Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=4)[N:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].Br[CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O>[CH2:1]([C:3]1[N:4]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([C:12]1[N:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[N:15]=[CH:14][CH:13]=1)=[CH:7]2)[CH3:2]
Reactant: CCc1n[nH]c2cc(-c3ccnn3-c3ccc(S(C)(=O)=O)cc3)ccc12
Reactant: CCC(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1c2ccc(-c3ccnn3-c3ccc(S(C)(=O)=O)cc3)cc2nn1C(CC)CC
Temperature: 60 °C
Reaction time: 48 h
Yield: 3.7 %

Procedure:
3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole (100 mg, 0.27 mmol), 3-bromopentane (70 mg, 0.46 mmol), potassium carbonate (45 mg, 0.33 mmol) and N,N-dimethylformamide (2 mL) were added to a 1-necked flask. The mixture was heated to 60° C. for 6 hours, then slowly cooled to room temperature and stirred for a further 48 hours. A further equivalent of 3-bromopentane (41 mg, 0.27 mmol) was then added, and the reaction was heated to 120° C. After cooling to room temperature, water and ethyl acetate were added. The product was extracted once with ethyl acetate, and washed with water and brine. The combined organics were dried, and filtered and concentrated. The reside was purified by column chromatography on silica gel (eluting using 50% ethyl acetate in hexanes for 10 minutes and then a linear gradient to 100% ethyl acetate in hexanes at 20 minutes) to give 4.4 mg (3.7%) of 3-ethyl-2-(1-ethylpropyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-2H-indazole. LC/MS (EI) tR 4.36 (Method C), m/z 437.1 (M++1), 1H NMR (CDCl3) δ 0.6 (t, 3H), 1.4 (t, 2H), 1.8 (m, 2H), 1.9 (m, 2H), 3.0 (m, 6H), 4.0 (m, 1H), 6.5 (s, 1H), 7.0 (d, 1H), 7.1 (s, 1H), 7.5 (d, 2H), 7.7 (m, 1H), 7.8 (s, 1H), 7.8 (d, 2H). 13 mg (11%) of the corresponding isomer (3-ethyl-1-(1-ethylpropyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole) was also isolated.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20]O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(N=NC(OCC)=O)=O>O1CCCC1>[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
4-Nitrophenol (4.01 g), 2-(tert-butoxycarbonylamino)ethanol (4.65 g) and triphenylphosphine (7.55 g) were dissolved into tetrahydrofuran (50 ml) and the solution was ice cooled. Azo dicarboxylic acid diethyl (5.52 g) dissolved in tetrahydrofuran (5 ml) was added drop-wise into the ice-cooled solution. After being stirred for one hour at room temperature, the reaction mixture was concentrated under vacuum. Residue was dissolved into ethyl acetate (50 ml). Hexane (400 ml) was added to the ethyl acetate solution and insoluble matter formed was removed from solution by filtration. Filtrate was concentrated under vacuum to small volume. Concentrate was purified by silica-gel column chromatography using ethyl acetate:hexane (1:1) as the solvent system to obtain N-(tert-butoxycarbonyl)-2-(4-nitrophenoxy)ethylamine (5.91 g) as color-less oily substance.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH:2]=1.Cl.[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[C:30]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31]>>[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[C:30]([CH:32]1[CH2:37][CH2:36][N:35]([C:14]([C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:20][CH:19]=2)=[O:16])[CH2:34][CH2:33]1)=[O:31]
Reactant: CCOC(=O)c1ccc(-n2cnc3cccnc32)cc1
Reactant: Cc1ccc(C(=O)C2CCNCC2)c(C)c1
Agent: Cl
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(-n4cnc5cccnc54)cc3)CC2)c(C)c1
Yield: 63.4 %

Procedure:
Using ethyl 4-(imidazo[4,5-b]pyridin-3-yl)benzoate (300 mg) described in Preparation Example 77 and (2,4-dimethylphenyl)(piperidin-4-yl)methanone hydrochloride (285 mg) and by the reaction and treatment in the same manner as in Example 170, the title compound (312 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][CH:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:35])=[O:34])[C:23]([Cl:41])=[CH:22][N:21]=1>>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:35])=[O:34])=[N:25][C:20]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][CH:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Reactant: COc1cc2c(cc1N)CCN(CC(C)O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCCC3)n1)CCN(CC(C)O)CC2
Yield: 67 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol and (2,5-Dichloro-pyrimidin-4-yl)-[2-(pyrrolidine-1-sulfonyl)-phenyl]-amine. The product was isolated as a yellow foam (75 mg, 67%). MS (ESI+): 587 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.44 (s, 1H), 8.55 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.56 (t, J=8 Hz, 1H), 7.52 (s, 1H), 7.26 (m, 1H), 6.67 (s, 1H), 3.89 (s, 4H), 3.28 (m, 4H), 2.92-2.52 (m, 10H), 2.27 (t, J=9 Hz, 1H), 1.79 (m, 4H), 1.17 (d, J=6 Hz, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[Li]C(C)(C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1.CCCCCC.CC(C)=O>CCOCC.C1COCC1>[F:31][C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[O:7][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:15])([CH3:14])[CH3:1]
Reactant: C[Si](C)(C)CCOCOc1cccnc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: C[Si](C)(C)CCOCOc1cnccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a stirred solution of 9 (12.39 g, 0.055 mol) in ether (200 mL) cooled to ≦−70° C. under an atmosphere of argon was slowly added t-BuLi (40 mL, 1.5 M pentane solution). During the addition, the reaction temperature was maintained at ≦−68° C. After the addition was complete the mixture was stirred an additional 60 minutes at ≦−70° C., then transferred via cannula to a stirred solution of N-fluorobenzenesulfonimide (18.92 g) in dry THF (200 mL) which was also cooled to ≦−70° C. under argon. After the addition was complete, the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature. Water (100 mL) was added and the organic phase was separated, dried (MgSO4) and concentrated to give a brown oil. Chromatography (silica gel, hexane-acetone, 9:1) gave the desired product 10 as an orange oil (7.5 g) which contained about 15% starting material. This crude mixture was used directly in the next reaction.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O(C(C)(C)C)[K].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([Cl:12])[N:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1cc2ccccc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)cc3ccccc23)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a degassed solution of 1,3-dichloro-isoquinoline (3.00 g, 15.15 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.64 g, 18.18 mmol, 1.2 equiv; commercially available) in toluene (35 mL) was added KOtert-Bu (2.38 g, 21.21 mmol, 1.4 equiv), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.38 g, 0.61 mmol, 0.04 equiv) and tris(dibenzylideneacetone)-dipalladium(0) (0.31 g, 0.30 mmol, 0.02 equiv). The reaction mixture was stirred at 80° C. for 18 h, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate providing 1.14 g (21%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.41-1.48 (m, 2H), 1.43 (s, 9H), 1.90-1.91 (m, 2H), 2.87-2.93 (m, 2H), 3.97-4.02 (m, 2H), 4.24-4.27 (m, 1H), 6.96 (s, 1H), 7.45-7.48 (m, 2H), 7.64-7.66 (m, 2H), 8.29 (d, J=8.4 Hz, 1H). MS (ISN): 360.0 [M−H]−.
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22]([OH:26])=[CH:21][C:20]=3[Cl:27])[C:14]2=[O:28])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].Br[CH:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:20]([Cl:27])=[CH:21][C:22]([O:26][CH:32]([CH3:34])[CH3:33])=[CH:23][C:24]=3[Cl:25])[C:14]2=[O:28])[CH2:9][CH2:8]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)Br
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(O)cc3Cl)C2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc(Cl)c(CC2CCN([C@H]3CC[C@@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)c(Cl)c1

Procedure:
Add 1-[cis-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(2,6-dichloro-4-hydroxy-benzyl)-pyrrolidin-2-one (Preparation 72) (0.543 g, 1.15 mmol), 2-bromopropane (0.212 g, 1.72 mmol), and potassium carbonate (0.365 g, 2.64 mmol) together with acetone (10 mL) and reflux overnight. Concentrate the reaction mixture under reduced pressure to give a residue. Purify the residue over silica gel, (98:2 dichloromethane in methanol) to give 0.080 g (14%) of the title compound: mass spectrum m/z: 516(M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]([CH2:20][CH2:21][C:22](=[O:24])[NH2:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]2=[O:11].CCOC(C)=O.C([O-])(O)=O.[Na+].[CH3:36][N:37](C=O)C>[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:36]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]([CH2:20][CH2:21][C:22](=[O:24])[NH2:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]2=[O:11])#[N:37]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)C(CCC(N)=O)N1Cc2c(Br)cccc2C1=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(CCC(N)=O)N1Cc2c(C#N)cccc2C1=O
Temperature: 120 °C
Yield: 74 %

Procedure:
A mixture of tert-butyl 2-(4-bromo-1-oxoisoindolin-2-yl)-4-carbamoylbutanoate (1.2 g, 3.02 mmol), zinc cyamide (0.21 g, 1.81 mmol), tris(dibenzylideneacetone)dipalladium (0.06 g, 0.06 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.067 g, 0.12 mmol) in deoxygenated DMF (15 mL) was heated to 120° C. under N2 for 6 hours. The mixture was cooled to room temperature and poured into EtOAc (100 mL) and sat. NaHCO3 (40 mL). The EtOAc solution was washed with water (2×40 mL), brine (40 mL), and dried (MgSO4). Solvent was removed and the residue was purified by chromatography (CH2Cl2: CH3OH 97.5:2.5) to afford tert-butyl 2-(4-cyano-1-oxoisoindolin-2-yl)-4-carbamoylbutanoate (0.77 g, 74%): 1H NMR (CDCl3) δ 8.07-8.03 (dd, J=0.7 and 7.4 Hz, 1H), 7.86-7.83 (dd, J=1.0 and 7.9 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 5.91 (s, 1H), 5.68 (s, 1H), 5.03-4.98 (m, 1H), 4.85 (d, J=17.9 Hz, 1H), 4.62 (d, J=17.9 Hz, 1H), 2.48-2.41 (m, 4H), 1.46 (s, 9H); 13C NMR (CDCl3) δ 173.56, 169.21, 167.70, 145.23, 134.94, 133.11, 128.93, 128.21, 115,65, 107.86, 82.98, 63.68, 54.47, 46.55, 32.34, 27.95, 25.46.
Reaction SMILES: C(N1C2C(=[O:17])NC(=O)N(C)C=2N=C1)C1C=CC=CC=1.CN1C2N=CN(CCC)C=2C(=O)NC1=O.[CH3:35][N:36]1[C:44]2[N:43]=[CH:42][N:41]([CH2:45][CH2:46][CH3:47])[C:40]=2[C:39](=[O:48])[N:38]([CH2:49][CH2:50][CH2:51][CH:52]=[C:53]([CH3:55])[CH3:54])[C:37]1=[O:56]>>[OH:17][C:53]([CH3:55])([CH3:54])[CH2:52][CH2:51][CH2:50][CH2:49][N:38]1[C:39](=[O:48])[C:40]2[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[N:43][C:44]=2[N:36]([CH3:35])[C:37]1=[O:56]
Reactant: CCCn1cnc2c1c(=O)n(CCCC=C(C)C)c(=O)n2C
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
The same compound was obtained, inter alia, by alkylation of the compound of Example 6 with 1-bromo- or 1-chloropropane analogously to Example 3, by reaction of 3-methyl-7-propylxanthine with the tertiary alcohol of Example 1a analogously to Example 2, or by acid-catalyzed hydration of 3-methyl-1-(5-methyl-4-hexenyl)-7-propylxanthine analogously to Example 14 below.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C:7]1[CH:12]=[C:11]([O:13]CC2C=CC=CC=2)[C:10]([CH2:21][CH:22]2[CH2:24][O:23]2)=[C:9]([O:25]CC2C=CC=CC=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>CO.[Pd]>[C:1]([O:5][C:6]([C:7]1[CH:8]=[C:9]([OH:25])[C:10]2[CH2:21][CH:22]([CH2:24][OH:23])[O:13][C:11]=2[CH:12]=1)=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(CC2CO2)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(CO)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
A mixture of 3,5-bis-benzyloxy-4-oxiranylmethyl-benzoic acid tert-butyl ester (200e) (55 g, 0.12 mol), 10% Pd on Carbon (5 g), Et3N (15 g, 0.14 mol), and K2CO3 (20 g, 0.14 mol) in MeOH (250 mL) was stirred under 760 mmHg of H2 at room temperature for 4 hr. TLC (EtOAc/petroleum oil=1/2) showed the reaction was complete. The mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography (EtOAc/petroleum ether=1/3) to give the title compound (18 g, 55% yield) as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:22]2[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[O:27])=[CH:24][CH:23]=2)[O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>CO.O>[CH:1]1([CH2:4][CH:5]([C:22]2[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:23]=2)[O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[N:14]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC2CC2)Oc2ccc(-n3cc(C(F)(F)F)cn3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCNC(=O)c1ccc(C(CC2CC2)Oc2ccc(-n3cc(C(F)(F)F)cn3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a mixture of methyl 3-(4-(2-cyclopropyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)ethyl)benzamido)propanoate (92 mg, 0.18 mmol) in methanol (0.9 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (38.4 mg, 0.92 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water and acidified with 1N hydrochloric acid to pH=6. The mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave (+/−)-3-(4-(2-cyclopropyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)ethyl)benzamido)propanoic acid (52 mg, 59%). 1HNMR (400 MHz, CD3OD, 6): 8.47 (s, 1H), 7.82 (s, 1H), 7.70 (d, 2H), 7.50 (d, 2H), 7.42 (d, 2H), 6.92 (d, 2H), 5.34 (m, 1H), 3.53 (m, 2H), 2.48 (m, 2H), 1.98-1.94 (m, 1H), 1.60-1.58 (m, 1H), 0.75-0.77 (m, 1H), 0.42-0.33 (m, 2H), 0.08-0.01 (m, 2H). MS (M+Na): 510.3.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH:26]=[CH:27][C:28]=1[F:29])[C:18]([CH:20]1[NH:25][CH2:24][CH2:23][CH:22]=[N:21]1)=[O:19]>C1COCC1.C(OCC)(=O)C.[Cl-].[NH4+].[Cu]I>[Br:14][C:15]1[CH:16]=[C:17]([C:18]([CH:20]2[NH:25][CH2:24][CH:23]=[CH:22][NH:21]2)([C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=2)[OH:19])[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: O=C(c1ccc(F)c(Br)c1)C1N=CCCN1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Cu]I
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(F)c(Br)c1)C1NC=CCN1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 277.6 %

Procedure:
A mixture of magnesium (2.13 g, 87.7 mmol) in THF at 50° C. is treated dropwise with a solution of 1-bromo-4-(trifluoromethoxy)benzene (21.1 g, 87.7 mmol) in THF over a period of 20 min., stirred at 50° C. for an additional 1.5 h, cooled to room temperature, treated with copper(I) iodide (0.13 g, 0.70 mmol) and a solution of 2-(3-bromo-4-fluorobenzoyl)-2,3,4,5-tetrahydropyrimidine (10.0 g, 14.9 mmol) in THF, heated at 65° C. overnight, cooled to room temperature and diluted with ethyl acetate and saturated aqueous ammonium chloride. The phases are separated. The organic phase is washed sequentially with water and brine, dried over sodium sulfate, and concentrated to afford 18.5 g of a brown oil. The oil is purified by flash chromatography (silica, 90:10:0.5 methylene chloride/methanol/concentrated ammonium hydroxide as eluent) to afford the title compound as a yellow oil, 10.0 g (64% yield), identified by NMR and mass spectral analyses. 1H NMR (300 MHz, CDCl3) δ 7.60 (dd, J=6.4, 2.3 Hz, 1H), 7.41 (dd, J=6.9, 2.0 Hz, 2H), 7.28-7.20 (m, 3H), 7.10 (t, J=8.3 Hz, 1H), 3.50 (m, 6H), 1.96 (m, 2H); ESI MS m/z 447 [C18H15BrF4N2O2+H]+.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[O:40][CH2:41][CH2:42][CH3:43]>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.C(O)C>[F:33][C:34]1[CH:35]=[C:36]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)[CH:37]=[CH:38][C:39]=1[O:40][CH2:41][CH2:42][CH3:43]
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Reactant: CCCOc1ccc(B(O)O)cc1F
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: CCO
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)cc1F
Yield: 61.9 %

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), aqueous sodium carbonate (2 M, 1 ml), (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.25 g, Example 40a), ethanol (1 ml), 3-fluoro-4-propoxybenzeneboronic acid (0.23 g) and tetrakis(triphenylphosphine)palladium(0) (22 mg) with heating at reflux for 4 hours. The residue obtained after work-up was purified by column chromatography over silica eluting with ethyl acetate to give the title compound as a white solid (0.19 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:29]=[C:12]3[CH:13]=[C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[CH:22][C:21]=4[C:26]([OH:28])=O)=[O:19])[CH:15]=[CH:16][N:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=[CH:42][CH:43]=[N:44][C:39]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N1CCC1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:29]=[C:12]3[CH:13]=[C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[CH:22][C:21]=4[C:26]([N:44]4[CH2:43][CH2:42][CH2:39]4)=[O:28])=[O:19])[CH:15]=[CH:16][N:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc3cc(NC(=O)c4c(C(=O)O)cnn4C)ccn3n2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cccc(-c2nc3cc(NC(=O)c4c(C(=O)N5CCC5)cnn4C)ccn3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
To a solution of 5-[2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid (4.0 g, 10.2 mmol) in DMF (50 ml) were added HATU (8.5 g, 22 mmol), azetidine hydrochloride (1.05 g, 93.5 mmol) and DIPEA (7.5 ml, 40 mmol) at 0° C. The resultant reaction mixture was stirred at 25° C. for 16 h. The mixture was diluted with water (100 ml) and stirred for 15 min. The resultant precipitated solid was filtered, washed thoroughly with water, and dried azeotropically with toluene followed by vacuum to yield 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide as off-white solid (1.9 g, 44%). LC-MS: m/z=432.4 [M+H]+.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].Br[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.[Cu]>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=[O:7])=[N:10][CH:11]=1
Reactant: O=c1cccc[nH]1
Reactant: Cc1ccc(Br)nc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2ccccc2=O)nc1

Procedure:
2-Pyridinone (1.00 g, 10.5 mmol), 2-bromo-5-methylpyridine (1.81 g, 10.5 mmol), Copper (0.013 g, 0.20 mmol) and K2CO3 (1.60 g, 11.6 mmol) were heated at 180° C. for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (2×) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc as eluent) to afford the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[C@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH2:31][C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=4)[C:35](O)=[O:36])[C:23]3=[O:41])[CH2:21]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[C@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH2:31][C:32]4[CH:40]=[CH:39][CH:38]=[C:34]([C:35]([N:10]5[CH2:9][CH2:8][N:7]([C:4]6[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=6)[CH2:12][CH2:11]5)=[O:36])[CH:33]=4)[C:23]3=[O:41])[CH2:21]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Reactant: c1cc(N2CCNCC2)ccn1
Product: O=C(c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1)N1CCN(c2ccncc2)CC1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 1-(pyridin-4-yl)piperazine, (3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-3-((2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd. for C33H29ClN4O2: 548, observed (M+H)+: 549.1 1H NMR (400 MHz, MeOD-d4) δppm 2.20-2.29 (m, 2 H) 3.26-3.31 (m, 1 H) 3.58 (br. s., 4 H) 3.88 (br. s., 4 H) 5.08-5.25 (m, 2 H) 6.14 (d, J=7.58 Hz, 1 H) 6.77 (t, J=7.58 Hz, 1 H) 6.92 (d, J=7.83 Hz, 1 H) 7.12 (t, J=7.20 Hz, 3 H) 7.21-7.32 (m, 4 H) 7.41 (s, 1 H) 7.45 (d, J=7.33 Hz, 1 H) 7.50-7.61 (m, 2 H) 8.19 (d, J=7.58 Hz, 2 H).