Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl.CCO>[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29].[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCc1ccc(N2CCNCC2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of the product of Step C (0.06 g; 0.16 mmol) in 60% TFA in CH2Cl2 (2 ml) was stirred for 15 min at room temperature and the mixture was diluted to 5 ml with EtOH and evaporated to dryness under reduced pressure and kept in vacuo for 1 h, to give a TFA salt of the title compound (0.07 g; 100%). 1H-NMR (CDCl3) 9.5 (broad s, 2H); 7.29 (m, 4H); 3.8-3.16 (m, 8H); 2.6 (t, 2H, J=8 Hz); 1.58 (m, 2H); 1.26 (m, 10H); 0.86 (t, 3H, J=6.9 Hz).
Reaction SMILES: 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.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:54][O:55][C:56](=[O:66])[CH2:57][CH2:58][CH2:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1.Br[C:68]1[CH:73]=[CH:72][C:71]([C:74]([CH3:77])([CH3:76])[CH3:75])=[CH:70][CH:69]=1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:54][O:55][C:56](=[O:66])[CH2:57][CH2:58][CH2:59][CH:60]1[CH2:65][CH2:64][N:63]([C:68]2[CH:73]=[CH:72][C:71]([C:74]([CH3:77])([CH3:76])[CH3:75])=[CH:70][CH:69]=2)[CH2:62][CH2:61]1
Reactant: COC(=O)CCCC1CCNCC1
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)CCCC1CCN(c2ccc(C(C)(C)C)cc2)CC1
Reaction time: 0.75 h
Yield: 60.5 %

Procedure:
A mixture of palladium (II) acetate (63 mg; 0.28 mmol), (±)-2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (258 mg; 0.41 mmol) and cesium carbonate (1.30 g; 4.00 mmol) in dioxane (3 mL) is placed in an ultrasonic bath for 45 minutes. 4-Piperidin-4-yl-butyric acid methyl ester hydrochloride (415 mg; 2.0 mmol, prepared in accordance with Example 131) and 1-bromo-4-tert-butyl-benzene (426 mg; 2.00 mmol) are then added and the reaction mixture is stirred for 2 hours under reflux. New catalyst solution (prepared as above from palladium (II) acetate (63 mg; 0.28 mmol), (±)-2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (258 mg; 0.41 mmol), cesium carbonate (1.30 g; 4.00 mmol) and dioxane (3 mL) is prepared with the aid of an ultrasonic bath and added to the reaction mixture. After stirring under reflux for 3 hours, the mixture is diluted with ethyl acetate and is filtered. The filtrate is concentrated under high vacuum and the obtained residue is purified by column chromatography on silica gel (hexanes/dichloromethane 50:50 v/v to 100) to afford the desired compound (385 mg; 1.21 mmol).
Reaction SMILES: [CH2:1]([N:4]1[C:8]([OH:9])=[C:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:6]([CH3:20])=[N:5]1)[CH:2]=[CH2:3].C1C=CC=CC=1.C(N(CC)CC)C.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>O>[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40]([O:9][C:8]2[N:4]([CH2:1][CH:2]=[CH2:3])[N:5]=[C:6]([CH3:20])[C:7]=2[C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCn1nc(C)c(C(=O)c2ccc(Cl)cc2Cl)c1O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: C=CCn1nc(C)c(C(=O)c2ccc(Cl)cc2Cl)c1OS(=O)(=O)c1ccc(C)cc1

Procedure:
To a solution of 180 mg. of 1-allyl-3-methyl-4-(2,4-dichlorobenzoyl)-5-hydroxypyrazole in 6 ml. of benzene and 58.4 mg. of triethylamine is added dropwise 110 mg. of 4-toluenesulfonyl chloride with stirring at room temperature. Then, the resulting mixture is heated under reflux for 1 hour. After completion of the reaction, water is added to the reaction mixture and an organic layer is separated. The organic layer is dried over anhydrous sodium sulfate, the solvent is distilled off and the resulting oily substance is recrystallized from benzene-n-hexane to give 173 mg. of the desired product as colorless prisms melting at 113°-114° C. Further, the solvent is distilled off from the mother liquor and recrystallization from n-hexane gives 26 mg. of the desired product. Total yield 73.9%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].OB(O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[CH3:10][C:5]1[CH:4]=[CH:3][C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(Br)cc1C#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccccc2)cc1C#N
Temperature: 75 °C
Reaction time: 11 h
Yield: 71.4 %

Procedure:
A mixture of 27.4 g (140 mmol) of 5-bromo-2-methylbenzonitrile, 19.5 g (160 mmol) of dihydroxyphenylborane, 629 mg (2.8 mmol) of palladium acetate (II), 45.1 g (140 mmol) of tetrabutylammonium bromide, 48.4 g (350 mmol) of potassium carbonate and 280 ml of water was stirred at 75° C. for 11 hours under nitrogen flow. To the reaction solution was added chloroform, the organic layer was washed with water, dried over anhydrous magnesium sulfate, then, concentrated. The residue was re-crystallized from methanol to give 19.9 g (99.9 mmol) of 2-methyl-5-phenylbenzonitrile.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.[N-]=C=O>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:15][NH:14][C:12](=[O:13])[CH2:11][C@@H:8]2[CH2:9][CH2:10][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:7]2)=[O:25])=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Agent: [N-]=C=O
Solvent: ClCCl
Product: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 27 h
Yield: 67.1 %

Procedure:
In a round bottom flask under nitrogen, a solution of 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (52.6 g, 249 mmol) in dichloromethane (356 mL) was cooled to 0° C. and 4-bromophenylisocyanate (49.3 g, 249 mmol) was added. Once the isocyanate dissolved, the cooling bath was removed and the reaction was allowed to warm to room temperature and was stirred for 27 h. White precipitate formed quickly. The reaction was filtered to collect the white precipitate, washed with 50 mL cold dichloromethane, and air dried. The white solid was washed with additional cold dichloromethane (300 mL) and dried under vacuum suction overnight to provide the title compound (108.29 g, 63% pure, 167 mmol, 67% yield). MS(ES)+ m/e 409.2, 411.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][C:18]([NH:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH2:34][CH3:35])[C:26]3[C:31]([C:32]=2[CH:33]=1)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:19].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:16][CH2:17][C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH2:34][CH3:35])[C:26]5[C:31]([C:32]=4[CH:33]=3)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:19])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: CCn1c2ccccc2c2cc(NC(=O)CCBr)ccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c2ccccc2c2cc(NC(=O)CCN3CCC(O)(c4ccc(Cl)cc4)CC3)ccc21
Yield: 81.1 %

Procedure:
4-(4-Chlorophenyl)-4-hydroxypiperidine (229 mg, 1.1 mmol, 1.5 equiv) was added in one portion to a solution of 3-bromo-N-(9-ethyl-9H-carbazol-3-yl)-propionamide (250 mg, 0.72 mmol, 1 equiv) and triethylamine (0.301 mL, 219 mg, 2.2 mmol) in DMF (2 mL). The resultant solution was maintained at room temperature for 21 hours and then diluted with ethyl acetate (25 mL). The mixture was washed with water (25 mL) and saturated aqueous sodium chloride (2×25 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by rotary chromatography (5% MeOH/CH2Cl2) to afford 3-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-propionamide (278 mg, 81%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[O:10])[CH:6]=[N:7][CH:8]=1.[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[N:7][CH:6]=[C:5]([CH:9]([OH:10])[C:12]([F:14])([F:13])[F:11])[CH:4]=1
Reactant: COc1cncc(C=O)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cncc(C(O)C(F)(F)F)c1
Yield: 100.5 %

Procedure:
According to Reference Example 8-12, by use of 5-methoxy-3-pyridinecarboxaldehyde (300 mg, 2.19 mmol), (trifluoromethyl)trimethylsilane (388 μL, 2.63 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 220 μL, 0.220 mmol) and tetrahydrofuran (6.0 mL), the mixture was stirred and reacted at room temperature for 30 minutes. Then, purification by silica gel column chromatography (chloroform/methanol=9/1) was performed to give 3-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound CV) (456 mg, yield: quantitative).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[NH:18])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:2].C([Li])CCC.Cl[P:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[N:18][P:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CC(C)P(Cl)C(C)C
Reactant: CCc1ccccc1NC(=N)c1ccc(C)cc1
Agent: [Li]CCCC
Product: CCc1ccccc1NC(=NP(C(C)C)C(C)C)c1ccc(C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.19 g of N1-(2-ethylphenyl)-4-methylbenzamidine (Amidine VIII, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow oil was isolated (1.77 g, 100%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[CH:25]=[C:24]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[F:37][C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[N:28]([C:26]([C:24]1[CH:25]=[CH:20][N:21]=[C:22]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:23]=1)=[O:27])[CH2:29][CH2:30]2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(c1ccnc(Cl)c1)N1CCc2cc(F)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccnc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c1)N1CCc2cc(F)ccc21
Temperature: 130 °C
Reaction time: 6 h

Procedure:
232 mg (0.8 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochloride were added to 220 mg (0.80 mmol) (2-chloropyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 0.52 mL (3.00 mmol) DIPEA in 3.0 mL N-methylpyrrolidone. The reaction mixture was stirred for 6 h at 130° C. After 4 h 400 mg potassium carbonate were added and the reaction mixture was stirred for a further 24 h at 130° C. Then the mixture was poured onto 100 mL water and extracted with EtOAc (3×100 mL). The combined organic phases were dried and evaporated down using the rotary evaporator. The residue was purified by preparative HPLC. The product fractions were combined and evaporated down i. vac. The residue was triturated with 30 mL diethyl ether. The precipitated solid was suction filtered and dried in the air.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[N:10])[CH:4]=1.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[Cl:13][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[N:10])[CH:4]=1
Reactant: N#Cc1cc(CO)ccn1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1cc(CCl)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In toluene, 4-hydroxymethylpyridine-2-carbonitrile (111 mg, 0.83 mmol) synthesized in Production Example 87 was dissolved, and thionyl chloride (73 μL) was added thereto. The mixture was refluxed for 30 minutes. Thereafter, the mixture was allowed to cool down to a room temperature and stirred for one hour. After the completion of the reaction was confirmed by HPLC, the solvent was distilled off. The resulting residue was used for the next reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([CH3:23])[CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH:17]3[O:21][C:20](=[O:22])[N:19]([CH3:23])[CH2:18]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CN1CC(CCCl)OC1=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CN1CC(CCN2CCN(c3ccc(F)cc3)CC2)OC1=O
Yield: 74.2 %

Procedure:
A mixture of 4.5 g (0.025 mol) of 1-(4-fluorophenyl)piperazine, 4.1 g (0.025 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 8.0 g (0.075 mol) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 150 mL of n-butanol was heated at reflux for 20 h. The mixture was concentrated under reduced pressure and the residue partitioned between water and benzene. The benzene layer was washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure to obtain a solid which was recrystallized from 2-propanol isopropyl/ether to obtain 5.7 g (74%) of white solid, mp 82°-84° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8]Br)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][C:13]1=[O:18]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:7]([CH2:8][N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1COCCN1
Reactant: BrCc1cccnc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C1COCCN1Cc1cccnc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
To a solution of 2-bromo-3-bromomethyl-pyridine (0.68 g, 2.36 mmol) in dimethylformamide (10 mL) are added sodium hydride (0.11 g, 60% suspension, 2.82 mmol), morpholin-3-one (0.20 g, 1.97 mmol) and tetrabutylammonium iodide (catalytic) at 0° C. The mixture is stirred at room temperature for 16 hours. After completion, the reaction mixture is partitioned between ethyl acetate (25 mL) and water (25 mL). The aqueous layer is extracted with ethyl acetate (2×25 mL) and the combined organic extracts are dried over sodium sulfate and concentrated in vacuo. The crude material is purified by column chromatography over silica gel eluting with hexane/ethyl acetate (55:45) to yield 0.35 g (66%) of the title compound. MS (m/z): 271/273 (M+1, M+3).
Reaction SMILES: Br[C:2]1[C:3](=[O:34])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:61]1[CH:66]=[C:65](B(O)O)[CH:64]=[N:63][CH:62]=1>>[CH3:33][S:30]([N:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][O:21][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([C:11]4[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=4)=[C:2]([C:65]4[CH:66]=[N:61][CH:62]=[N:63][CH:64]=4)[C:3]3=[O:34])=[CH:8][CH:7]=2)[CH2:25][CH2:26]1)(=[O:31])=[O:32]
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(C(F)(F)F)cc2)CC1
Reactant: OB(O)c1cncnc1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2cncnc2)=C3c2ccc(C(F)(F)F)cc2)CC1
Yield: 14 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-6-[2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy]-3-[4-(trifluoromethyl)phenyl]-1H-inden-1-one obtained in Step 1 of Example 47 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, and 5-pyrimidinylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (14%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.[BH4-].[Na+].Cl>CO.[OH-].[Na+]>[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([NH:6][C:3]3[NH:2][N:1]=[CH:5][CH:4]=3)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Nc1cc[nH]n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cc(NC2CCC3(CC2)OCCO3)[nH]n1
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of 1H-pyrazol-3-amine (10.0 g) and 1,4-dioxaspiro[4.5]decan-8-one (20.7 g) in methanol (30 mL) was stirred at room temperature for 30 min. After stirring, a solution of sodium tetrahydroborate (3.6 g) in 1 M sodium hydroxide (30 mL) was added dropwise at 0° C. After warming to room temperature, the mixture was stirred for 4 hr, 1 M hydrochloric acid (100 mL) was added dropwise at 0° C., and the mixture was stirred for 1 hr. The resulting solid was collected by filtration, washed with water, and dried by heating under reduced pressure to give the title compound as a pale-yellow solid (17.2 g, 64%).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([Cl:37])[CH:32]=3)[CH:23]=2)[C:10]=1[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])C.[OH-].[Na+]>>[C:40]([CH2:39][CH2:38][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([Cl:37])[CH:32]=3)[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:45])=[O:3])([OH:42])=[O:41]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccnc(Cl)c3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccnc(Cl)c2)c1
Yield: 98.4 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-{6-[3-(2-chloro-pyridin-4-yl)-5-ethoxy-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (105 mg, 0.16 mmol) and 1.0 N aqueous sodium hydroxide (1.6 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-[3-(2-chloro-pyridin-4-yl)-5-ethoxy-phenoxy]-hexyl]-phenoxy]-butyric acid (92 mg, 96%) as a light brown solid: ES(+)-HRMS m/e calcd for C32H38ClNO7 (M+H)+ 584.2410. found 584.2412.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([NH:25][CH:26]([CH3:28])[CH3:27])[C:5]([C:6]([NH:8][NH:9][C:10](=[O:22])[CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][OH:13])=[O:7])=[CH:4][N:3]=1.N1C=CN=C1.[C:34]([Si:38](Cl)([CH3:40])[CH3:39])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[Si:38]([O:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])[C:10]([NH:9][NH:8][C:6](=[O:7])[C:5]1[C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[CH:24][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:22])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NNC(=O)C(CO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)Nc1cc(Cl)ncc1C(=O)NNC(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl (1-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-3-hydroxy-1-oxopropan-2-yl)carbamate (53) (1 g, 2 mmol) in DCM (10 mL), imidazole (7 mmol, 3 equiv.) was added and stirred at room temperature for 10 min. Reaction mixture was cooled to 0° C., t-butyl dimethyl silyl chloride (3.6 mmol, 1.5 equiv.) was added in portions and stirred the reaction mixture overnight at room temperature. Diluted the reaction mixture using DCM, the DCM layer was washed with water. The organic layer was collected, dried over Na2SO4, filtered and concentrated to get tert-butyl (3-((tert-butyldimethylsilyl)oxy)-1-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate (54). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 2.319 min; LCMS (ES-API), m/z 530.2 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](Cl)=[O:7])=[CH:2]1.Cl.[CH3:10][NH:11][O:12][CH3:13].C(N(CC)CC)C.O>ClCCl>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:7]
Reactant: CNOC
Reactant: O=C(Cl)c1ccsc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a solution of this crude thiophene-3-carbonyl chloride (97.7 g, 666 mmol) and N,O-dimethylhydroxylamine hydrochloride (71.5 g, 733 mmol) in dichloromethane (600 mL) at 0° C. was added dropwise triethylamine (186 mL, 1.33 mol). After stirring at room temperature for 3 h, the reaction mixture was poured into water (2 L), the layers were separated and the aqueous layer extracted with dichloromethane (2×200 mL). The combined organic layers were washed with water (200 mL), then dried over MgSO4 and concentrated in vacuo to afford N-methoxy-N-methylthiophene-3-carboxamide [102.2 g, yield 90%; HPLC/MS: m/z=172 (M+H); log P(HCOOH)=1.30].
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH:24][CH2:25][C:26]#[N:27].C(N(CC)CC)C.O>C(Cl)Cl>[C:26]([CH2:25][O:24][C:14](=[O:15])[CH:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:2]([F:23])([F:1])[F:22])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1)[CH3:17])#[N:27]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Reactant: N#CCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
17.2 g (0.05 mole) of 4-(4'-trifluoromethylphenoxy)-α-phenoxypropionyl chloride are added dropwise at 10° C. to a mixture of 3.13 g (0.055 mole) of 100% hydroxyacetonitrile (cyanomethanol) and 5.5 g (0.54 mole) of triethylamine in 50 ml of methylene chloride. The reaction mixture is then stirred for 1 hour at room temperature. Then 100 ml of water are added and the organic phase is separated, filtered over a small column of silica gel and concentrated. The residual solid is triturated with petroleum ether, collected by filtration and dried, affording 13.2 g (72.5% of theory) of 4-(4'-trifluoromethylphenoxy)-α-phenoxy-propionic acid cyanomethyl ester with a melting point of 53°-56° C.
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]1[CH2:10][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]1=[O:21])=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:5][C@H:6]1[CH2:10][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:7]1=[O:21]
Reactant: CC(C)CN1C(=O)[C@@H](NC(=O)C(F)(F)F)C[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)CN1C(=O)[C@@H](N)C[C@H]1c1ccccc1
Reaction time: 27 h
Yield: 92.6 %

Procedure:
To a solution of cis-2,2,2-trifluoro-N-(1-isobutyl-2-oxo-5-phenylpyrrolidin-3-yl)acetamide (50.0 mg, 0.152 mmol) in methanol (3 mL) and water (1 mL) was added potassium carbonate (63.1 mg, 0.447 mmol). After 27 hours, the reaction solution was concentrated, and worked up with methylene chloride and water. The organic extracts were dried over sodium sulfate, filtered and concentrated to produce the title compound (32.7 mg). MS 233 (M+1).