Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:15](=O)[C:16]([N:18]([CH2:22][CH2:23][N:24]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][C:26]#[C:27][C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[CH:19]([CH3:21])[CH3:20])=[O:17])[CH:9]2C(O)=O)=[CH:4][C:3]=1[O:41][CH3:42].C(N(CCC#CC1SC=CC=1)C(=O)C(N1CCC2C(=CC([N+]([O-])=O)=C(OC)C=2)C1C(OCC)=O)=O)(C)(C)C.C([O-])(=O)C.[Na+].[NH4+].[OH-]>C(OC(=O)C)(=O)C.O>[Br:1][C:2]1[C:3]([O:41][CH3:42])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:15]4[C:16](=[O:17])[N:18]([CH:19]([CH3:20])[CH3:21])[CH2:22][CH2:23][N:24]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:25][C:26]=4[C:27]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[C:9]3[C:10]=2[CH:11]=1
Reactant: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCN(CC#Cc1cccs1)C(=O)OC(C)(C)C)C(C)C)CC2
Agent: CC(=O)[O-]
Agent: CCOC(=O)C1c2cc([N+](=O)[O-])c(OC)cc2CCN1C(=O)C(=O)N(CCC#Cc1cccs1)C(C)(C)C
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1Br)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 600 mg of 10k in 8 ml of acetic anhydride and 1g of anhydrous sodium acetate was heated under N2 for 45 min at 100° C. The reaction mixture was cooled and 20 ml of water was added and the mixture was stirred for another 1 hr at ambient temperature. The reaction mixture was then treated with cold conc. aq. NH4OH to make it slightly basic and the product was extracted with ethyl acetate. The crude material thus isolated was purified by chromatography over silica gel, using a gradient of heptane/acetone as eluent. The product isolated, was triturated with diisopropyl ether and provided 350 mg of white crystalline 10l. Mp: 233-234° C., Rf 0.55 (toluene/ethylactetate 1/1). NMR (CDCl3) δ 1.25-1.45 (bs, 15, tertC4H9+isoC3H7), 3.87 (s, 3, OCH3), 4.65 (bm, 1, isoC3H7), 6.72 (bs, 1, Ar—H), 6.93 (bm, 1, thiophene-H), 7.15 (bm, 2, thiophene-H+Ar—H), 7.43 (bm, 1, thiophene-H).
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][C@@H:4]([C:9](=[O:31])[NH:10][C@H:11]1[CH2:28][C:27]2=[CH:29][N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=32)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:30])[CH2:5][C:6]([OH:8])=[O:7].[CH2:33](O)[CH3:34].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:33]([O:7][C:6](=[O:8])[CH2:5][C@H:4]([C:9](=[O:31])[NH:10][C@H:11]1[CH2:28][C:27]2=[CH:29][N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=32)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:30])[CH2:3][CH:2]([CH3:32])[CH3:1])[CH3:34]
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](CC(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reaction time: 8 h
Yield: 55 %

Procedure:
(3R,10S)-5-Methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]-nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid (183 mg) was taken up in 40 mL of dry CH2Cl2 and at 0° C. ethanol (0.5 mL, 5 eq) was added followed by N,N-dimethylaminopyridine (0.1 eq, 5 mg) and finally EDCI (209 mg, 5 eq). The resulting solution was stirred from 0° C. to room temperature overnight. Additional CH2Cl2 (100 mL) was added and the mixture was washed with 0.5N HCl (2×50 mL), saturated NaHCO3 (2×50 mL) and finally with brine (1×50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Recrystallization from ethyl acetate and petroleum ether gave (3R,10S)-5-Methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid ethyl ester as a white solid (Yield: 108 mg, 55%), MS: 470 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13]C(N)=O>C(C1C=CC2C(=CC=CC=2)C=1C(C)C)(C)C.P(O)(O)O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(N)=O
Agent: CC(C)c1ccc2ccccc2c1C(C)C
Agent: OP(O)O
Product: NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
83.5 g (0.5 mol) of 4-nitrobenzoic acid, 33.0 g (0.55 mol) of urea and 0.5 g of phosphorous acid are heated in 250 ml of diisopropylnaphthalene with stirring at from 150° to 158° C. for 8 h. After cooling the batch to 25° C. the solid is filtered off with suction and washed with 50 ml of diisopropylnaphthalene. The filter cake is introduced into 250 ml of water, and the mixture is adjusted to a pH of 12 using aqueous sodium hydroxide solution and is stirred at 25° C. for 30 min. Subsequently the solid is filtered off with suction and dried at 100° C. 81.4 g of 4-nitrobenzamide are obtained having a melting point of from 191° to 194° C. This corresponds to a yield of 98% of theory.
Reaction SMILES: [CH3:1][C@:2]12[C@@H:11]3[CH2:12][CH2:13][C@@:14]4([O:19][C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)[C:16]([CH2:18][C@@:10]3([CH2:15]4)[CH2:9][CH2:8][C@@H:7]1[C@@:6]([C:43]([O:45][C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)=[O:44])([CH3:42])[CH2:5][CH2:4][CH2:3]2)=[CH2:17].C[C@]12[C@@H]3CC[C@@]4(O[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)[C@H]5O)C(C[C@@]3(C4)CC[C@@H]1[C@@](C(O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)=O)(C)CCC2)=C>>[CH3:1][C@:2]12[C@@H:11]3[CH2:12][CH2:13][C@@:14]4([OH:19])[C:16]([CH2:18][C@@:10]3([CH2:15]4)[CH2:9][CH2:8][C@@H:7]1[C@@:6]([C:43]([OH:45])=[O:44])([CH3:42])[CH2:5][CH2:4][CH2:3]2)=[CH2:17]
Reactant: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@@H]2CC[C@]1(O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)C3
Agent: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@@H]2CC[C@]1(O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1O)C3
Product: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O)[C@@H]2CC[C@]1(O)C3

Procedure:
Various enzymes and enzyme preparations (collectively referred to as “enzymes” were evaluated for their ability to cleave stevioside and rebaudioside A to produce steviol. 50 mg Stevia extract RV140-54 (19% Rebaudioside A, 19% Stevioside [w %]), was solubilized in 5 ml buffer pH 4.1 (0.1 mol/l H3PO4+NaOH), 50 μl enzyme solution or 10 mg lyophilized powder; 40° C. (rem 1). Results are shown in Table 1, below.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Oc1ccnc(NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncccc1Oc1ccnc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
tert-Butyl 4-(2-methylpyridin-3-yloxy)pyridin-2-ylcarbamate (5.5 g, 18.3 mmol) was diluted in dichloromethane (20 mL). Trifluoroacetic acid (20 mL) was added and the reaction was stirred for 3 hours at ambient temperature. The reaction was concentrated, and saturated sodium bicarbonate solution was added to the residue. The aqueous layer was extracted with ethyl acetate and organic layer was dried and concentrated to give the title compound (3.67 g, 99% yield) as light yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[C:21]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:6]1[CH3:31].[OH-].[Li+]>O1CCCC1>[C:25]1([S:22]([C:21]2[C:16]([CH2:15][C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=4)[N:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]=3[CH3:31])=[N:17][CH:18]=[CH:19][CH:20]=2)(=[O:24])=[O:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)Cn1c(C)c(Cc2ncccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ncccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
A mixture of [3-(3-benzenesulfonylpyridin-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.19 g) and tetrahydrofuran (5.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.62 mL), and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, pH adjusted to 4 by the addition of 0.1 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (1:19 to 49:1 by volume) to afford the title compound as a white solid (0.15 g).
Reaction SMILES: ClS([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=O)=O>N1C=CC=CC=1.O>[C:9]([OH:11])(=[O:10])[C:8]1[CH:12]=[CH:13][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1
Reaction time: 72 h
Yield: 59.8 %

Procedure:
To a solution of N-(9-Amino-1,2-dihydro-1-oxobenzo(quinazolin-3-yl)pivalamide (1.38 g, 4.5 mmoles) in dry pyridine (10 ml) was added 4-(chlorosulfonyl)benzoic acid (5.0 g, 22.6 mmoles) at room temperature under a nitrogen atmosphere. After stirring for 3 days, the pyridine was removed under reduced pressure to leave a gummy brown residue which was suspended in water (30 ml), filtered, washed with water and dried to give 4-((N-(1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide)-9-yl)amino)sulfonyl)benzoic acid (1.65 g).
Reaction SMILES: [F:1][CH:2]1[CH:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][N:4]([CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH3:17])[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][CH:2]1[CH:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][N:4]([CH2:14][CH2:15][NH:16][CH3:17])[CH2:3]1
Reactant: CCOC(=O)CC1CCN(CCN(C)C(=O)OC(C)(C)C)CC1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC1CCN(CCNC)CC1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a solution of ethyl 3-fluoro-1-[2-(N-tert-butoxycarbonyl-N-methylamino)ethyl]4-piperidinylacetate (236 mg, 0.68 mmol) in CH2Cl2 (10 mL) was added TFA (5 mL) at 0° C. After being stirred at room temperature for 4 hr, the reaction mixture was concentrated. The residue was taken up with sat. NaHCO3 solution and extracted with CHCl3. The extracts were dried over MgSO4 and concentrated to afford ethyl 3-fluoro-1-[2-(N-methylamino)ethyl]4-piperidinylacetate (117 mg, 70%) as a reddish oil. 1H-NMR (CDCl3)δ 1.26 (t, J=7.1 Hz, 3H), 1.58 (m, 1H), 1.70 (m, 1H), 1.99 (m, 1H), 2.14 (m, 1H), 2.27–2.33 (m, 1H), 2.47 (s, 3H), 2.48–2.56 (m, 4H), 2.72 (t, J=6.3 Hz, 2H), 2.90 (m, 1H), 3.16 (m, 1H), 4.14 (q, J=7.1 Hz, 2H), 4.67 (d, J=48.3 Hz, 1H); ESI-MS m/z 247 (M++1)
Reaction SMILES: NC1C2(CC2)CNC1.N[C@H]1C2(CC2)CNC1.C(OC([NH:24][CH:25]1[C:29]2([CH2:31][CH2:30]2)[CH2:28][N:27]([C:32]2[C:41]([Cl:42])=[C:40]3[C:35]([C:36](=[O:49])[C:37]([C:46]([OH:48])=[O:47])=[CH:38][N:39]3[CH:43]3[CH2:45][CH2:44]3)=[CH:34][C:33]=2[F:50])[CH2:26]1)=O)(C)(C)C>>[NH2:24][CH:25]1[C:29]2([CH2:30][CH2:31]2)[CH2:28][N:27]([C:32]2[C:41]([Cl:42])=[C:40]3[C:35]([C:36](=[O:49])[C:37]([C:46]([OH:48])=[O:47])=[CH:38][N:39]3[CH:43]3[CH2:45][CH2:44]3)=[CH:34][C:33]=2[F:50])[CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC12CC2
Agent: NC1CNCC12CC2
Agent: N[C@@H]1CNCC12CC2
Product: NC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC12CC2

Procedure:
For example, as for the antimicrobial activity of the two enantiomers having a 7-amino-5-azaspiro[2,4]heptane structure, one of them has more potent antimicrobial activity than the other. It has been revealed that the derivative of the 7-(S)-amino-5-azaspiro[2.4]heptane is the more potent enantiomer. This fact was confirmed by X-ray crystallographycal analysis of the one of the isomers of 7-(7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane-5-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid which gives the more potent isomer of 7-(7-amino-5-azaspiro[2.4]heptane-5-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-].CCOCC>C1COCC1>[Br:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([CH2:4][OH:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1cc2cc(Br)ccc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 6.7 g (19 mmol) of 5-bromo-1-(benzyl)indole-2-carboxylic acid ethyl ester in 25 mL of anhydrous THF at 0° C. were added portionwise 1.42 g (37 mmol) of LiAlH4 and the resulting mixture was stirred at 0° C. for 2 h. After addition of a saturated aqueous solution of NH4Cl and Et2O, the phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 5.8 g (ca 19 mmol) of [5-bromo-1-(benzyl)-1H-indol-2-yl]-methanol, that was dissolved in 30 mL of CH2Cl2 and treated at 0° C. with 4.75 mL (28 mmol) of DIPEA 7.5 mL (28 mmol) of TIPSOTf. The mixture was stirred at RT for 1 h and added to saturated aqueous NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 7.3 g (81%) of 5-bromo-1-(benzyl)-2-triisopropylsilanyloxymethyl-1H-indole, off-white solid, MS: 473 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([N:19]=[N:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.C(O)C.[OH-].[Na+].Cl>C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([N:19]=[N:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(N=Nc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)azo]-benzoate (Compound 46a) 16.5 mg, 0.042 mmol) in THF (2 ml) and ethanol (1 ml) was added 80.0 mg (2.00 mmol) of NaOH (2.0 ml, 1M aqueous solution). The mixture was stirred for 12 hours at room temperature, acidified with 10% HCl, and extracted with EtOAc. The combined organic layers were washed with water, and saturated aqueous NaCl, then dried over MgSO4. Removal of the solvents under reduced pressure, and recrystallization of the residue from EtOAC/hexane, afforded the title compound as a red solid. 1H NMR (acetone-d6): δ 8.19 (2H, d, J=8.4 Hz), 7.92 (2H, d, J 8.5 hz), 7.88 (2H, dd, J=2.1, 6.1 Hz), 7.66 (1H, s), 7.64 (2H, d, J=2.3 Hz), 7.28 (4H, d, J=3.0 Hz), 6.09 (1H, t, J=2.5 Hz), 2.42 (2H, d, J=4.8 Hz), 2.39 (3H, s), 1.40 (6H, s).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH2:17].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>O1CCCC1>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][C:15]([O:14][CH3:13])=[O:18])=[O:6]
Reactant: O=C(O)c1cccc(F)c1F
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)c1cccc(F)c1F
Reaction time: 8 h

Procedure:
To a solution of 2,3-difluorobenzoic acid (0.190 g, 1.2 mmol) in tetrahydrofuran (5 mL) were added glycine methyl ester hydrochloride (0.150 g, 1.2 mmol), HOBt (0.162 g, 1.2 mmol), DIEA (0.209 mL, 1.2 mmol) and EDCI (0.252 g, 1.3 mmol). The reaction mixture was allowed to stir overnight. The reaction mixture was quenched with a saturated solution of sodium bicarbonate and the product partitioned into DCM. Separation of the organic layer followed by removal of the solvent gave methyl [(2,3-difluorobenzoyl)amino]acetate which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:35])[CH2:9][NH:10][C@H:11]([CH3:34])[CH2:12][C:13]2[C:21]3[C:16](=[C:17]([C:22]([NH:24][C@@H:25]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:26]([O:28]C)=[O:27])=[O:23])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C([O-])=O.[OH-].[K+].Cl>O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:35])[CH2:9][NH:10][C@H:11]([CH3:34])[CH2:12][C:13]2[C:21]3[C:16](=[C:17]([C:22]([NH:24][C@@H:25]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:26]([OH:28])=[O:27])=[O:23])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c12
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c12)C(=O)O

Procedure:
A solution of methyl (2S)-2-[(3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethylamino]propyl}-1H-indole-7-carbonyl)amino]-4-methyl-pentanoate.trifluoroacetate (20 mg, 0.0326 mmol) and potassium hydroxide (60 mg, 1.1 mmol) in water (0.5 mL) and methanol (2 mL) is stirred at room temperature for 3 hours. The mixture is acidified with 1N hydrochloric acid, and purified by preparative reversed phase HPLC (octadecylsilyl, trifluoroacetic acid/acetonitrile/water) to give the desired (2S)-2-[(3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethyl-amino]propyl}-1H-indole-7-carbonyl)amino]-4-methylpentanoic acid.trifluoroacetate (18 mg, yield: 92%).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:6][NH:7][C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:17][O:18][CH2:19][CH2:20][OH:21]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](COCCO)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](COCCO)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
N-((1R)-1-(2-Hydroxyethoxymethyl)-2-phenylethyl)-N-methylcarbamic acid tert-butylester (0.29 g, 0.90 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added. The solution was stirred at 0° C. for 15 min. The solvents were removed in vacuo. The residue was dissolved in dichloromethane (10 mL) and extracted with 1N sodium hydroxide (10 mL). The organic phase was dried over magnesium sulfate. The solvent was removed in vacuo to give 0.11 g of crude 2-((2R)-2-methylamino-3-phenylpropoxy)ethanol, which was used for further syntheses.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:16]3[CH:15]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[NH:13][C:12]=3[CH2:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1>[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)CC=C2c1cc(C)cc(C)c1
Agent: [Pd]
Product: COC(=O)c1cc2c([nH]1)CCC2c1cc(C)cc(C)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.5 g, 2.79 mmol) and 3,5-dimethylphenylmagnesium bromide (14 mL, 6.97 mmol, 0.5 M in THF, 2.5 equiv) were reacted according to General Procedure 3 to give the endo olefin-containing compound methyl 4-(3,5-dimethylphenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate, which was then hydrogenated according to General Procedure 6 (with 5% Pd/C), and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.20-2.36 (m, 7H), 2.71-2.98 (m, 3H), 3.83-3.86 (m, 3H), 4.17 (t, J=7.35 Hz, 1H), 6.49 (s, 1H), 6.67 (d, J=1.42 Hz, 1H), 6.82-6.88 (m, 2H), 9.02 (br. s, 1H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([O:9][CH2:10][C:11]([OH:13])=[O:12])[CH3:8].Cl[CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH2:7]([O:9][CH2:10][C:11]([O:13][CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12])[CH3:8]
Reactant: CCOCC(=O)O
Reactant: ClCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCC(=O)OCSc1ccccc1
Temperature: 70 °C
Yield: 68.7 %

Procedure:
To a mixture of Cs2CO3 (29.5 g, 91 mmol) in DMF (150 mL) at 0° C. was added 2-ethoxyacetic acid (18.0 mL, 191 mmol), and the resulting mixture was heated at 70° C. for 30 min. The reaction was cooled to 0° C., chloromethyl phenylsulfide (10.56 mL, 79 mmol) was added, and the reaction was heated at 70° C. for 90 min. The mixture was cooled to room temperature, and then 0° C., before diluting with H2O (200 mL; an exotherm was observed). The reaction mixture was divided into two equal portions and one portion was further diluted with water (400 mL) and extracted with Et2O (200 mL×2, 100 mL×1). The combined organic extracts were diluted with hexane (100 mL) and washed successively with 1.0 M aqueous NaOH (100 mL) and brine (2×200 mL), dried over anhydrous MgSO4, filtered, and concentrated. The second portion of the reaction mixture from above was processed in an identical fashion and the two lots were combined and concentrated in vacuo to afford the title compound as a yellow oil (12.28 g, 97%): 1H NMR (400 MHz, CDCl3) δ 7.48-7.41 (m, 2H), 7.31 (ddd, J=12.6, 7.9, 6.3 Hz, 3H), 5.51 (s, 2H), 4.11 (s, 2H), 3.59 (q, J=7.0 Hz, 2H), 1.24 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.00, 134.35, 130.53, 129.16, 127.55, 68.46, 68.10, 67.32, 14.99; ESIMS: m/z 226 ([M]+).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:26][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCCC1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1cccnc1
Product: O=C(Nc1nc2cccc(NC3CCCCC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and cyclohexylamine (1.0 mL) as a white powder (37 mg, 42%). HPLC, Rt: 2.60 min. (purity 99.6%). LC/MS, M+(ESI): 337.1, M−(ESI): 335.2.
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[CH:14][N:13]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH2:33]([C:38]1[CH:39]=[N:40]C(Br)=[N:42][CH:43]=1)[CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:33]([C:38]1[CH:39]=[N:40][C:24]([N:21]2[CH2:22][CH2:23][CH:18]([C:15]3[CH:16]=[CH:17][C:12]([CH2:11][O:10][C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[N:4][N:3]=[N:2]5)=[CH:32][CH:31]=4)=[N:13][CH:14]=3)[CH2:19][CH2:20]2)=[N:42][CH:43]=1)[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCc1cnc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(-n4cnnn4)cc3)nc2)CC1
Product: CCCCCc1cnc(N2CCC(c3ccc(COc4ccc(-n5cnnn5)cc4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tert-butyl 4-[2-[4-(tetrazol-1-yl)phenoxymethyl]pyridin-5-yl]piperidine-1-carboxylate (Example 17) (52 mg, 0.12 mmol) and 5-pentyl-2-bromopyrimidine (41 μL, 0.24 mmol) following a procedure analogous to that in Example 48 as a white crystal (26 mg, yield 45%).