Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:81]=[CH:80][C:33]([CH2:34][O:35][C:36]([NH:38][C:39](=[N:66][C:67]([O:69][CH2:70][C:71]2[CH:76]=[CH:75][C:74]([N+:77]([O-:79])=[O:78])=[CH:73][CH:72]=2)=[O:68])[NH:40][CH2:41][CH2:42][CH2:43][S:44][C:45]2[N:46]=[CH:47][N:48]3[CH:52]=[C:51]([Sn](CCCC)(CCCC)CCCC)[S:50][C:49]=23)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[N+:77]([C:74]1[CH:75]=[CH:76][C:71]([CH2:70][O:69][C:67]([NH:66][C:39](=[N:38][C:36]([O:35][CH2:34][C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:81][CH:80]=2)=[O:37])[NH:40][CH2:41][CH2:42][CH2:43][S:44][C:45]2[N:46]=[CH:47][N:48]3[CH:52]=[C:51]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]5[C:7]=4[C:12]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=4)=[O:13])[S:50][C:49]=23)=[O:68])=[CH:72][CH:73]=1)([O-:79])=[O:78]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCCNC(=NC(=O)OCc3ccc([N+](=O)[O-])cc3)NC(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCCNC(=NC(=O)OCc5ccc([N+](=O)[O-])cc5)NC(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)[C@H](C)[C@H]12
Yield: 55.5 %

Procedure:
The procedure of Example 1a) was repeated, except that 297 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 777 mg of 7-[3-N,N′-bis(4-nitrobenzyloxycarbonyl)guanidinopropyl]thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 436 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-[3-N,N′-bis(4-nitrobenzyloxycarbonyl)guanidinopropyl]thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C([O-])(=O)C([O-])=O.[K].[NH:24]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[C@H:25]([C:35](ON1C(=O)CCC1=O)=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CCOCC.CN(C=O)C>[NH:24]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[C@H:25]([C:35]([NH:1][C@H:2]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:7])([CH3:8])[CH3:6])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: C[C@@H](OC(C)(C)C)[C@H](N)C(=O)OC(C)(C)C
Agent: O=C([O-])C(=O)[O-]
Agent: [K]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
After suspending 3.3 g (11.0 mmol) of H-Thr(tBu)-OtBu.oxalate in 60 ml of ether, the suspension is shaken with 30 ml of 5% aqueous potassium hydrogenocarbonate solution until dissolving. The organic phase is separated, washed with an additional 20 ml of 5% aqueous potassium hydrogenocarbonate solution and then with 20 ml of water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. To the solution of the oily residue in 20 ml of DMF, 4.12 g (9.5 mmol) of Z-Glu(OtBu)-OSu are added. The mixture is stirred at room temperature for 2 hours then evaporated under reduced pressure. The residue is dissolved in 50 ml of ethyl acetate and successively washed three times, three times with 15 ml of 10% aqueous citric acid solution each, twice with 15 ml of 5% aqueous sodium hydrogenocarbonate solution each, and finally with 15 ml of water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. 4.4 g (8.0 mmol) of oily Z-Glu(OtBu)-Thr(tBu)-OtBu protected dipeptide (Rf1 =0.85) are obtained which is dissolved in 50 ml of methanol and hydrogenated as described in Example 1. After filtering off the catalyst, the filtrate is evaporated to yield the free H-Glu(Ot -Bu)-Thr(tBu) -OtBu dipeptide (Rf2 =0.22) which is then dissolved in 20 ml of DMF and after adding 4.77 g (10 mmol) of Z-Lys(Boc) -OSu, the reaction mixture is stirred at room temperature for 2 hours and evaporated under reduced pressure. After dissolving the oily residue in 50 ml of ethyl acetate, the solution is purified by several washings in the usual manner, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The oily evaporation residue is recrystallized in ether to yield 4.75 g (74%) of Z-Lys(Boc)-Glu(OtBu)-Thr(tBu)-OtBu protected tripeptide, m.p.: 114°-115° C.; Rf2 =0.80; /α/D20 = -22.8° (c=1, methanol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH:8]=[C:9]2[C:14]=1[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]2[CH2:18][CH:19]([CH3:21])[CH3:20].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH3:33][S:34]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH:8]=[C:9]2[C:14]=1[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]2[CH2:18][CH:19]([CH3:21])[CH3:20])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)n(Cc3cccc4ccccc34)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCOS(C)(=O)=O)n(Cc3cccc4ccccc34)cc21
Reaction time: 8 h

Procedure:
5-[(3-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (J. Med. Chem., 1995, 38, 2557) (260 mg), methanesulphonyl chloride (54 μl) and triethylamine (97 μl) were dissolved in dichloromethane (15 ml) and the mixture was stirred overnight. The reaction mixture was poured onto sodium bicarbonate (aqueous) and extracted twice with ethyl acetate. The extracts were combined, dried, filtered and evaporated to give the subtitle compound as a gum (391 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:13](O)(=O)C.Cl.S(Cl)([Cl:20])=O>[Rh].CO>[ClH:20].[CH3:13][O:11][C:10]([CH:8]1[CH2:7][CH2:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:9]1)=[O:12]
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: O=S(Cl)Cl
Reactant: CC(=O)O
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCc2[nH]cnc2C1
Temperature: 80 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
In a 350 ml steel autoclave with teflon insert was placed 1H-benzimidazole-5-carboxylic acid (10 g, 61.7 mmol), 50% aqueous acetic acid (160 ml), 35% aqueous HCl solution (7 ml) and 6 g Rh/C (5%). The reaction mixture was hydrogenated at 60 bar H2 at 120° C. for 24 hours. After cooling and filtration through Celite, the filtrate was evaporated to dryness and the residue further dried under reduced pressure. The residue was mixed with methanol (200 ml) and (9 ml, 0.123 mol) thionyl chloride and heated at 80° C. for 2 hours. After cooling, the reaction mixture was evaporated to dryness and the white solid further dried under reduced pressure to yield 13.6 g (92%) of 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid methyl ester hydrochloride. The hydrochloride was treated with saturated sodium hydrogen carbonate solution (300 ml) and extracted with DCM (3×300 ml) to obtain 10.8 g (81%) of 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3][CH2:2]1.CC1C=C(O)C=CC=1C.[O:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[C:28]1=[O:37].C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[OH:36][C:29]1([C:9]2[C:8]([OH:11])=[CH:7][C:6]3[O:1][CH2:2][O:3][CH2:4][C:5]=3[CH:10]=2)[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]([CH2:26][C@H:22]2[CH2:23][CH2:24][CH2:25][O:21]2)[C:28]1=[O:37]
Reactant: Oc1ccc2c(c1)OCOC2
Reactant: O=C1C(=O)N(C[C@H]2CCCO2)c2ccccc21
Agent: Cc1ccc(O)cc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C1(O)c1cc2c(cc1O)OCOC2

Procedure:
Following the procedure as described in PREPARATION 6A, and making non-critical variations using 4H-benzo[d][1,3]dioxin-7-ol to replace 3,4-dimethylphenol, and (R)-1-((tetrahydrofuran-2-yl)methyl)indoline-2,3-dione to replace 1-(diphenylmethyl)-1H-indole-2,3-dione, 3-hydroxy-3-(7-hydroxy-4H-1,3-benzodioxin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one was obtained (62%) as a colorless solid: MS (ES+) m/z 366.2 (M−17).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27]OS(C)(=O)=O)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCOS(C)(=O)=O)ccc23)CC1
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCN4CCNCC4)ccc23)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-[7-(3-Methanesulfonyloxy-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (0. 1 mmol), prepared as described in Example 27, was dissolved in anhydrous dioxane together with piperazine (0.5 mmol) and the mixture was stirred at 100° C. overnight and then concentrated in vacuo, then diluted with water and extracted with DCM. The DCM extract was washed with water thrice, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain 4-[7-(3-piperazin-1-yl-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester. This (0.05 mmol) was dissolved in anhydrous DCM (1 mL) and treated with Et3N (0.1 mmol) followed by methanesulfonyl chloride (0. 1 mmol) and the mixture was stirred at rt overnight and then washed with water thrice, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. To this was added 3M HCl/MeOH (1 mL) and the mixture was stirred at rt for 2 h and then concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]#[CH:11])[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][NH:22]C(=O)C(F)(F)F)=[CH:19][CH:18]=1.Cl.ClCCl.CO>CO>[NH2:22][CH2:21][C:20]1[CH:29]=[CH:30][C:17]([NH:16][C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]#[CH:11])[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][N:3]=2)=[CH:18][CH:19]=1
Reactant: Nc1ccc(CNC(=O)C(F)(F)F)cc1
Reactant: C#CCNc1nc(Cl)ncc1C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C#CCNc1nc(Nc2ccc(CN)cc2)ncc1C(F)(F)F
Yield: 37.4 %

Procedure:
A mixture of 2-chloro-4-(prop-2-ynylamino)-5-trifluoromethyl-pyrimidine (235 mg), N-(4-aminobenzyl)-2,2,2-trifluoro-acetamide (410 mg) and hydrochloric acid (37% in water, 0.2 mL) in methanol (5 mL) was refluxed for 1 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the aqueous phase extracted with ethyl acetate, the combined organic phases dried (Na2SO4), concentrated, filtered through silica using dichloromethane/methanol, and the filtrate evaporated. To a solution of the residue in methanol (9 mL), tetrahydrofuran (9 mL) and diethyl ether (4-5 mL) was added lithium hydroxide (150 mg) and the mixture was refluxed for 6 h, after which it was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with additional ethyl acetate, the combined organic phases dried (Na2SO4) and evaporated, which gave, after chromatography on silica using dichloromethane/methanol, the title compound (120 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([NH:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=4)[C:8]=23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][C:35](O)=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:17]([NH:16][C:15]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:2][CH2:3][N:4]([C:35](=[O:36])[CH2:34][CH2:33][NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:5][CH2:6]2)[NH:13][CH:14]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: O=C(Nc1c[nH]c2nccc(N3CCNCC3)c12)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCN(c2ccnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Reaction time: 2 h
Yield: 48.9 %

Procedure:
N-(4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.025 g, 0.058 mmol, see Example 50), 3-(tert-butoxycarbonylamino)propanoic acid (0.0121 g, 0.0637 mmol), HOBT-H2O (0.0124 g, 0.0811 mmol), and EDCI (0.0144 g, 0.0753 mmol) were placed in DCM (3 mL). DIEA (d 0.742; 0.0504 mL, 0.290 mmol) was then added. The reaction was stirred for 2 hours and quenched with saturated Na2CO3. The mixture was then extracted with DCM. The organic fractions were dried, filtered, and concentrated to give a crude oil that was purified by column chromatography (500:20-500:40) to give tert-butyl 3-(4-(3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (0.014 g, 48.9% yield).
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4](C(OC(C)(C)C)=O)[C:3]1=[O:21].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][C:3]1=[O:21]
Reactant: C[C@@H]1OC[C@@H](c2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1OC[C@@H](c2ccccc2)NC1=O
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (2S,5R)-2-methyl-3-oxo-5-phenylmorpholine-4-carboxylate from Step D (160 mg, 0.55 mmol) in CH2Cl2 (2 mL) at ambient temperature was added TFA (0.41 mL, 5.5 mmol). After stirring for 1 h, the reaction mixture was concentrated in vacuo to give the title compound. MS: m/z=192 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])=[O:6].[H][H].Cl.[CH3:16]N(C)C=O>>[CH3:16][C:7]1([C:5]([O:4][CH3:3])=[O:6])[CH2:11][CH2:10][CH2:9][C:8]1=[O:12]
Reactant: COC(=O)C1CCCC1=O
Reactant: [H][H]
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1(C)CCCC1=O

Procedure:
2.52 g of sodium hydride (60% oily sodium hydride washed with anhydrous benzene) was added to 50 ml of anhydrous dimethylformamide under nitrogen atmosphere while stirring. 14.2 g of 2-methoxycarbonylcylopentanone was added to the mixture, followed by stirring at room temperature until generation of hydrogen was terminated. Next, 15 g of methyl iodide was added, and the mixture was stirred for a further 2 hours at 60° C. The reaction mixture thus obtained was poured into 300 ml of diluted hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent under reduced pressure. The oily residue obtained was purified by vacuum distillation to obtain 14.5 g of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[C:24]1([CH3:35])[CH:29]=[CH:28][C:27]([O:30]CC(O)=O)=[CH:26][CH:25]=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>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][O:30][C:27]2[CH:28]=[CH:29][C:24]([CH3:35])=[CH:25][CH:26]=2)[CH2:6][CH2:7]1)(=[O:13])=[O:12]
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: Cc1ccc(OCC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OCC(=O)N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 4, 0.2 g, 0.64 mmol) and 2-(p-tolyloxy)acetic acid (106 mg, 0.64 mmol) in dry DCM (20 mL), DIPEA (495 mg, 3.86 mmol) followed by HATU (486 mg, 1.27 mmol) was added at room temperature and stirred overnight. The mixture was then diluted with DCM and washed with water (2×10 mL) & brine (2×10 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (0.21 g, 77.5%) as an off-white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][N:33]=[CH:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:32]=[N:33][N:34]=[CH:35]4)[CH:26]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2cnnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3cnnc3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionylamino]biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K68) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (79 mg).
Reaction SMILES: [CH3:1][NH:2][CH3:3].CCN(CC)CC.[CH3:11][C:12]([CH3:43])([CH3:42])[C:13](=[O:41])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([C:37](Cl)=[O:38])[CH:31]=[CH:30]3)([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:40].Cl>O>[CH3:1][N:2]([CH3:3])[C:37]([C:32]1[CH:31]=[CH:30][C:29]2[C:34](=[CH:35][CH:36]=[C:27]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13](=[O:41])[C:12]([CH3:43])([CH3:42])[CH3:11])=[C:17]([CH3:40])[CH:18]=3)([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:28]=2)[CH:33]=1)=[O:38]
Reactant: CNC
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)Cl)ccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)N(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
Treat a solution of dimethylamine (2.0 M in THF) (0.12 mL, 0.25 mmol) and Et3N (0.034 mL, 0.25 mmol) in CH2CL2 (3 mL) with 6-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}naphthalene-2-carbonyl chloride (0.057 g, 0.123 mmol) in CH2CL2 (1 mL). Stir the mixture at RT for 16 h; dilute with CH2CL2 and water. Acidify the resulting mixture to pH 1 using 5N HCl. Separate the organic layer from the aqueous layer. Wash the organic layer with brine, dry over Na2SO4, and filter. Concentrate the filtrate to give the title compound as a yellow solid (0.033 g, 57%). MS (ES) m/e 474 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH2:11]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: Oc1ccc(CCNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 519.9 %

Procedure:
Combine tyramine (3.0 g, 3.3 mmol), benzaldehyde (3.0, 2.2 mmol), 3 Å molecular sieves (5 g), ethanol (3 mL) and stir overnight at room temperature. Filter off the sieves then add sodium borohydride (2.5 g) to the reaction at 0° C. then stirred at room temperature overnight. Concentrate on a rotary evaporator, take up residue in water, and then extract with dichloromethane (3×100 mL). Dry the dichloromethane extracts over sodium chloride/magnesium sulfate, filter, then concentrate on a rotary evaporator to yield 4.3 g of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with 10% conc. ammonium hydroxide in ethanol and chloroform to yield 4-(2-benzylamino-ethyl)-phenol (2.6 g): 1H NMR (DMSO-D6, 300.00 MHz): 9.17 (s, 1H), 7.31 (m, 5H), 6.99 (d, 2H, J=8.4 Hz), 6.67 (d, 2H, J=8.8 Hz), 3.70 (s, 2H), 2.64 (m, 4H), 2.11 (s, 1H). Step 2 Benzyl-[2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[Cl:20]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:18]([F:19])=[CH:17][C:16]([Cl:20])=[C:4]([CH:3]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(N)c2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1(Cc2cc(N)c(F)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
2.0 g (7.54 mmol) of tert-butyl 1-(3-amino-4-fluorobenzyl)cyclopropanecarboxylate were dissolved in 20.0 ml of acetonitrile, and 1.06 g (7.92 mmol) of N-chlorosuccinimide were added in several portions at RT. The reaction mixture was stirred at RT for 80 min and then at 45° C. for 8 h. After cooling, the acetonitrile was removed under reduced pressure. The residue was taken up in dichloromethane and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. By chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 30:1) 1.41 g (62.3% of theory) of the title compound were isolated from the crude product obtained in this manner.
Reaction SMILES: ClCCl.[OH:4][C:5]([CH3:14])([CH3:13])[C:6]#[C:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].ClS([N:19]=[C:20]=[O:21])(=O)=O>O>[C:20]([O:4][C:5]([CH3:13])([CH3:14])[C:6]#[C:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:21])[NH2:19]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)C#CC(C)(C)O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C#CC(C)(C)OC(N)=O
Yield: 33.6 %

Procedure:
To 100 ml of a dichloromethane solution containing 4.9 g (31.4 millimoles) of ethyl 4-hydroxy-4-methyl-2-pentynoate, 3 ml (34.5 millimoles) of chlorosulfonyl isocyanate was added at a temperature of -10° C. The mixture was reacted for 30 minutes at -10° C. under stirring. The reaction mixture was returned to room temperature, and 20 ml of water was added thereto. The mixture was stirred for 15 minutes for hydrolysis treatment. The dichloromethane phase was separated by phase separation, washed with a 10% barium chloride solution and water successively, dried over sodium sulfate and then concentrated under reduced pressure, whereby 2.1 g (yield: 33%) of ethyl 4-carbamoyloxy-4-methyl-2-pentynoate in crystal form was obtained.