Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Ni]>[N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/C(=O)O)n2)cc1
Agent: [Ni]
Product: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(CCC(=O)O)n2)cc1
Temperature: 25 °C

Procedure:
A solution of compound 2, vide supra, (3 g) in alcohol (100 mL) containing Raney nickel (1 g) was stirred under hydrogen at room temperature and pressure until the calculated quantity of hydrogen had been absorbed (ca. 45 minutes). The reduced ester was recovered by filtration and evaporation and purified by column chromatography on silica gel using petroleum ether as eluent. Butyllithium (10 mL, 1.64M in hexane) was added under nitrogen to a stirred suspension of triphenyl-2-pyrrolidinoethylphosphonium bromide (7.2 g) in dry toluene (75 mL) to prepare a Wittig reagent. Treatment of this ester with Wittig reagent by the method of Example 1 followed by saponification gave a mixture of two isomeric acids which were separated by fractional crystallization from ethyl acetate/petroleum ether mixtures. The less soluble E isomer, 3-{6-[3-Pyrrolidino-1-(4-tolyl)prop-1E-enyl]-2-pyridyl]-propionic acid (Compound B), melted at 156°-157°.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1CC=C[NH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17](O)C>>[CH2:1]([O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH2:15])/[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C1=CNC=CC1
Reactant: CCO
Product: C/C(N)=C/C(=O)OCc1ccccc1
Yield: 75 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-trifluoromethylbenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid benzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-'2'-trifluoromethylphenyl)-1,4-dihydropyridine-5-carboxylic acid benzyl ester of melting point 136° C (from ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH:46]1([C:49](Cl)=[O:50])[CH2:48][CH2:47]1>C(Cl)Cl>[C:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:49]([CH:46]2[CH2:48][CH2:47]2)=[O:50])=[CH:3][CH:4]=1)[CH:9]1[CH2:10][CH2:11][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]2[C:21]([CH3:27])=[CH:22][CH:23]=[CH:24][C:25]=2[CH3:26])[CH2:13][CH2:14]1)#[N:38]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(N)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(NC(=O)C3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
To a solution of COMPOUND 142 (61 mg, 0.12 mmol) in CH2Cl2 (1 mL) and Et3N (33 μL, 0.24 mmol) was added cyclopropanecarbonyl chloride (17 μL, 0.18 mmol) and the solution was stirred at room temperature for 4 hours to afford COMPOUND 153 as a white solid (69 mg, 100%) following work-up and purification. 1H NMR (CDCl3) δ 0.75-0.83 (m, 2H), 1.01 (m, 6H), 1.01-1.16 (m, 1H), 1.42-1.61 (m, 2H), 1.61-1.77 (m, 3H), 2.15 (t, 1H, J=11.1 Hz), 2.30 (s, 6H), 2.55 (t, 1H, J=10.8 Hz), 2.74-2.86 (m, 3H), 3.28 (t, 1H, J=11.1 Hz), 3.54 (m, 1H), 3.76 (s, 2H), 3.85 (m, 1H), 6.50 (d, 2H, J=6.49 (d, 2H, J=8.4 Hz), 6.91-6.99 (m, 3H), 7.24 (d, 2H, J=9.3 Hz), 7.36-7.44 (m, 4H), 7.50 (br s, 1H), 8.40 (br s, 1H). 13C NMR (CDCl3) δ 7.98, 8.39, 13.77, 15.72, 19.54, 29.29, 30.57, 31.31, 40.14, 44.03, 48.66, 52.46, 57.39, 60.82, 112.78, 114.85, 119.40, 122.01, 127.67, 128.79, 129.56, 129.66, 130.50, 130.82, 131.47, 134.45, 138.91, 142.66, 145.31, 170.35, 172.09. ES-MS m/z 578 (M+H). Anal. Calcd. for C36H43N5O2.0.3CH2Cl2: C, 72.28; H, 7.28; N, 11.61. Found. C, 72.57; H, 7.38; N, 11.30.
Reaction SMILES: [CH3:1][N:2]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:3]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:7]2[N:6]=[CH:5][C:4]=1[C:13]([O:15]CC)=[O:14].[OH-].[K+:35]>O1CCCC1>[CH3:1][N:2]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)(=[O:20])=[O:19])[C:3]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:7]2[N:6]=[CH:5][C:4]=1[C:13]([O-:15])=[O:14].[K+:35]
Reactant: CCOC(=O)c1cnc2cc(C)nn2c1N(C)S(=O)(=O)c1ccc(Oc2ccncc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc2ncc(C(=O)[O-])c(N(C)S(=O)(=O)c3ccc(Oc4ccncc4)cc3)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.25 g (2.67 mmol) of the preceding ester and 3.21 ml of 1 N KOH in 15 ml of tetrahydrofuran was stirred at room temperature overnight. The mixture was filtered and the solid washed with diethyl ether and ethyl acetate to give 0.5 g of potassium 7-{methyl-[4-(4-pyridinyloxy)benzene-sulfonyl]amino}-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate. A 0.15 g sample of the preceding compound was dissolved in water and the pH adjusted to pH 6 with 2 N citric acid. The mixture was filtered to give 0.12 g of 7-{methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-2-methylpyrazolo[1,5a]pyrimidine-6-carboxylic acid as a white solid, m.p. 246-248° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])=[CH:10][C:8]=2[CH:9]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH3:22][S:23]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]3[CH:21]=[CH:20][CH:19]=[C:16]([C:17]#[N:18])[CH:15]=3)=[CH:10][C:8]=2[CH:9]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cccc(-c2ccc3oc(CCCO)cc3c2)c1
Product: CS(=O)(=O)OCCCc1cc2cc(-c3cccc(C#N)c3)ccc2o1

Procedure:
The product from Example 170B and methanesulfonyl chloride is processed as described in Example 112D to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:7][C:6]2=1)#N.C(O)=[O:31]>CO>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:12]1[C:11]2[CH2:10][CH2:9][CH:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([CH:1]=[O:31])[CH:4]=2
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(F)c2)C1
Reactant: O=CO
Solvent: CO
Product: CC(C)C(=O)NC1CCc2c(c3cc(C=O)ccc3n2Cc2cccc(F)c2)C1

Procedure:
Mix N-(6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (Preparation 3) (8.1 g, 20.8 mmol), Al—Ni catalyst (15.0 g, 231 mmol) in 90% formic acid (125 mL). Heat at reflux for 3 h, then dilute with MeOH and filter hot. Concentrate and partition the residue between aqueous NaHCO3/EtOAc. Dry the organic layer (MgSO4) and concentrate to give 5.9 g yellow semi-solid. Purify using silica gel chromotagraphy, eluting with 30-75% EtOAc in hexane to give 3.3 g (40%) as a white solid. MS (ES): m/z 393 (M+1), 391 (M−1); HPLC (Method B): Rt=4.41 (100%).
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][C:8]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:15](O)[CH3:16]>>[OH:1][C:2]1[N:10]=[CH:9][C:8]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:15][CH3:16])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)O)cnc1O
Reactant: CCO
Product: CCOC(=O)c1cc(S(=O)(=O)O)cnc1O
Temperature: 80 °C
Yield: 74 %

Procedure:
2-Hydroxy-5-sulfonicotinic acid (500 g, 2.28 mol) was dissolved in ethanol (2.5 L) with stirring and heated to 80° C. After 30 mins 0.5 L of solvent was distilled off, then replaced with fresh ethanol (0.5 L) and taken back to 80° C. After a further 60 mins 1.0 L of solvent was distilled off, then replaced with fresh ethanol (1.0 L) and taken back to 80° C. After a further 60 mins 1.0 L of solvent was distilled off, the reaction cooled to 22° C. and stirred for 16 hr. The precipitated product was filtered, washed with ethanol (0.5 L) and dried at 50° C. under vacuum to afford the title compound (416 g, 74%) as a white solid. Decomposition pt 237° C. δ (DMSOd6): 1.25 (3H, t), 4.19 (2H,q), 7.66 (1H, d), 8.13 (1H, d). m/z (Found: 248 [M+H]+, 100%. C8H10NO6S requires 248.22).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[I:9][C:10]1[CH:19]=[CH:18]C2C(=CC=CC=2)N=1.N1C2C(=CC=CC=2)C=CC=1>>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:18][CH:19]=[C:10]2[I:9]
Reactant: Nc1ccccc1Br
Reactant: Ic1ccc2ccccc2n1
Solvent: c1ccc2ncccc2c1
Product: Brc1cccc2c(I)ccnc12

Procedure:
8-bromo-4-iodoquinoline 43a is synthesized from 2-bromoaniline using the same protocols as those described for the preparation of iodoquinoline fragment 1i in Example 1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=[O:10])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1.[Sn](C)(C)(C)[CH3:18]>CN(C=O)C.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>[NH2:1][C:2]1[N:7]=[C:6]([CH3:18])[C:5]([CH:9]=[O:10])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(Cl)c1C=O
Reactant: C[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCCNc1nc(N)nc(C)c1C=O
Temperature: 100 °C

Procedure:
To the product from step (i) (20 g) in DMF (200 ml), Pd(PPh3)4 (2 g) was added followed by SnMe4 (20 ml) and the mixture heated at 100° C. for 16 h. The solvent was evaporated and the residue partitioned between EtOAc and brine, the organics were dried and solvent removed. The product was purified by silica chromatography to give the subtitle compound, 14.4 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1

Procedure:
4-Benzyloxybenzoic acid chloride and an optically active 1,1,1-trifluoro-2-alkanol were allowed to react to give 1,1,1-trifluoro-2-alkyl 4-benzyloxybenzoate, which was subjected to hydrogenolysis to give 1,1,1-trifluoro-2-alkyl 4-hydroxybenzoate. An alkyl bromide and 2-hydroxynaphthalene-6-carboxylic acid methyl ester were allowed to react in the presence of potassium carbonate in a solvent such as dimethylformamide and then subjected to hydrolysis with an aqueous sodium hydroxide. The hydrolyzed product was allowed to react with 1,1,1-trifluoro-2-alkyl 4-hydroxybenzoate in the presence of dicyclohexylcarbodiimide to give 6-alkyloxynaphthalene-2-carboxylic acid 4-(1,1,1-trifluoro-2-alkyloxycarbonyl)phenyl ester. ##STR17## (B) 4-Hydroxybiphenyl-4'-carboxylic acid was dissolved in methanol and heated under refluxing in the presence of concentrated sulfuric acid to give 4-hydroxy-biphenyl-4'-carboxylic acid methyl ester. Then the ester and benzyl bromide were dissolved in a solvent such as DMF and the solution was allowed to react in the presence of anhydrous potassium carbonate to give 4-benzyloxybiphenyl-4'-carboxylic acid methyl ester. The compound obtained was subjected to hydrolysis with an aqueous sodium hydroxide solution to give 4-benzyloxy-biphenyl-4'-carboxylic acid. The compound was further allowed to react with thionyl chloride to give 4-benzyloxy-biphenyl-4'-carboxylic acid chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][C:23]([C:29](O)=[O:30])=[CH:22]2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][O:15][C:29]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][C:19]([O:18][CH3:17])=[CH:28][CH:27]=3)=[O:30])[CH2:12][CH2:13]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Reactant: COc1ccc2ncc(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)cc2c1
Temperature: 30 °C
Reaction time: 15 h

Procedure:
trans-(4-Hydroxymethyl-cyclohexyl)-carbamic acid tert-butyl ester (480 mg, 2.46 mmol, 1.0 eq) is added at room temperature to a stirred solution of 6-methoxy-quinoline-3-carboxylic acid (564 mg, 2.46 mmol, 1.0 eq) in dichloromethane (15 mL), followed by 1-hydroxybenzotriazole (532 mg, 3.94 mmol, 1.6 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.04 g, 5.41 mmol, 2.2 eq) and triethylamine (754 μL, 5.41 mmol, 2.2 eq). After 15 hours stirring at 30° C., solvent is evaporated and the residue is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 4:1, v/v) to afford 6-methoxy-quinoline-3-carboxylic acid trans-4-tert-butoxycarbonylamino-cyclohexylmethyl ester as a white powder (787 mg, 77% yield).
Reaction SMILES: [CH2:1]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21]([NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[N:7]=1)(=[O:23])=[O:22]
Reactant: CCCCCc1csc(N)n1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: CCCCCc1csc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)n1

Procedure:
The title compound was prepared from 4-pentyl-1,3-thiazol-2-ylamine (METHOD I) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (28.6 mg) with purity >90%. MS (pos) m/z 393.1, 395.1.
Reaction SMILES: [N:1]1([C:5](=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=2)[CH2:4][CH2:3][CH2:2]1.[CH:16]([C:19]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([C@H:30]3[CH2:32][C@H:31]3[CH2:33][CH2:34]O)[CH2:26][CH2:25]2)[O:21][N:20]=1)([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[N:1]1([C:5](=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C@@H:31]3[CH2:32][C@@H:30]3[CH:27]3[CH2:26][CH2:25][N:24]([C:22]4[O:21][N:20]=[C:19]([CH:16]([CH3:17])[CH3:18])[N:23]=4)[CH2:29][CH2:28]3)=[C:9]([F:14])[CH:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCO)CC2)n1
Reactant: O=C(Cc1ccc(O)c(F)c1)N1CCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)cc3F)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(azetidin-1-yl)-2-(3-fluoro-4-hydroxyphenyl)ethanone (65.0 mg, 0.236 mmol) in 5 ml anhydrous dichloromethane at RT was added a solution of 2-{(1S,2R)-2-[1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl]cyclopropyl}ethanol (59.0 mg, 0.283 mmol), triphenylphosphine, polymer-bound (186 mg, 0.534 mmol), and di-tert-butyl azodicarboxylate (109 mg, 0.472 mmol). The reaction mixture as stirred at RT for 3 hours. The mixture was filtered by Celite and concentrated. The residue The reaction mixture was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-100% acetonitrile in 0.1% formic acid in water gradient), to give the title compound. LC/MS (m/z) 471.3 (M+H)+. Human EC50: 5.3 nM
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15].[NH2:27][C@H:28]([C:39]([NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:40])[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1>C1COCC1>[NH:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:14]([C:17]([NH:27][C@H:28]([C:39]([NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:40])[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:19])([CH3:15])[CH3:16]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.3 %

Procedure:
2.78 g (14.5 mmol) of EDCl was added to 40 ml of THF solution of 1.47 g (7.25 mmol) of Boc-Aib-OH (manufactured by Sigma-Aldrich Corporation), and 2.03 g (7.25 mmol) of H-Trp-NHPh obtained in Synthesis Example 4-2, followed by stirring for 16 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), it was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1 to 0/1 (volume ratio)), thereby obtaining 2.20 g of the product with a yield of 65.3%.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[C:29]([O:39][CH3:40])[N:28]=3)[CH2:12]1)[C:8](=[O:41])[NH:7]2)=[O:5])C.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[CH3:40][O:39][C:29]1[N:28]=[C:27]([O:26][CH:11]2[CH2:10][CH:9]3[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]4[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]3=[O:41])[CH2:23]4)[CH2:12]2)[CH:32]=[C:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:30]=1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4ccccc4)nc(OC)n3)CC1C(=O)N2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of compound 13d (470 mg, 0.83 mmol) in a mixture of THF methanol 1:1 (30 ml) was added 1 M LiOH solution (10 ml) and the mixture was stirred for four days at room temperature. A 5% solution of citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was dried with sodium sulphate and evaporated on silica gel. The product was isolated by silica gel chromatography eluted with DCM methanol, (400 mg, 88%), (M+H)+535.
Reaction SMILES: [CH:1]1[C:13]2[O:12][N:11]=[C:6]3[N:7]=[CH:8][CH2:9][O:10][C:4]([C:5]=23)=[CH:3][CH:2]=1.[H-].[Na+].[CH2:16](Br)[C:17]#[CH:18]>CN(C)C=O>[CH2:18]([C:3]1[CH:2]=[CH:1][C:13]2[O:12][N:11]=[C:6]3[N:7]=[CH:8][CH2:9][O:10][C:4]=1[C:5]=23)[C:17]#[CH:16]
Reactant: C#CCBr
Reactant: C1=Nc2noc3cccc(c23)OC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCc1ccc2onc3c2c1OCC=N3
Temperature: 80 °C
Yield: 53.3 %

Procedure:
A solution of 4,5-dihydroisoxazolo[3,4,5-ef][1,4]benzoxazepine of Example 7(b) (3.9 g; 22.1 mmoles) in 120 ml dimethylformamide was added to a suspension of sodium hydride (1.4 g; 27.7 mmoles). This was followed by a solution of propargyl bromide (2.7 ml of 80% solution; 24.4 mmoles). The reaction was heated at 80° C. for 1.5 hours and then quenched into water (400 ml). The resulting precipitate was filtered, rinsed and dried, then passed through a column of florisil (ethyl acetate/dichloromethane). This gave 3.5 g of a solid, mp 100°-104° C., which was recrystallized from isopropanol to give 2.5 g (53%) of 4,5-dihydro-3-(2-propynyl)isoxazolo[3,4,5-ef][1,4]benzoxazepine, mp 104°-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[S:14]([C@H:17]1[CH2:21][N:20]([C:22]([C:24]2([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:26][CH2:25]2)=[O:23])[C@H:19]([C:34](O)=[O:35])[CH2:18]1)(=[O:16])=[O:15].[CH:37]1([NH:40][C:41](=[O:48])[C:42](=[O:47])[C@@H:43]([NH2:46])[CH2:44][CH3:45])[CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[S:14]([C@H:17]1[CH2:21][N:20]([C:22]([C:24]2([C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[CH2:26][CH2:25]2)=[O:23])[C@H:19]([C:34]([NH:46][C@@H:43]([CH2:44][CH3:45])[C:42](=[O:47])[C:41]([NH:40][CH:37]2[CH2:39][CH2:38]2)=[O:48])=[O:35])[CH2:18]1)(=[O:15])=[O:16]
Reactant: CC[C@H](N)C(=O)C(=O)NC1CC1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(N3CCOCC3)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Product: CC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(N3CCOCC3)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-Chloro-4-morpholin-4-yl-benzenesulfonyl)-1-[1-(4-chloro-phenyl)-cyclopropane carbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-Amino-2-oxo-pentanoic acid cyclopropylamide in step 1. MS (m/e)=705.19 [M+H+].
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[N:10]=2)=[CH:4][C:3]=1[CH3:17].[F:18][C:19]1[CH:20]=[CH:21][C:22](B2OC(C)(C)C(C)(C)O2)=[C:23]2[C:27]=1[C@H:26]([O:28][C:29]1[CH:42]=[CH:41][C:32]3[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=1)[CH2:25][CH2:24]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[N:10]=3)=[CH:4][C:3]=2[CH3:17])=[C:23]2[C:27]=1[C@H:26]([O:28][C:29]1[CH:42]=[CH:41][C:32]3[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=1)[CH2:25][CH2:24]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: COc1nccc(-c2cc(C)c(I)c(C)c2)n1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccnc(OC)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 4-(4-iodo-3,5-dimethylphenyl)-2-methoxypyrimidine and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.82 min; Mass spectrum (ESI+): m/z=555 [M+H]+.
Reaction SMILES: [CH2:1]1[O:17][C:16]2[C:3](=[CH:4][C:5]3[CH:6]=[C:7]([C:26]([N:28]4[CH2:35][CH2:34][CH2:33][C@H:29]4[C:30]([OH:32])=[O:31])=[O:27])[C:8]4[C:13]([C:14]=3[CH:15]=2)=[CH:12][C:11]([O:18]CC2C=CC=CC=2)=[CH:10][CH:9]=4)[O:2]1.N>>[CH2:1]1[O:17][C:16]2[C:3](=[CH:4][C:5]3[CH:6]=[C:7]([C:26]([N:28]4[CH2:35][CH2:34][CH2:33][C@H:29]4[C:30]([OH:32])=[O:31])=[O:27])[C:8]4[C:13]([C:14]=3[CH:15]=2)=[CH:12][C:11]([OH:18])=[CH:10][CH:9]=4)[O:2]1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)c1cc2cc3c(cc2c2cc(OCc4ccccc4)ccc12)OCO3
Agent: N
Product: O=C(O)[C@@H]1CCCN1C(=O)c1cc2cc3c(cc2c2cc(O)ccc12)OCO3

Procedure:
General procedure g from 16 (92%); white powder; mp 230-231° C.; 1H NMR (400.13 MHz) δ 7.73 (d, J=4 Hz, 1H), 7.67 (s, 1H), 7.50 (d, J=2 Hz, 1H), 7.35 (s, 1H), 7.21 (dd, J=4 Hz, 2 Hz, 1H), 7.06 (m, 1H), 6.01 (s, 2H), 4.67 (t, J=7 Hz, 1H), 3.22 (m, 2H), 2.38 (m, 2H), 2.18 (m, 2H), 1.86 (m, 2H); MS (DCI/NH3) m/e: 380 (M+H)+.