Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:35]([O:36][CH3:37])=[CH:34][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[CH:6]=1)[N:14]=[CH:13][C:12]([C:17]#[N:18])=[C:11]3[NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)=[C:22]([Cl:33])[CH:21]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.[I-].[Na+].C(=O)(O)[O-].[Na+]>COCCOC>[Cl:33][C:22]1[CH:21]=[C:20]([NH:19][C:11]2[C:10]3[C:15](=[CH:16][C:7]4[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[C:35]([O:36][CH3:37])=[CH:34][C:8]=4[CH:9]=3)[N:14]=[CH:13][C:12]=2[C:17]#[N:18])[CH:25]=[CH:24][C:23]=1[S:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1
Reactant: C1COCCN1
Reactant: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCN1CCOCC1

Procedure:
A mixture of 1.27 g (2.3 mmol) of 8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxybenzo[g]quinoline-3-carbonitrile, 4.0 mL of morpholine and 0.1 g of sodium iodide in 10 mL of 1,2-dimethoxyethane is heated under reflux for 16 hours. After allowing the reaction to cool, the solvent is evaporated to yield a residue, which is stirred with saturated sodium bicarbonate. The solid is collected by filtration, is washed with water and dried. The crude product is purified by silica gel chromatography, utilizing a gradient of 98:2 to 90:10 of methylene chloride/methanol to give 0.53 g of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile as a yellow solid, mp>300° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C@@H:9]1[CH3:22])=O)(C)(C)C.[ClH:23]>>[ClH:23].[ClH:23].[CH2:15]([N:11]1[CH2:10][C@@H:9]([CH3:22])[NH:8][CH2:13][C@@H:12]1[CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1Cc1ccccc1
Agent: Cl
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1
Reaction time: 1 h

Procedure:
To 9.76 g (32.06 mmol.) of trans-1-tert-butoxycarbonyl-2,5-dimethyl-4-benzyl piperazine was added, at room temperature, 10 ml (120 mmol.) of 12N hydrochloric acid. The mixture was stirred for one hour. The solvent was distilled off under reduced pressure. To the residue was added 2-propanol, which was further concentrated. To the concentrate was added diethyl ether. The resulting crystals were collected by filtration and washed with 2-propanol and diethyl ether to give the object compound as white crystals. The yield was 7.97 g (90%).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31]C(OC(C)(C)C)=O)[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH2:31])[CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[CH2:21][CH2:22][CH:6]12)=[O:4]
Reactant: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(N)C1CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
A solution containing 50 (226 mg, 0.42 mmol) in DCM (5 mL) was cooled to 0° C. TFA (2 mL) was added and the reaction mixture was warmed to ambient temperature. After 90 min, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 172 mg of 51 as an off-white-colored foam which was used without further purification. Mass spectrum, m/z [443.3] (M+H)+.
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].[C:12]1([C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15])[OH:13]>CC(C)=O>[O:13]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[O:15][CH2:5][CH:2]1[C:3]#[N:4]
Reactant: C=C(Cl)C#N
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CC1COc2ccccc2O1

Procedure:
1.45 g (15.5 mmol) of 2-chloroacrylonitrile and 6 g (43.5 mmol) of dry potassium carbonate are added in succession to 6.6 g (60 mmol) of catechol dissolved in 80 ml of anhydrous acetone. The operation is repeated 4 times within one hour; the mixture is then heated to boiling. After 18 hours at reflux under argon, the reaction mixture is cooled and then filtered over Celite. After evaporation of the solvent, the residue is taken up in a water/ethyl acetate mixture (50:50) and then the aqueous phase is extracted with ethyl acetate. The organic phase, dried over magnesium sulphate and then filtered, is evaporated under reduced pressure. The title nitrile is obtained pure in the form of a white solid after purification on a silica column (eluant: AcOEt/PE 30/70).
Reaction SMILES: [N:1](CCOCCON)=[N+:2]=[N-:3].[OH:11][C:12]([CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]1[C@@H:26]2[C@@H:21]([NH:22][C:23]([NH:25]2)=[O:24])[CH2:20][S:19]1)=[O:13].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:1]([CH:14]([CH2:15][CH2:16][CH2:17][C@H:18]1[C@@H:26]2[C@@H:21]([NH:22][C:23]([NH:25]2)=[O:24])[CH2:20][S:19]1)[C:12](=[O:11])[OH:13])=[N+:2]=[N-:3]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: [N-]=[N+]=NCCOCCON
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NC(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of O-(2-(2-azidoethoxy)ethyl)hydroxylamine (10 mg, 0.068 mmol), biotin (225 mg, 0.103 mmol) and DIPEA (29 mg, 0.206 mmol) in 0.8 mL of DMF was added PyBOP (54 mg, 0.103 mmol). The reaction was allowed to stir at room temperature for 2 h. Solvent was then removed in vacuo, and the crude product was purified by silica gel column chromatography (ethyl acetate: methanol 4:1) to afford azido-biotin (22 mg, 0.059 mmol, 88%) as a pale yellow solid. 1H NMR (CD3OD, 500 MHz) δ (ppm): 1.35 (m, 1H), 1.43 (m, 2H), 1.68 (stack, 4H), 2.11 (t, J=7.3 Hz, 2H), 2.70 (d, J=12.8 Hz, 1H), 2.92 (dd, J=5.0, 12.8 Hz, 1H), 3.20 (m, 1H), 3.43 (m, 2H), 3.67 (m, 2H), 3.72 (m, 2H), 3.98 (m, 2H), 4.30 (m, 1H), 4.48 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4](=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:5][OH:6].[CH:11]([N:14]([P:18](N(C(C)C)C(C)C)Cl)[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]>C1COCC1>[CH:11]([N:14]([CH:15]([CH3:17])[CH3:16])[P:18]1[O:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[CH2:2][O:1]1)([CH3:13])[CH3:12]
Reactant: CC(C)N(C(C)C)P(Cl)N(C(C)C)C(C)C
Reactant: OCc1ccccc1CO
Solvent: C1CCOC1
Product: CC(C)N(C(C)C)P1OCc2ccccc2CO1

Procedure:
Phthalyl alcohol (1.15 g, 8.31 mmol) was dissolved in 5 ml of THF, and bisdiisopropylaminochlorophosphine (2.21 g, 8.31 mmol) which was dissolved in 5 ml of THF was added dropwise to the solution at -15° C. under a nitrogen atmosphere. Afterward, the temperature of the solution was adjusted to room temperature, and after the disappearance of phthalyl alcohol had been confirmed, hydrochloride of diisopropylamine was washed with ether. The wash liquor was concentrated and then distilled in order to obtain the desired product having a melting point of from 150° to 155° C. (0.7 mmHg).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[OH:18])[CH:2]=[CH2:3].[CH2:19](Br)[CH:20]=[CH2:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C(C(C)=O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:18][CH2:21][CH:20]=[CH2:19])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(OCc2ccccc2)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(OCc2ccccc2)cc1CC=C
Reaction time: 23 h

Procedure:
A mixture of 2-allyl-4-benzyloxy-phenol (ER2-YYR-17) (35.56 g, 148 mmol), allyl bromide (21.5 g, 178 mmol), cesium carbonate (58 g, 178 mmol) and methyl ethyl ketone (400 mL) was refluxed with stirring in a 1 L round bottomed flask. After 23 h, the reaction was cooled and concentrated. The residue was partitioned between water (500 mL) and EtOAc (400 mL). The organic layer was dried (MgSO4) and concentrated to a tan oil, 39.37 (95%) ER0-LKW-190A: 1H NMR (CDCl3) δ 3.45 (dd, 2H), 4.54 (dd, 2H), 5.04 (s, 2H), 5.18 (m, 2H), 5.29 (dd, 1H), 5.46 (dd, 1H), 5.94-6.18 (m, 2H), 6.81 (s, 2H), 6.88 (s, 1H), 7.30-7.48 (m, 5H), MS (ES) m/e 281 [M+1].
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C@@H:18]([NH2:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C@@H:18]([NH:20][C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][NH:26]2)[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1Cc1ccccc1
Temperature: 90 °C
Yield: 30.1 %

Procedure:
A mixture of (S)-1-(1-benzyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (322 mg, 1.20 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (286 mg, 1.20 mmol) and DIPEA (1.07 mL, 5.98 mmol) in IPA (5 mL) was heated at 90° C. in a sealed vial overnight. The resultant mixture was allowed to cool to RT and then concentrated in vacuo. The residue was passed down an Isolute® SCX-2 cartridge, eluting with DCM, MeOH and 2M NH3 in MeOH solution to afford a pale red gum. This was purified by column chromatography (silica gel, gradient 0-10% [2M NH3 in MeOH] in DCM) to afford 393 as a white solid (140 mg, 31%). LCMS (Method K): RT 3.21 min [M+H]+ 388.1 1H NMR (DMSO-d6, 400 MHz): δ 8.20 (1H, s), 8.13 (1H, s), 8.04-7.93 (1H, s), 7.63 (1H, dd, J=8.80, 4.92 Hz), 7.35-7.17 (4H, m), 7.16-7.10 (2H, m), 7.03 (1H, ddd, J=9.91, 8.78, 2.52 Hz), 5.93-5.75 (1H, m), 5.61 (2H, s), 1.59 (3H, d, J=6.77 Hz)
Reaction SMILES: ClC(Cl)(Cl)C([N:5]=[C:6]=[O:7])=O.[CH3:10][O:11][C:12](=[O:58])/[CH:13]=[CH:14]\[C@H:15]([CH3:57])[C@H:16]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[C@@H:17]([CH3:48])/[CH:18]=[C:19](/[CH3:47])\[CH2:20][C@H:21]([CH3:46])[C@@H:22]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C@H:23]([CH3:37])[C@@H:24]([OH:36])[C@@H:25]([CH3:35])[CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH3:10][O:11][C:12](=[O:58])/[CH:13]=[CH:14]\[C@H:15]([CH3:57])[C@H:16]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:51])[CH3:52])[C@@H:17]([CH3:48])/[CH:18]=[C:19](/[CH3:47])\[CH2:20][C@H:21]([CH3:46])[C@@H:22]([O:38][Si:39]([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:41])[CH3:40])[C@H:23]([CH3:37])[C@@H:24]([O:36][C:6]([NH2:5])=[O:7])[C@@H:25]([CH3:35])[CH2:26][O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)/C=C\[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C(/C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C)[C@@H](O)[C@@H](C)COCc1ccccc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)/C=C\[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C(/C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C)[C@@H](OC(N)=O)[C@@H](C)COCc1ccccc1
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
Trichloroacetyl isocyanate (106 mg, 0.56 mmol, 1.5 eq) is added to a solution of (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S)-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-13-hydroxy-4,6,8,10,12,14-hexamethyl-15-(phenylmethoxy)-2,7-pentadecadienoic acid methyl ester (266 mg, 0.37 mmol) in CH2Cl2 (5 mL) at 23° C. The mixture is stirred for 30 min. The solvent is removed. The residue is chromatographed (10% EtOAc in hexane) to give 208 mg (74%) of the desired compound as a white foam.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])(=[O:26])=[O:25])=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH2:30]([N:27]([CH2:28][CH3:29])[S:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:8](=[O:10])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:19][CH:20]=1)(=[O:26])=[O:25])[CH3:31]
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: CCN(CC)S(=O)(=O)c1ccc(N)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCN(CC)S(=O)(=O)c1ccc(NC(=O)C(c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of diphenylacetic acid (223 mg, 1.05 mmol), 4-Amino-N,N-diethyl-benzenesulfonamide (240 mg, 1.05 mmol), HOBT (213 mg, 1.58 mmol), and EDC (242 mg, 1.26 mmol) in dichloromethane (20 mL) was stirred at 23° C. for 15 hours. The reaction mixture was washed with 1N aqueous sodium hydroxide (10 mL), 1N aqueous hydrochloric acid (10 mL), and saturated aqueous sodium chloride (10 mL). The organics were dried over magnesium sulfate and were concentrated. Flash chromatography (20% THF in hexanes grading to 40% THF in hexanes) provided the title compound as orange oil that solidified upon standing (224 mg). MS 423 (M+1)
Reaction SMILES: C(OC(N1C(C)C2C(O[C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:40])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH:23]=[CH:22]4)=NC=NC=2C1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]([NH:29][C:28]([N:24]2[C:25]3[C:21](=[CH:20][CH:19]=[CH:27][CH:26]=3)[CH:22]=[CH:23]2)=[O:40])[CH:35]=[CH:34][CH:33]=1
Reactant: CC1c2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 5-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester in DCM (20 mL), TFA (20 ml, 134 mmol) is added at 0° C. After 30 min the reaction is warmed to rt. At this point, the reaction is evaporated and the crude product is dissolved in EtOAc. A Few drops of NH4OH are added to freebase the amine and the whole mixture is then evaporated. The crude product is added to a silica gel column and is eluted with DCM/MeOH/NH4OH (100:0:0 to 93:6:1) to give racemic 545-Methyl-6,7-dihydro-5H-pyrrolo[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 454.9 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.50 (s, 1 H) 8.33 (s, 1 H) 8.06 (s, 1 H) 7.94 (br. S., 2 H) 7.57 (s, 1 H) 7.42 (br. S., 2 H) 7.12 (d, J=9.09 Hz, 1 H) 6.75 (d, J=3.03 Hz, 1 H) 4.70 (br. S., 1 H) 4.10-4.22 (m, 2 H) 1.60 (d, J=6.57 Hz, 3 H). Racemate is then separated using chiral HPLC (IA column; 40% heptane, 60% Ethanol) to give the corresponding enantiomers D-1 and D-2.
Reaction SMILES: O[C:2]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1>C(O)=O>[C:9]1([C:2]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)=[CH:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CCc2cc(C(O)(Cn3ccnc3)c3ccccc3)ccc2N1
Solvent: O=CO
Product: O=C1CCc2cc(C(=Cn3ccnc3)c3ccccc3)ccc2N1

Procedure:
A solution of 600 mg of 6-[1-hydroxy-1-phenyl-2-(imidazol-1-yl)ethyl]-3,4-dihydrocarbostyril in 20 ml of anhydrous formic acid was refluxed for 24 hours. The solvent was removed under reduced pressure and the residue partitioned between 5% methanol in methylene chloride and aqueous potassium carbonate. The organic solution was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 5% methanol in methylene chloride, affording 6-[1-phenyl-2-(imidazol-1-yl)ethenyl]-3,4-dihydrocarbostyril as a mixture of (E) and (Z) isomers.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[N:15]1[NH:16][CH:17]=[C:18]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20][C:19]=12>ClCCl.CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:16]2[CH:17]=[C:18]3[C:19]([CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]3)=[N:15]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]nc2CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(NS(C)(=O)=O)cc3)nc2CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To {4-[(methylsulfonyl)amino]phenyl}boronic acid (commercially available from e.g. Combi-Blocks) (127 mg, 0.29 mmol) in dichloromethane (3 ml) was added copper(II) acetate (107 mg, 0.59 mmol) and 4 Å molecular sieves (190 mg), and the reaction stirred at room temperature, open to air, for 10 minutes. 1,1-Dimethylethyl 4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 9) (70 mg, 0.29 mmol) was added and the reaction stirred at room temperature, open to air, overnight. The reaction mixture was diluted with methanol and filtered through a celite pad, washing with methanol. Solvent was evaporated in vacuo. Ethyl acetate and water were added, and the product was extracted into ethyl acetate (×3), washed with water (×1), then saturated sodium bicarbonate solution (×1), and then dried over magnesium sulfate. Solvent was evaporated in vacuo. The resulting crude product was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate in hexane (0-50%). Relevant fractions were combined and solvent evaporated in vacuo. The resulting crude product was purified further by Mass Directed Autopreparation to afford the title compound (D39). MS (ES+) m/e 407 [M+H]+.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-:18].[C:19]([O:23][C:24]([N:26]([CH3:52])[C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]2[CH:51]=[CH:50][C:38]([O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44]OS(C)(=O)=O)=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].ClCCl>C1COCC1>[C:19]([O:23][C:24](=[O:25])[N:26]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]2[CH:51]=[CH:50][C:38]([O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][F:18])=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)[CH3:52])([CH3:22])([CH3:21])[CH3:20]
Reactant: [F-]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C=Cc2ccc(OCCOCCOS(C)(=O)=O)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(C=Cc2ccc(OCCOCCF)cc2)cc1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
Anhydrous TBAF (Cox D P, et al., J Org Chem. 1984; 49:3216-19) (38.5 mg 0.15 mmol) was added to a solution of compound 10a (14.5 mg, 0.03 mmol) in anhydrous THF (3 ml). The mixture was refluxed for 4 hours. After cooled to room temperature, standard workup with dichloromethane was applied and the residue was purified by silica gel preparative TLC (2% methanol in dichloromethane) to afford compound 11a (7 mg, 57%): 1H NMR δ 7.43 (d, 4H, J=8.6 Hz), 7.20 (d, 2H, J=8.4 Hz), 6.97 (q, 2H), 6.91 (d, 2H, J=8.6 Hz), 4.60 (d, t, 2H, J1=47 Hz, J2=4.0 Hz), 4.17 (t, 2H), 3.90 (t, 3H), 3.75 (t, 1H), 3.27 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[C:14]([OH:19])(=[O:18])[C:15]([CH3:17])=O.C([BH3-])#N.[Na+]>O>[C:14]([CH:15]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH3:17])([OH:19])=[O:18]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(=O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CC(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O
Yield: 91.5 %

Procedure:
A solution of L-alanyl-L-proline (372 mg) and pyruvic acid (881 mg) in water is adjusted to pH 7 and treated with 377 mg of sodium cyanoborohydride at room temperature until reaction is complete. The product is absorbed on strong acid ion-exchange resin and then eluted with 2% pyridine in water. Freeze drying gives 472 mg of N-(1-carboxyethyl)-L-alanyl-L-proline. Nmr and mass spectrogram are consistent with structure. The nmr spectrum shows multiplets centered at 4.5, 3.7, and 2.2 ppm, and a pair of doublets and 1.6 ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClS([N:24]=[C:25]=[O:26])(=O)=O>ClCCl>[C:25]([C:14]1[NH:13][CH:12]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:26])[NH2:24]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]c(C(N)=O)c1-c1ccc([N+](=O)[O-])cc1
Temperature: -24 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To 18 g (69.16 mmol) of ethyl 4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate suspended in 300 cm3 of dichloromethane are added, at a temperature in the region of −24° C. under an argon atmosphere, 8.1 cm3 (91.29 mmol) of chlorosulfonyl isocyanate dissolved in 100 cm3 of dichloromethane. After stirring for 30 minutes at a temperature in the region of −24° C., the reaction medium is allowed to warm to a temperature in the region of 20° C. over 2 hours. After initiating the crystallization using a glass rod, the reaction mixture is stirred at a temperature in the region of 20° C. for 30 minutes. The reaction mixture is then cooled to a temperature in the region of 5° C. and then filtered through a No 3 sinter funnel. The solid is washed with three times 40 cm3 of dichloromethane and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. for 3 hours. The solid is then suspended in 500 cm3 of water; the resulting mixture is then heated at a temperature in the region of 40° C. for 3 hours and then cooled at a temperature in the region of 5° C. for 1 hour before filtering through a No 3 sinter funnel. The solid is successively washed with twice 50 cm3 of water and twice 30 cm3 of petroleum ether and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. for 16 hours to give 15.4 g of ethyl 5-carbamoyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate in the form of a beige-coloured solid; EI: m/z=303: M+; m/z=274 [M-CH2CH3]+; m/z=258 [M-OCH2CH3]+; m/z=241 [258-OH]+ base peak.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[CH3:19])=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:38].C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)C>[ClH:38].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:43])[NH2:27])=[CH:22][CH:21]=3)[CH3:19])=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 77 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 77% of theory, C28H31N7O3 (513.6); EKA mass spectrum: (M+H)+=514; (M+H+Na)++=268.7.