]([O-:28])=[O:27])[CH:20]=[CH:21][C:22]=1[O:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: Oc1c(F)cccc1F
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Oc2c(F)cccc2F)c(F)c1F
Temperature: 130 °C
Reaction time: 8 h

Procedure:
470 mg of 2,6-difluoro-phenol and 1.5 g of tetrabutylammonium bromide were added to an N-methylpyrrolidinone (13 ml) solution of 500 mg of 2,3,4-trifluoro-nitrobenzene, and the reaction liquid was stirred overnight at 130° C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1) to obtain the entitled compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=[O:6]
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 2-fluoro-5-methoxy-4-nitro-benzoic acid (Intermediate 29; 861 mg, 4.00 mmol) in DMA (20 mL) was added 4-amino-1-methylpiperidine (Fluorochem; 503 mg, 4.40 mmol) followed by DIPEA (1.4 mL, 8.00 mmol) and HATU (1.68 g, 4.40 mmol) and the resulting yellow solution stirred at room temperature for 1 hr. The solvent was removed under reduced pressure and the residue taken up in methanol (approx 10 mL) and loaded onto a 20 g SCX-2 cartridge washing with methanol (50 mL) and eluting with 7 N methanolic ammonia (50 mL) to give a yellow solid, 1.47 g. This was purified by flash silica chromatography (Companion, 40 g, 0-5% ammonia in methanol/DCM) to give the desired product as a pale yellow solid (1.25 g, 4.00 mmol, 100%.)
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12]C)=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[C:8]([CH:14]([CH3:16])[CH3:15])[O:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[NH2:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)=[C:8]([CH:14]([CH3:15])[CH3:16])[O:9]2)=[CH:4][CH:3]=1
Reactant: COc1c(N)ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)c1oc2c(O)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of 7-amino-3-(4-chlorophenyl)-2-isopropyl-8-methoxy-chromen-4-one (0.178 g, 0.52 mmol) in methylene chloride (5 ml) under an argon atmosphere is cooled to −78° C. and treated with boron tribromide (1M solution in methylene chloride, 3.2 ml, 3.2 mmol, 6.2 eq.). The reaction mixture is stirred at −78° C. for 1 h and at room temperature for 45 min, whereupon HPLC analysis indicates that the reaction is complete. The reaction mixture is treated with water (32 ml) and stirred at ambient temperature overnight. The mixture is washed with methylene chloride, and the organic layer is washed with 5% sodium thiosulfate solution, followed by brine. The organic phase is dried over anhydrous magnesium sulfate and filtered, and the solvent is removed by evaporation in vacuo to afford a brown oil. The oil is purified by flash chromatography (hexane/ethyl acetate=9:1 through 1% methanol in ethyl acetate to methylene chloride/methanol=9:1) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:58][N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[C:16]([C:18]([N:62]3[CH2:63][CH2:64][N:59]([CH3:58])[CH2:60][CH2:61]3)=[O:20])[CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)n1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cccc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.8 %

Procedure:
To a dichloromethane (5 ml) solution of 6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]picolinic acid (130 mg, 0.307 mmol) were added N-methylmorpholine (41 μl, 0.368 mmol), 1-hydroxybenzotriazole (13 mg, 0.368 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71 mg, 0.368 mmol) and 1-methylpiperazine (40 μl, 0.368 mmol). The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the dichloromethane:methanol=30:1 eluate was concentrated under reduced pressure to give the title compound (40 mg, 0.0791 mmol, 26%) as a white amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[CH3:18][C:19]1([O:22][CH2:21]1)[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])[C:6]=2[N:14]=1
Reactant: CC1(C)CO1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Yield: 70.1 %

Procedure:
2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 200 mg, 0.884 mmol), isobutylene oxide (0.196 mL, 2.21 mmol) and cesium carbonate (460 mg, 1.40 mmol) in N,N-dimethylformamide (2.5 mL) were stirred at 100° C. under microwave irradiation for 10 min. The volatiles were removed in vacuo then the crude residue was adsorbed onto silica gel using methanol and purified by silica gel chromatography (5-10% methanol in methylene chloride gradient) to afford the title compound (43, 185 mg, 70%). NH4OAc standard conditions. DAD Retention time =5.93 min. M+H=299. 1H NMR (300 MHz, MeOD-d4): Δ 8.64 (d, J=4.9 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.34 (dd, J=7.6, 7.3 Hz, 1H), 7.20 (dd, J=7.8, 7.3 Hz, 1H), 5.49 (s, 2H), 1.28 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11][CH2:10]2.[CH:20]([O:23][C:24]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=1[C:26](O)=[O:27])([CH3:22])[CH3:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12]([C:26]([C:25]1[CH:29]=[C:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=[CH:32][C:24]=1[O:23][CH:20]([CH3:22])[CH3:21])=[O:27])[CH2:11][CH2:10]2
Reactant: Fc1cccc(COc2ccc3c(c2)CCNC3)c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(OCc3cccc(F)c3)ccc2C1

Procedure:
Prepared in analogy to example 1.1 from 6-(3-fluoro-benzyloxy)-1,2,3,4-tetrahydro-isoquinoline ((CA [620606-74-8]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 498.4 (M+H+).
Reaction SMILES: N1C=CN=C1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([OH:16])[CH2:14][OH:15])=[CH:9][C:8]=1[F:17].[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl>[Si:22]([O:15][CH2:14][C@@H:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[C:8]([F:17])[CH:9]=1)[OH:16])([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H](O)c1ccc(Cl)c(F)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
Imidazole (13.1 g, 193 mmol) was added to a cold (0° C.) solution of (R)-1-(4-chloro-3-fluorophenyl)ethane-1,2-diol (14.7 g, 77.1 mmol) in DCM (100 mL), followed by TBSCl (12.8 g, 84.8 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then quenched with water (50 mL). The layers were separated, and the organics were dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (100:1) to give (R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanol (11.0 g, 47% over two steps). 1H NMR (400 MHz, CDCl3) δ 7.36 (m, 1H), 7.20 (m, 1H), 7.08 (m, 1H), 4.71 (m, 1H), 3.75 (m, 1H), 3.49 (m, 1H), 2.96 (d, J=2.6 Hz, 1H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.[Li]CCCC.Cl>C1COCC1.C1(C)C=CC=CC=1>[F:19][C:17]1[CH:18]=[C:2]([B:20]([OH:25])[OH:21])[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH:16]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)c1cc(F)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: -20 °C
Yield: 180.1 %

Procedure:
2-(3-Bromo-5-fluorophenoxy)-5-(trifluoromethyl)pyridine (2 g, 0.005 mol) and tri-isopropyl borate (1.6 mL, 0.007 mol) were dissolved in dry THF (40 mL) and toluene (10 mL) under inert atmosphere and cooled to −78° C. n-BuLi (4.48 mL, 0.005 mol) was then added dropwise at −78° C. The reaction was warmed to −20° C. and 2N HCl (2 mL) was added and then the mixture was warmed to RT. The reaction mixture was concentrated and extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (2.71 g, 70%); m/z (300.4, M− H−).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>[OH-].[Na+].C(O)C>[O:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:12][C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=3)[C:7]=2[CH:8]=[CH:9]1
Reactant: Oc1cccc2occc12
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc(COc2cccc3occc23)cc1
Reaction time: 5 h

Procedure:
4-Hydroxybenzofuran (1.34 g, 0.01 M), ethyl 4-bromomethylbenzoate (2.43 g, 0.01 M), anhydrous potassium carbonate (1.49 g), sodium iodide (0.05 g) and 95% ethanol (10 ml) were refluxed with stirring (5 hr). The cooled reaction mixture was diluted with 0.5 N sodium hydroxide solution and cooled in ice. The precipitated solid was filtered off, washed well with water and recrystallised form ethanol-water to give ethyl 4-(4-benzofuranyloxymethyl)benzoate, m.p. 70°-72° C. (Found: C, 72.79; H, 5.46. C18H16O4 requires C, 72.96; H, 5.44%).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([OH:12])=O)[N:8]=1)=O.[NH2:16][CH:17]1[C:50](=[O:51])[N:19]2[C:20]([C:39]([O:41][CH2:42][O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[O:40])=[C:21]([CH2:24][S:25][C:26]3[N:31]4[N:32]=[C:33]([CH2:35][O:36][CH3:37])[N:34]=[C:30]4[N:29]=[C:28]([CH3:38])[CH:27]=3)[CH2:22][S:23][C@H:18]12.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>CN(C=O)C.CCOCC.C(OCC)(=O)C.O.CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([NH:16][CH:17]2[C:50](=[O:51])[N:19]3[C:20]([C:39]([O:41][CH2:42][O:43][C:44](=[O:49])[C:45]([CH3:46])([CH3:48])[CH3:47])=[O:40])=[C:21]([CH2:24][S:25][C:26]4[N:31]5[N:32]=[C:33]([CH2:35][O:36][CH3:37])[N:34]=[C:30]5[N:29]=[C:28]([CH3:38])[CH:27]=4)[CH2:22][S:23][C@H:18]23)=[O:12])[N:8]=1
Reactant: COCc1nc2nc(C)cc(SCC3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)C(N)[C@H]4SC3)n2n1
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1nc2nc(C)cc(SCC3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)C(NC(=O)C(=NOC)c5csc(N)n5)[C@H]4SC3)n2n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 31.6 %

Procedure:
In 50 ml of DMF were added 3.43 g of 2-(2-formylamino1,3-thiazol-4-yl)-2-methoxyiminoacetic acid, 10.1 g of pivaloyloxymethyl 7-amino-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate and 2.76 g of 1-hydroxybenzotriazole and ice-cooled, and 3.71 g of DCC was added to the solution and the mixture was stirred for 1.5 hours under ice-cooling. After filtration of the reaction mixture, 20 ml of chloroform was added to the filtrate, and the mixture was added dropwise into 4 liters of ether. Precipitates were collected by filtration and dried to obtain a powder. To 1.57 ml of phosphorus oxychloride was added 80 ml of ice-cooled methanol, and the powder previously obtained was added thereto and the mixture was stirred for 1.5 hours under ice-cooling. After the mixture was condensed to a half, the residue was added dropwise to a mixed solution of 200 ml of water and 200 ml of ethyl acetate and the mixture was neutralized with addition of sodium hydrogencarbonate. An organic layer was separated, washed with water and then dried over anhydrous magnesium sulfate, followed by evaporation of a solvent to obtain an oily product. The oily product was purified through silica gel column chromatography. To the oily product obtained was added ether to powderize, and it was collected by filtration and dried to obtain 3.4 g of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][N:26]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:24][C:25]1[N:26]=[CH:27][C:28]([S:31]([N:15]([CH3:16])[C:12]2[CH:13]=[CH:14][C:9]([CH2:8][N:6]3[CH2:5][CH2:4][N:3]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C@@H:2]([CH3:1])[CH2:7]3)=[CH:10][CH:11]=2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)S(=O)(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
D3 (500 mg, 1.57 mmol) and 2-chloro-pyridine-5-sulfonyl chloride (330 mg, 1.57 mmol) were combined in DCM (10 mL) under Ar. Triethylamine (0.44 mL, 3.13 mmol) was added and the solution stirred overnight. The solution was diluted with DCM and washed with water. The water layer was re-extracted with DCM. The combined organic layers were washed with brine, dried and concentrated. The crude product was purified by column chromatography. Elution with 0-50% Et2O/petroleum ether yielded the product as a white foam (685 mg), δH (CDCl3, 400 MHz): 1.24 (3H, d), 1.46 (9H, s), 2.01 (1H, m), 2.16 (1H, m), 2.56 (1H, d), 2.73 (1H, d), 3.10 (1H, m), 3.22 (3H, s), 3.40-3.50 (2H, AB), 3.81 (1H, d), 4.20 (1H, br.s), 7.05 (2H, d), 7.31 (2H, d), 7.42 (1H, d), 7.74 (1H, dd), 8.54 (1H, d). MS (ES+): MH+ 495.1/497.1