Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14]CC)=O)=[C:7](O)[CH2:6][CH2:5]2.[NH2:18][C:19]([NH2:21])=[NH:20]>>[NH2:20][C:19]1[NH:21][C:12](=[O:14])[C:8]2[C:9]3[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=3[CH2:5][CH2:6][C:7]=2[N:18]=1
Reactant: CCOC(=O)C1=C(O)CCc2cc(Br)ccc21
Reactant: N=C(N)N
Product: Nc1nc2c(c(=O)[nH]1)-c1ccc(Br)cc1CC2

Procedure:
Ethyl 6-bromo-3,4-dihydro-2-hydroxy-1-naphthoate (6.0 g, 20.2 mmoles) was reacted with guanidine (6.9 g of hydrochloride salt, 72.2 mmoles) in the same manner as in example 1. The product was precipitated from aqueous sodium hydroxide with acetic acid, filtered, washed with water and dried to give 3-amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one as an off-white solid. (2.75 g, 46%) 1H NMR (DMSO-d6, 300 MHZ) δ: 2.55(t, J=7.5 Hz, 2H, CH2); 2.79(t, J=7.4 Hz, 2H, CH2); 6.75(br s, 2H, NH2); 7.32(dd, J=8.4, 2.3 Hz, 1H, Ar); 7.34(s, 1H, Ar); 8.40(d, J=8.4 Hz, 1H, Ar); 11.00(br s, 1H, NH).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH:6]([C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=2)[CH2:5]1)[CH2:2][CH3:3].N1C=CC=CC=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.CC[O-].[Na+]>C(Cl)Cl.CCO>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:15][C:12]2[CH:11]=[N:10][C:9]([CH:6]3[CH2:7][CH2:8][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5]3)=[N:14][CH:13]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: CCCN1CCC(c2ncc(N)cn2)C1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN1CCC(c2ncc(NS(=O)(=O)c3ccc(Br)cc3)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
The crude 2-(1-propyl-pyrrolidin-3-yl)-pyrimidin-5-ylamine (about 1.11 mmol) was dissolved in CH2Cl2:pyridine, 9:1 (50 ml) and 4-bromobenzensulfonyl chloride (566 mg, 2.21 mmol) was added. After stirring at room temperature overnight, the reaction mixture was filtered and concentrated. The raw material was then dissolved in a solution of EtONa (400 mg, 5.87 mmol) in EtOH (35 ml) and the resulting solution was heated under reflux for 1 h. Silica gel (1 g) was next added to the mixture and the solvent removed under reduced pressure. Following flash column chromatography (CH2Cl2:methanol, 9:1) provides the title compound (100 mg, 21% for four steps) as a yellow gum.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Br:15][C:16]1[C:17]([O:27][CH2:28][CH3:29])=[C:18]([CH:24](O)[CH3:25])[CH:19]=[C:20]([Cl:23])[C:21]=1[CH3:22]>C(Cl)Cl>[Br:15][C:16]1[C:21]([CH3:22])=[C:20]([Cl:23])[CH:19]=[C:18]([CH:24]([Cl:3])[CH3:25])[C:17]=1[O:27][CH2:28][CH3:29]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCOc1c(C(C)O)cc(Cl)c(C)c1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1c(C(C)Cl)cc(Cl)c(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (1.7 g, 9.2 mmol) and N,N-dimethylformamide (710 μL, 9.2 mmol) was stirred at room temperature for 10 minutes and then a solution of 1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethanol (1.72 g, 6.15 mmol) in methylene chloride (34 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 10% EtOAc in hexanes (1.01 g, 60%).
Reaction SMILES: [N:1]12CCCN=[C:7]1CCCC[CH2:2]2.S(C[N+]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[O:25]1[CH2:30][CH2:29][CH:28]=[CH:27][C:26]1=[O:31]>O1CCCC1>[CH:2]1[NH:1][CH:7]=[C:27]2[C:26](=[O:31])[O:25][CH2:30][CH2:29][C:28]=12
Reactant: O=C1C=CCCO1
Reactant: C1CCC2=NCCCN2CC1
Agent: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: C1CCOC1
Product: O=C1OCCc2c[nH]cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 8.39 mL, 56.1 mmol) was added to a stirred mixture of tosylmethyl isocyanide (10.95 g, 56.1 mmol) in tetrahydrofuran (THF, 56 mL) at 0° C. After 15 minutes, to the mixture was added 5,6-dihydro-2H-pyran-2-one (5 g, 51 mmol). The mixture was then stirred at room temperature for 2 hours. The reaction was quenched with brine and extracted with THF several times. The combined extracts were dried (sodium sulfate), filter and concentrated to give 6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:64][CH2:65][S:66][C:67]2[S:71][C:70]([CH3:72])=[N:69][N:68]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(O)C>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:64][CH2:65][S:66][C:67]4[S:71][C:70]([CH3:72])=[N:69][N:68]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: Cc1nnc(SCSC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)[C@H]3SC2)s1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: COc1ccccc1
Product: Cc1nnc(SCSC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)s1
Reaction time: 0.67 h
Yield: 74.2 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (388 mg: 0.368 mMol.) in a mixture of anisole (1 ml) and nitromethane (4 ml) at -30° C. is added a solution of aluminum chloride (0.45 g: 9.2 equivalents: 3.4 mMol.) in anisole (1.5 ml), and the mixture is stirred for 40 minutes. The reaction mixture is mixed with ethanol (2 ml), stirred for 5 minutes at the same temperature, and diluted with 1N-hydrochloric acid (6 ml) and water (200 ml). The aqueous layer is taken, washed with ethyl acetate, concentrated under reduced pressure to remove the organic solvents, and passed through a column of styrene-divinylbenzene copolymer. The column is eluted with methanol-water(4:1). The eluate is concentrated to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethylthio)-3 -cephem-4-carboxylic acid (149 mg). Yield: 75%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([OH:22])[N:5]([C:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:6]2=[O:12].CN(CCN(C)C)C.[I:31]I>C1COCC1>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([I:31])=[C:7]2[C:3]=1[CH:4]([OH:22])[N:5]([C:13]([CH3:14])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:21])[C:6]2=[O:12]
Reactant: II
Reactant: Cc1ccc2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: Cc1cc(I)c2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 62.8 %

Procedure:
In a similar manner to Step. 3 of Example 16, 4-chloro-5-methyl-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (400 mg, 1.27 mmol) was dissolved in THF (16 mL), and the solution was treated with TMEDA (0.33 mL, 2.2 mmol), sec-butyl lithium-hexane solution (1.01 mol/L, 2.8 mL, 2.8 mmol) and iodine (387 mg, 1.52 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=95/5 to 80/20 to 70/30) to obtain 4-chloro-5-methyl-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (352 mg, yield 63%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH:14]([NH2:17])([CH3:16])[CH3:15].CCN(CC)CC>CO>[CH:14]([NH:17][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)N
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To the solution of 2-nitrobenzene-1-sulfonyl chloride (1.11 g, 5.0 mmol) in MeOH (30 mL) was added isopropylamine (0.85 mL, 2.0 eq) and Et3N (1.4 mL, 2.0 eq). The mixture was stirred overnight at room temperature. The solvent was removed and the crude was purified by silica gel chromatography to obtain the desired product N-isopropyl-2-nitrobenzenesulfonamide (0.774 g, isolated yield 63%).
Reaction SMILES: [CH:1]([N:4]1[C:30](=[O:31])[C:29]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:27][CH3:28])[C:18]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][C:20]=4[C:11]3=[C:10]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:9]=2[CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:37][C:38](OC(C)=O)=[O:39].O.[NH4+].[OH-]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:38]([N:7]1[CH2:8][C:9]2[C:10]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[C:11]3[C:20]4[CH:19]=[C:18]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)[C:17]([O:27][CH3:28])=[CH:16][C:15]=4[CH2:14][CH2:13][N:12]3[C:29]=2[C:30](=[O:31])[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)(=[O:39])[CH3:37]
Reactant: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(C)=O)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 32 mg of 10n in 200 μl of pyridine was treated with 30 μl of Ac2O and 1 mg of DMAP and was stirred at RT for 1 hr. Then, 2 ml of water was added and stirring was continued for 1 hr at RT. The mixture was made slightly alkaline by addition of conc. aq. NH4OH and was extracted with ethyl acetate. The organic layer was washed with a small amount of sat. NaCl, dried, concentrated and treated with diisopropyl ether, to give 30 mg of white crystalline 10p. Mp: 225-226° C.; Rf 0.40 (CH2Cl2/acetone 1/1). MS-ESI: [M+1] 541.12.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.Br[CH2:13][CH2:14][O:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C.O>[CH3:16][O:15][CH2:14][CH2:13][N:9]1[CH2:8][CH2:7][CH:6]([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCCN1CCC(C(=O)O)CC1

Procedure:
To ethylpiperidine-4-carboxylate (1 eq) in ethanol was added 2-bromo-1-methoxyethane (1 eq) and potassium carbonate 2 eq) and the resulting mixture was refluxed for 16 h. The mixture was then filtered and concentrated. To it was then added ethanol and water (3:1) and sodium hydroxide (1 eq) and it was refluxed for 16 h. The resulting 1-(2-methoxyethyl)piperidine-4-carboxylic acid was then azeotroped with toluene. MS: MH+=188.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][C:22]3[CH:23]=[C:24]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])[CH:18]=2)[CH2:13]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:11][C@@H:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][C:22]3[CH:23]=[C:24]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])[CH:18]=2)[CH2:13]1
Reactant: [H][H]
Reactant: COC(=O)c1cc(Cc2ccc3c(c2)C[C@@H](NC(=O)OCc2ccccc2)C3)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cc(Cc2ccc3c(c2)C[C@@H](N)C3)cc(C(F)(F)F)c1

Procedure:
A suspension of (S)-methyl 3-((2-(benzyloxycarbonylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)benzoate (0.254 mmol, 123 g) and palladium hydroxide (0.064 mmol, 45 mg) in ethanol (9 mL) was treated under hydrogenation conditions (2 bar hydrogen) for 30 minutes. The reaction mixture was filtered through celite and the pad washed with EtOH & EtOAc before the filtrate was concentrated under reduced pressure to give a light brown film (82 mg, 92%). MS (ESI): m/z [M+H]+ 350.0
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:28])[C@@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C@H:17]1[C:25](Cl)=[O:26].N1C=CC=CC=1.Cl>C1C=CC=CC=1>[CH3:15][C:16]1([CH3:28])[C@@H:18]([CH:19]=[C:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C@H:17]1[C:25]([O:14][CH2:13][C:10]1[S:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:12][CH:11]=1)=[O:26]
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C1CCCC1
Reactant: OCc1cnc(Oc2ccccc2)s1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C(=O)OCc2cnc(Oc3ccccc3)s2)[C@@H]1C=C1CCCC1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
3.1 g of (2-phenoxy-5-thiazolyl)-methanol were added to a solution of (1R,3S) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-1-carboxylic acid chloride prepared from 2.9 g of the corresponding acid [described in French Pat. No. 70-00265 published under No. 2.076.204] in 45 ml of benzene and 1.2 ml of pyridine were added dropwise thereto at 10° C. The mixture was stirred at 20° C. for 17 hours and was poured into dilute aqueous hydrochloric acid solution. The decanted aqueous phasewas extracted with ether and the combined organic phases were washed with water, dried and evaporated to dryness under reduced pressure. The residuewas chromatographed over silica gel and was eluted with a 7-3 hexane-isopropyl ether mixture to obtain 1.3 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3S) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-1-carboxylate meltingat less than 50° C.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[C:18]1(=[O:23])[CH2:22][CH2:21][CH:20]=[CH:19]1>CO.[NH4+].[Cl-]>[CH3:14][O:13][C:11](=[O:12])[CH:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH:20]1[CH2:21][CH2:22][C:18](=[O:23])[CH2:19]1
Reactant: O=C1C=CCC1
Reactant: COC(=O)CS(=O)(=O)c1ccccc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)C(C1CCC(=O)C1)S(=O)(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 76.6 %

Procedure:
To a stirred solution of 1.26 g (5.9 mmol) of methyl phenylsulfonylacetate in 20 mL of MeOH at 0° C., 0.22 mL (1.17 mmol, 0.2 eq) of a solution of sodium methoxide (5.4 M in MeOH) were added. After 15 min, 0.53 g (6.5 mmol, 1.1 eq) of cyclopent-2-enone were added. The reaction mixture was allowed to reached RT within 4 hours, diluted with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel with heptane/EtOAc 1:1 yielded 1.34 g (77%) of benzenesulfonyl-(3-oxo-cyclopentyl)-acetic acid methyl ester as a racemic mixture of diastereomers, colorless oil, MS: 297 (MH+.
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:5][CH:4]([C:6]2[C:14]([C:15]3[NH:19][C:18]([CH2:20][CH3:21])=[N:17][N:16]=3)=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([CH3:22])[CH:7]=2)[CH2:3]1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:23][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[C:14]([C:15]3[NH:19][C:18]([CH2:20][CH3:21])=[N:17][N:16]=3)=[CH:13][C:9]([C:10]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:11])=[C:8]([CH3:22])[CH:7]=2)[CH2:3]1
Reactant: CCc1nnc(-c2cc(C(=O)O)c(C)cc2C2CC(F)(F)C2)[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CC(F)(F)C2)[nH]1
Temperature: 30 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
To a round-bottom flask was added a solution of 4-(3,3-difluorocyclobutyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 231.5, 211 mg, 0.660 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 146 mg, 0.660 mmol, 1.00 equiv), EDC.HCl (252 mg, 1.31 mmol, 2.00 equiv) and 4-dimethylaminopyridine (160 mg, 1.31 mmol, 2.00 equiv) were added to the reaction. The resulting solution was stirred for 3 h at 30° C. in an oil bath, then diluted with 30 mL of ethyl acetate. The mixture was washed with 3×40 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (448 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (48.0% CH3CN up to 62.0% in 6 min, up to 100.0% in 4 min, down to 48.0% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 186 mg (58%) of the title compound as a white solid. m/z (ES+) 490 (M+H)+. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.68 (d, J=8 Hz, 2H), 7.59-7.44 (m, 4H), 4.89-4.80 (m, 1H), 4.03-3.98 (m, 1H), 3.67-3.61 (m, 1H), 3.28-3.24 (m, 1H), 3.04-3.00 (m, 2H), 2.97-2.89 (m, 2H), 2.87-2.83 (m, 2H), 2.62-2.60 (m, 2H), 2.48 and 2.38 (2 singlets, amide rotamers, ArCH3, 3H), 2.05-2.00 (m, 1H), 1.88-1.58 (m, 3H), 1.41 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@@H:5]([NH:9]C(OC(C)(C)C)=O)[C:6]([OH:8])=[O:7])[CH3:3].[CH2:17]1[CH:21]2[CH:22]3C(=O)N(O)C(=O)[CH:23]3[CH:18]1[CH:19]=[CH:20]2.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CCOC(C)=O>[NH2:9][C@H:5]([C:6]([O:8][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7])[CH2:4][CH:2]([CH3:1])[CH3:3]
Reactant: O=C1C2C3C=CC(C3)C2C(=O)N1O
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
pTos (21.6 g) was dissolved in DMF (100 ml), and the solution was cooled with ice. TEA (7.7 ml) and Boc-D-Leu-ONB (prepared from Boc-D-Leu--OH. H2O (12.5 g), HONB (9.86 g) and DCC (11.4 g) were added thereto, followed by stirring overnight. The resulting DCU was separated by filtration, and the filtrate was concentrated to obtain a residue. The residue was dissolved in AcOEt, and the resulting solution was washed with 4% aqueous NaHCO3 and 10% aqueous citric acid. After washing with water, the solution was dried with Na2SO4 and concentrated. Ether was added to the resulting residue to separate out a precipitate, which was collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][OH:32])[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:33])=[O:18].[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1.CCOC(C)=O.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][O:32][S:41]([C:38]3[CH:39]=[CH:40][C:35]([CH3:34])=[CH:36][CH:37]=3)(=[O:43])=[O:42])[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:33])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCc2cn(-c3ccc(C)c(C(=O)c4ccc(Nc5ccc(F)cc5F)cc4Cl)c3)nn2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of compound 128 (250 mg, 0.53 mmol) in dry pyridine (2.0 mL) was flushed with argon and cooled to 0° C. 4-Methyl-benzenesulfonyl chloride (102 mg, 0.53 mmol) was added and the reaction was allowed to come to RT overnight under stirring. The reaction mixture was poured into a mixture of EtOAc/water. The organic phase was washed with water, brine, filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 25:75 to 50:50 as the eluent to afford the title compound.
Reaction SMILES: [C:1]1([CH:7]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH:10]3[C:8]2([C:23]([OH:25])=O)[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:28])=O>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]1([CH:7]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH:10]3[C:8]2([C:23]([Cl:28])=[O:25])[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N2CC3CC3(C(=O)O)C2c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CC3CC3(C(=O)Cl)C2c2ccccc2)cc1
Temperature: 25 °C
Yield: 101.4 %

Procedure:
To a stirring solution of racemic 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (1.5 g, 4.2 mmol) (Intermediate 2) and one drop DMF in 10 mL of toluene at 0° C. was added thionyl chloride (8.6 mL, 11.8 mmol). The reaction was allowed to warm to room temperature and then heated to 73° C. for 2.5 hours. The solvent and excess thionyl chloride were evaporated at reduced pressure to leave 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carbonyl chloride (1.6 g, 100% crude yield).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][OH:16])=[CH:9][CH:8]=1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].[NH4+].[Cl-]>C1COCC1>[C:19]([CH2:18][O:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][O:16][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:9][CH:8]=1)([OH:21])=[O:20]
Reactant: COC(=O)CBr
Reactant: OCC#Cc1ccc(C#CCO)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)COCC#Cc1ccc(C#CCOCC(=O)O)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 103.8 %

Procedure:
A 60% suspension of NaH (2.1 g, 53.7 mmol) is added to a solution of 3-[4-(3-hydroxyprop-1-ynyl)-phenyl]prop-2-yn-1-ol (A6, 0.5 g, 2.68 mmol) in absolute THF (20 ml), and the mixture is stirred at 70° C. for 2 h. After cooling to RT, methyl bromoacetate (5.2 ml, 53.7 mmol) is added dropwise to the reaction solution, and the mixture is stirred at RT overnight. For work-up, the reaction solution is poured into an ice-cooled semisaturated aqueous NH4Cl solution (25 ml) and extracted (2×) with ethyl acetate. The combined organic phases are dried over MgSO4, filtered off and concentrated under reduced pressure. The title compound (0.88 g) is obtained as a colorless powder. TLC, silica gel, glass plates, [Tol/Ac (7:3)], Rf=0.70.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([OH:6])=[O:5].O[Li].O.S(OC)(O[CH3:19])(=O)=O.[NH4+].[Cl-]>C1COCC1>[CH3:19][O:5][C:4](=[O:6])[C:3]1[C:7]([I:11])=[CH:8][CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O=C(O)c1c(F)cccc1I
Reactant: COS(=O)(=O)OC
Agent: [Cl-]
Agent: [Li]O
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(F)cccc1I
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a 200 mL round-bottomed flask were added 2-fluoro-6-iodo-benzoic acid (7.5 g, 28.2 mmol), LiOH.H2O (1.42 g, 33.8 mmol), and THF (100 mL). The resulting mixture was warmed to 50° C. and stirred for 2 h. Dimethyl sulfate (4.03 mL, 42.3 mmol) was then added and the mixture was warmed to 65° C. After 2 h, the mixture was cooled to room temperature and NH4Cl(aq) (50 mL, 13 wt % solution) was added. The two resulting layers were thoroughly mixed and then separated. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to a light brown oil (7.79 g, 99% yield). 1H NMR (400 MHz, CDCl3): 7.68-7.60 (m, 1H), 7.15-7.06 (m, 2H), 3.98 (s, 3H).