Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH:17]=1)=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[C:33]1([C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=3)[CH:17]=2)=[C:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:7][CH2:8]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 90 °C
Yield: 65.3 %

Procedure:
To a solution of tert-butyl 4-(bromo(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methylene)piperidine-1-carboxylate (Example 71, Step 2) (91 mg, 0.18 mmol) in anhydrous toluene (3 mL) and ethanol (3 mL) was added phenyl boronic acid (43.7 mg, 0.358 mmol) and 2M Na2CO3 (0.53 mL, 1.08 mmol). This solution was degassed for 20 min and Pd(PPh3)4 (19 mg, 10 mol %) was added. The reaction was heated at 90° C. overnight. The reaction was cooled and extracted with EtOAc (3×). The organic layer was dried over MgSO4 and concentrated. Purification by silica gel column chromatography (0-5% MeOH/CH2Cl2) gave the title compound as a foam (60 mg, 66% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([SH:10])=[S:9])([CH3:4])([CH3:3])[CH3:2].[CH2:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([S:10][CH:20]([CH3:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[S:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=S)S)cc(C(C)(C)C)c1O
Reactant: C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CC(SC(=S)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1ccccc1

Procedure:
A solution of 14.1 g (0.05 mol) 3,5-di-t-butyl-4-hydroxydithiobenzoic acid and 10.4 g (0.1 mol) styrene in 100 ml toluene was heated at reflux for about 1 hour. The reaction mixture was filtered through silica gel and evaporated under reduced pressure to give the product, m.p. 70°-72° C. Elemental analysis of the product is tabulated in Table I.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[F:8][C:9]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](CC)([O-])=O>[F:8][C:9]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:10]=1[CH2:11][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:2](=[O:4])(=[O:3])[NH:5][C:6]1=[O:7]
Reactant: Fc1cc(F)c(CNc2ccccc2)c(F)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: O=C1NS(=O)(=O)c2ccccc2N1Cc1c(F)cc(F)cc1F
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 42.9 %

Procedure:
A solution of chlorosulfonylisocyanate (4.72 mL, 54.2 mmol) in nitroethane (75 mL) was cooled to approximately −40° C. and a solution of N-(2,4,6-trifluorobenzyl)aniline (9.90 g, 41.7 mmol) in nitroethane (75 mL) added dropwise over approximately 10 min. The mixture was stirred at −40° C. for 10 min, then at 0° C. for 30 min. Aluminium chloride (5.56 g, 41.7 mmol) was added and the mixture heated at reflux for 30 min, before cooling to rt and cautious addition to stirred ice-H2O (approximately 250 mL). The title compound (6.12 g, 17.9 mmol) was isolated by filtration.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]([OH:15])=O)=[CH:11][N:12]=2)[CH:9]=1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[F:27][C:28]1([F:45])[CH2:31][CH:30]([C:32]2[O:36][N:35]=[C:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:44])=[C:41]([CH:43]=3)[NH2:42])[N:33]=2)[CH2:29]1>ClCCl.N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]([NH:42][C:41]3[CH:43]=[C:37]([C:34]4[N:33]=[C:32]([CH:30]5[CH2:29][C:28]([F:45])([F:27])[CH2:31]5)[O:36][N:35]=4)[CH:38]=[CH:39][C:40]=3[CH3:44])=[O:15])=[CH:11][N:12]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1N
Reactant: CC(=O)c1ccc2ncc(C(=O)O)n2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)c1ccc2ncc(C(=O)Nc3cc(-c4noc(C5CC(F)(F)C5)n4)ccc3C)n2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of 6-acetylimidazo[1,2-a]pyridine-3-carboxylic acid (24r) (71 mg, 0.39 mmol) in dichloromethane (2 mL) was added dropwise oxalyl chloride (173 uL, 1.98 mmol) and a drop of anhydrous N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 30 minutes and concentrated. The residue was treated with 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (37) (85 mg, 0.29 mmol) in anhydrous pyridine (2 mL) with stirring at room temperature for 30 minutes. The crude product was purified on silica gel using 10% MeOH in dichloromethane to give 6-acetyl-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (115). 1H NMR (400 MHz, d6-DMSO) δ 10.24 (s, 1H), 10.13 (s, 1H), 8.70 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.95 (dd, J=2.0, 9.6 Hz, 1H), 7.88-7.84 (m, 2H), 7.52 (d, J=8.4 Hz, 1H), 3.92-3.84 (m, 1H), 3.24-3.02 (m, 4H), 2.64 (s, 3H), 2.38 (s, 3H). MS m/z 433.16 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:21])C=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][N+:8]([O-:21])=[C:7]([CH3:11])[C:6]=1[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nccc(C(C)(C)C)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C(C)(C)C)cc[n+]([O-])c1C

Procedure:
A solution of 10.5 g of 4-tert-butyl-2,3-dimethylpyridine in 120 ml of methylene chloride is treated at room temperature with 14.4 g of m-chloroperbenzoic acid. The reaction mixture is made basic with a saturated sodium carbonate solution and extracted. The organic solution is dried and concentrated. The residue is purified on a silica qel column, whereby the medium pressure flash chromatography method (solvent: methylene chloride/ethyl acetate, with increasing ethyl acetate concentrations) is used and the pressure is produced with nitrogen gas. The 4-tert-butyl-2,3-dimethylpyridine N-oxide obtained is processed directly.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([CH2:28][CH3:29])=[C:15]2[CH2:30][C:31]([NH2:33])=[O:32].[OH-].[Na+].Cl>C(O)C>[NH2:33][C:31](=[O:32])[CH2:30][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([O:11][CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:34])=[O:2])[CH:13]=2)[N:17]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]=1[CH2:28][CH3:29]
Reactant: CCc1c(CC(N)=O)c2cc(OCc3ccccc3C(=O)OC)ccc2n1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1c(CC(N)=O)c2cc(OCc3ccccc3C(=O)O)ccc2n1Cc1ccccc1
Reaction time: 17 h
Yield: 92.1 %

Procedure:
A mixture of 495 mg (1.08 mmol) of 2-[[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]methyl]benzoic acid methyl ester and 2 mL of 5N NaOH in 25 mL of ethanol was stirred for 17 hours, the mixture made acidic with 5N HCl and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (Na2SO4) and concentrated at reduced pressure. The residue was crystallized from methylene chloride/ether to give 440 mg (92% yield) of 2-[[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]methyl]benzoic acid, mp, approximately 100° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C([Cl:91])N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[C:36]([Cl:91])[N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Product: Cc1cc2nc3c(Cl)n2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Yield: 42 %

Procedure:
Prepared in 42% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17,18-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.45-7.36 (m, 3H), 7.32 (s, 1H), 5.91-5.64 (m, 1H), 4.65 (d, J=4.8 Hz, 1H), 4.01-3.86 (m, 2H), 3.55-3.48 (m, 1H), 3.40-3.30 (m, 1H), 2.55 (s, 1H), 2.43 (br. s., 3H), 2.33 (br. s., 1H), 2.00-1.48 (m, 10H), 1.19 (br. s., 3H), 1.17 (s, 9H), 1.06 (d, J=5.9 Hz, 3H) LCMS (ESI, M): 695.3.
Reaction SMILES: N[CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6](CSC1N(C)N=NN=1)=[C:7]2[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C1(N=C=NC2CCCCC2)CCCCC1>>[O:10]=[C:9]1[N:8]2[CH:3]([S:4][CH2:5][CH:6]=[C:7]2[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:2]1
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=CCSC2CC(=O)N12

Procedure:
7-Amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester and L-α-[[[(4-methoxyphenyl)methoxy]carbonyl]-amino]phenylacetic acid from part (a) are reacted in the presence of dicyclohexylcarbodiimide according to the procedure of example 1(b) to yield 7β-[[[[[(4-methoxyphenyl)methoxy]-carbonyl]amino](L-phenyl)acetyl]amino]-3-[[(1-methyl-1H)tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, diphenylmethyl ester; m.p. 117° (dec.).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:8]=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[N:6]=1)(=O)=O.[CH3:30][NH:31][CH3:32].CO>>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([C:7]2[N:6]=[C:5]([N:31]([CH3:32])[CH3:30])[N:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:8]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CNC
Reactant: COc1ccc(CCNc2cc(-c3cccc(OC)c3)nc(S(C)(=O)=O)n2)cc1
Solvent: CO
Product: COc1ccc(CCNc2cc(-c3cccc(OC)c3)nc(N(C)C)n2)cc1

Procedure:
A solution of [2-methanesulfonyl-6-(3-methoxy-phenyl)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [200 mg, 0.42 mmol, Intermediate (34) prepared as in Example 18, step 1] in a 2 M solution of dimethylamine in MeOH (2 mL, 4 mmol) is heated to 150° C. for 20 minutes in a Microwave. The mixture is concentrated, and the residue is subjected to chromatography on silica gel eluting with 70% EtOAc in heptane to afford 6-(3-methoxy-phenyl)-N*4*-[2-(4-methoxy-phenyl)-ethyl]-N*2*,N*2*-dimethyl-pyrimidine-2,4-diamine, which is treated with a solution of saturated hydrogen chloride in EtOAc (1 mL). The resulting precipitate is filtered and dried to afford 6-(3-methoxy-phenyl)-N*4*-[2-(4-methoxy-phenyl)-ethyl]-N*2*,N*2*-dimethyl-pyrimidine-2,4-diamine hydrochloride [0.11 g, 70%, Example 19] as a solid. LCMS: RT=2.85 minutes, MS: 379 (M+H). 1H NMR (300 MHz, CD3OD), □7.46 (1H, t, J=8.1 Hz), 7.26-7.1 (5H, m), 6.83 (2H, d, J=8.1 Hz), 6.27 (1H, s), 4.85 (1H, brs), 3.87 (3H, s), 3.74 (3H, s), 3.71 (2H, t, J=7.2 Hz), 3.28 (6H, s), 2.89 (2H, t, J=7.2 Hz). IC50=4652 nM
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:16]([OH:18])=[O:17])=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:9]1[C:10]([C:16]([OH:18])=[O:17])=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cnc(Cl)cc1C(=O)O
Reaction time: 8 h
Yield: 86.9 %

Procedure:
A stirred suspension of 5-[N-(tert-butoxycarbonyl)amino]-2-chloropyridine-4-carboxylic acid (1.91 g, 7 mmol) in CH2Cl2 (200 mL) is treated slowly with trifluoroacetic acid until homogeneous (ca. 12 mL). The solution is stirred overnight and extracted with dilute NH4OH, and the aqueous layer is then acidified with dilute HCl to gave a precipitate of 5-amino-2-chloropyridine-4-carboxylic acid (1.05 g, 87% yield). 1H NMR (DMSO) δ 9.01 (2H, m), 8.03 (1H, s) 7.48 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:25])([F:24])[C:19]1[CH:20]=[N:21][NH:22][CH:23]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>N.C(OCC)(=O)C.[Cu](I)I.CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:21]2[CH:20]=[C:19]([C:18]([F:25])([F:24])[F:17])[CH:23]=[N:22]2)=[CH:11][C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(I)ccc1OCc1ccccc1
Reactant: FC(F)(F)c1cn[nH]c1
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: N
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1-(benzyloxy)-4-iodo-2-methylbenzene (850 mg, 2.6 mmol), 4-(trifluoromethyl)-1H-pyrazole (535 mg, 3.9 mmol), copper iodide (100 mg, 0.52 mmol), dimethylglycine (54 mg, 0.52 mmol), potassium carbonate (906 mg, 6.6 mmol), and DMSO (10 ml) was stirred at +120° for 20 hours. The reaction was cooled to the ambient temperature, diluted with 10 ml of 5% aqueous ammonia and 10 ml of ethyl acetate and vigorously stirred for 20 min. The mixture was extracted with ethyl acetate (2×20 ml). The combined organic extract was washed with brine, dried over anhydrous magnesium sulfate, and loaded on silica gel. Chromatography on a silica gel column, eluting with a gradient from 5% to 30% of ethyl acetate in heptane gave the target product as an oil, which crystallized upon standing to a colorless solid (670 mg, 77%). MS (M+1): 333.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([N:16]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:17][C:18](=[O:41])[C@@H:19]([CH:24]([C:34]([O:36]C(C)(C)C)=[O:35])[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([N:16]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:17][C:18](=[O:41])[C@@H:19]([CH:24]([C:34]([OH:36])=[O:35])[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1)C(CCCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1)C(CCCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.4 %

Procedure:
A solution of 1.26 g of 2′-(N-benzyloxycarbonyl-D-alanyl)-2(R)-[1(RS)-(tert.-butoxycarbonyl)-4-phenylbutyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml dichloromethane was treated with 5 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to give 1.30 g of 2′-(N-benzyloxycarbonyl-D-alanyl)-2(R)-[1(RS)-(carboxy)-4-phenylbutyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[CH2:39][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:19]1=[O:18]
Reactant: NCc1ccccc1Cl
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(NCc1ccccc1Cl)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-chlorobenzylamine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-chlorobenzyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)methyl]benzamide was obtained (88%) as a colorless solid: mp 148-150° C.; 1H NMR (300 MHz, DMSO-d6) δ9.12 (t, J=5.8 Hz, 1H), 7.57 (dd, J=7.2, 1.5 Hz, 1H), 7.51-7.24 (m, 6H), 7.23-7.11 (m, 3H), 7.00 (dd, J=7.2, 7.2 Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 6.52 (s, 1H), 6.40 (s, 1H), 5.15-4.95 (m, 2H), 4.86 (d, J=9.4 Hz, 1H), 4.71 (d, J=9.4 Hz, 1H), 4.57-4.41 (m, 2H), 3.01-2.88 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.8, 169.0, 161.6, 161.2, 142.8, 136.6, 135.9, 134.6, 132.6, 132.5, 130.8, 129.7, 129.4, 129.2, 129.1, 128.4, 127.7, 127.0, 124.2, 123.6, 120.9, 120.4, 119.6, 109.7, 92.9, 80.4, 72.6, 57.4, 41.4, 41.1, 28.8; MS (ES+) m/z 537.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=1.[CH3:29][C:30]1([CH3:47])[CH2:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]([CH3:46])([CH3:45])[NH:31]1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C:25]1[CH:24]=[C:23]([CH3:27])[NH:22][C:21](=[O:28])[C:20]=1[CH2:19][NH:18][C:16]([C:4]1[C:5]2[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=[C:2]([C:34]2[CH2:33][C:32]([CH3:46])([CH3:45])[NH:31][C:30]([CH3:47])([CH3:29])[CH:35]=2)[CH:3]=1)=[O:17]
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Reactant: CCc1nn(C(C)C)c2nc(Br)cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CCc1nn(C(C)C)c2nc(C3=CC(C)(C)NC(C)(C)C3)cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-ethyl-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.15 g, 0.336 mmol), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.106 g, 0.403 mmol) and Pd(PPh3)4 (0.020 g, 0.017 mmol) in 1,4-dioxane (3 mL) was purged with argon for 10 min. Then, 2M Na2CO3 solution (0.128 g, 1.21 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (59% yield). LCMS: 505.30 (M+1)+; HPLC: 99.84% (@ 254 nm) (Rt; 5.386); 1H NMR (DMSO-d6, 400 MHz) δ 11.49 (s, 1H), 8.68 (t, 1H), 7.32 (s, 1H), 6.72 (s, 1H), 5.88 (s, 1H), 5.17-5.10 (m, 1H), 4.33 (d, 2H, J=4.4 Hz), 2.84-2.79 (q, 2H, J=7.6 Hz), 2.39 (s, 2H), 2.25 (s, 3H), 2.11 (s, 3H), 1.46 (d, 6H, J=6.8 Hz), 1.22 (s, 6H), 1.13 (s, 6H), 1.06 (t, 3H, J=7.6 Hz).
Reaction SMILES: [CH2:1]1[CH2:15][C@H:14]2[C@@H:4]([CH2:5][C:6]3[C:16]4[C:9](=[CH:10][CH:11]=[CH:12][C:13]2=4)[NH:8][CH:7]=3)[NH:3][CH2:2]1.[C:17](OC(=O)C)(=[O:19])C.C([O-])(=O)C.[Na+].N>C(O)(=O)C>[OH:19][CH2:17][C:7]1[NH:8][C:9]2[C:16]3[C:6]=1[CH2:5][C@@H:4]1[C@@H:14]([C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:1][CH2:2][NH:3]1
Reactant: c1cc2c3c(c[nH]c3c1)C[C@H]1NCCC[C@H]21
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1[nH]c2cccc3c2c1C[C@H]1NCCC[C@H]31
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 mmol of ergoline is dissolved in 10 ml of glacial acetic acid. 5 ml (0.05 mol) of acetic anhydride and 0.8 g (0.01 mol) of anhydrous sodium acetate are added and allowed to stir overnight at room temperature. For working up, ice is added, it is stirred for 30 minutes and mixed with NH3 solution. After extraction with dichloromethane, drying of the organic phases on Na2SO4 and removal of the solvent in a vacuum, the raw product is obtained which is further purified by crystallization or chromatography.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].S(O[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)CCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of potassium phthalimide (2.96 g, 16.0 mmoles) and 100 ml of dried N,N-dimethylformamide was heated at 110° C. To this mixture was added dropwise 80 ml of a solution of methyl 18-tosyloxyoctadecanoate (5.0 g, 10.7 mmoles) in 80 ml of N,N-dimethylformamide, and the mixture was heated with stirring at 110° C. for 2 hours. The reaction mixture was poured into ice water to a total volume of 1.2 1, and stirred for 30 minutes. Thereafter, the precipitates that formed were collected by filtration and dissolved in chloroform. The obtained solution was washed with water and then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and isolated and purified by silica gel column chromatography [eluent: mixture of benzene and methylene chloride (volume ratio: 2:1)], to give methyl 18-phtahlimideocatadecanoate (4.15 g, 88%) having the following properties.