Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:28])[C:25]=1[CH2:26][OH:27].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[N:22][CH:23]=[C:24]([Cl:28])[C:25]=2[CH2:26][OH:27])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Reactant: OCc1c(Cl)cncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cncc(Cl)c2CO)cc1Cl
Temperature: 100 °C
Yield: 42 %

Procedure:
To the solution of 2-Chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (320 mg, 1.21 mmol), (3-Bromo-5-chloro-pyridin-4-yl)-methanol (220 mg, 1.21 mmol) and PdCl2(dppf). CH2Cl2 adduct (79 mg, 0.09 mmol) in DMF (4 mL) was added 2M Na2CO3 solution (1.82 ml, 3.64 mmol) under Nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. After letting cool to room temperature, solvent was removed in vacuo. The resulting residue was dissolved in DCM and saturated NH4Cl solution. After extraction with DCM and separation, the combined extracts were concentrated and purified by ISCO 12 g (0-30% EtOAc/Hep) to give 2-Chloro-4-(5-chloro-4-hydroxymethyl-pyridin-3-yl)-benzonitrile (142 mg, 52%) as colorless solid; ESI-MS m/z; 279 [M+1]+, Retention time 1.41 min. 1H-NMR (CDCl3, 400 MHz) δ 4.66 (s, 2H), 7.53 (d, J==8.0 Hz, 1H), 7.69 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 8.47 (s, 1H), 8.72 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[S:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Product: COc1nc2ccccc2cc1NC(=S)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 79 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 109 to obtain the titled compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([CH2:12][O:13][C:14]2[N:19]=[C:18]([C@H:20]([OH:24])[CH2:21][C:22]#[N:23])[CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.N.CO.C(Cl)Cl>>[NH2:23][CH2:22][CH2:21][C@H:20]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH2:12][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]2)[N:19]=1)[OH:24]
Reactant: N#CC[C@@H](O)c1cccc(OCC2CCCC2)n1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: NCC[C@@H](O)c1cccc(OCC2CCCC2)n1

Procedure:
LiAlH4 reduction of (R)-3-(6-(cyclopentylmethoxy)pyridin-2-yl)-3-hydroxypropanenitrile following the method described in Example 1 gave after flash chromatography purification (20%-30% 7N NH3/MeOH—CH2Cl2 gradient) Example 33 as a colorless oil. Yield (0.33 g, 24%); 1H NMR (400 MHz, DMSO-d6) δ 7.60 (t, J=7.6 Hz, 1H), 7.00 (d, J=6.8 Hz, 1H), 6.56 (d, J=8.0 Hz, 1H), 4.57-4.51 (m, 1H), 4.10-4.04 (m, 2H), 2.71-2.58 (m, 2H), 2.30-2.02 (m, 1H), 1.82-1.21 (m, 10H); RP-HPLC tR=7.71 min; ESI-MS m/z 251.3 [M+H]+.
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C[O:22][C:23]([C:25]1([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:29][C:28](=[O:30])[N:27]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:26]1)=O>C1COCC1>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([NH:11][C:23]([C:25]2([CH:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:29][C:28](=[O:30])[N:27]([C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:38])[CH2:26]2)=[O:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C1(C2CCCC2)CC(=O)N(c2c(C)cccc2C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1CC(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(C2CCCC2)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
n-BuLi (2.5 M solution in hexanes, 456 μL, 1.14 mmol) was added to a solution of 3,5-bis-trifluoromethylaniline (177 μL, 0.1.14 mmol) in THF (3 mL) at room temperature. The resulting dark brown colored solution was stirred for 10 min at room temperature. A solution of 3-cyclopentyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 120 mg, 0.38 mmol) in THF (2 mL) was added and stirred for 2 h at 70° C. The reaction mixture was then purified by automated flash chromatography. Pure fractions were combined and concentrated under reduced pressure. The material was recrystallized from MeOH to obtain the desired product 3-cyclopentyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (60 mg, 31% yield) as white crystals. LC-MS: R, (retention time): 3.32 min, MS: (ES) m/z 513.2 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.4 (s, 1H), 8.05 (s, 2H), 7.6 (s, 1H), 7.08-7.13 (m, 2H), 7.02-7.06 (m, 2H), 4.14 (d, 1H, J=11.5 Hz), 3.56 (d, 1H, J=11.5 Hz) 3.17 (d, 1H, J=16.9 Hz), 2.74 (d, 1H, J=16.9 Hz), 2.42-2.52 (m, 1H), 2.2 (s, 3H), 2.14 (s, 3H), 1.75-1.88 (m, 2H), 1.6-1.68 (m, 4H), 1.25-1.48 (m, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:25]=[CH:24][C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:25][CH:24]=1)(=[O:17])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1

Procedure:
The product (770 mg) is obtained according to the method of stage 1 of Example 4, by using 1.5 mL of 2-fluoro-nitrobenzene and 4.2 g of 4-aminobenzophenone in the presence of 2.54 g of potassium tert-butanolate in 40 mL of DMSO.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH:5]=[C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8](=O)[O:7]1.O.[NH2:21][NH2:22]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8](=[O:7])[NH:22][N:21]=1
Reactant: NN
Reactant: O=C1OC(=Cc2ccc(F)c(Br)c2)C2=C1CCCC2
Solvent: O
Product: O=c1[nH]nc(Cc2ccc(F)c(Br)c2)c2c1CCCC2
Temperature: 85 °C

Procedure:
To 3-(3-bromo-4-fluoro-benzylidene)-4,5,6,7-tetrahydro-3H-isobenzofuran-1-one (8) (cis l trans mixture) (20.78 g, 64.3 mmol) suspended in water (150 ml) was added hydrazine hydrate (12.5 ml, 257.2 mmol). The reaction was heated to 85° C. for 18 hours and then cooled to room temperature. A beige suspension was isolated by filtration and washed with water (1×50 ml), hexane (1×50 ml), and ether (1×25 ml) before being dried overnight in a vacuum oven. Main peak in LC-MS, (19.1 g, 91% purity) and required no further purification; m/z (LC-MS, ESP), RT=3.92 mins (M+H 337 & 339).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][C@H:4]([C@H:8]([OH:12])[CH2:9][CH2:10][CH3:11])[C:5]([OH:7])=O.[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][NH2:21].C(Cl)CCl>ClCCl.CCOC(C)=O>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][NH:21][C:5](=[O:7])[C@H:4]([CH2:3][CH:2]([CH3:1])[CH3:13])[C@H:8]([OH:12])[CH2:9][CH2:10][CH3:11]
Reactant: NOC1CCCCO1
Reactant: CCC[C@@H](O)[C@@H](CC(C)C)C(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC[C@@H](O)[C@@H](CC(C)C)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
To a stirred solution of (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxyhexanoic acid (6.0 g, 32.3 mmol) in 33 mL of dichloromethane at 0° C. is added 2-tetrahydropyranyloxyamine (7.70 g, 65.8 mmol) followed by EDC (7.50 g, 39.4 mmol). The reaction mixture is allowed to warm to 25° C., stirred 12 h, then diluted with 100 mL of EtOAc and washed successively with 50 mL each of water, 1 M aqueous sodium bisulfate solution, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The combined organic layers are dried over sodium sulfate and filtered, and the solvents are removed under reduced pressure. Purification by flash chromatography on silica gel eluting with 10% EtOAc-hexanes affords 9.0 g (97%) of (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxyhexanoic acid 2-tetrahydropyranyloxyamide as a gum.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][C:21]=1[C:35]1[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=1>CN(C)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>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]3[N:7]=[CH:8][CH:9]=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:22][C:21]=1[C:35]1[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Brc1cnc2nccnn12
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1-c1cc(-c2cnc3nccnn23)ccc1F
Temperature: 80 °C
Yield: 21.2 %

Procedure:
A stirred mixture of 7-bromoimidazo[1,2-b][1,2,4]triazine (0.22 g, 1.105 mmol), dried potassium phosphate (0.425 g, 2.002 mmol) and 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-2-carbonitrile (0.649 g, 2.008 mmol) in anhydrous N,N-dimethylacetamide (4 ml) was degassed by evacuation and refilling with nitrogen three times. Tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.05 mmol) was added and the mixture was degassed with two more evacuation-refilling cycles before heating at 80° C. for 4.5 h. The mixture was cooled to ambient temperature, diluted with ethyl acetate and filtered. The filtrate was washed with brine (200 ml), and the aqueous portion extracted with more ethyl acetate. The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography (silica gel, EtOAc) then recrystallisation (EtOAc) to give 74 mg (24%) of the title compound: mp 211-215° C.; 1H NMR (360 MHz, CDCl3) δ 7.36-7.41 (1H, t, J 7.2 Hz), 7.53-7.61 (2H, m), 7.70-7.74 (1H, m), 7.83 (1H, d, J 7.7 Hz), 8.12-8.16 (2H, m), 8.35 (1H, s), 8.50 (1H, dd, J 2.1, 11.6 Hz); MS (ES+) m/z 316 [M+H]+.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([CH3:10])[CH:8]=1)[C:3](=[O:14])[N:23]([CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][C:16]([F:15])([F:26])[F:27])=[CH:19][CH:20]=1)[CH2:12]2
Reactant: COC(=O)c1c(C)cc(Br)cc1CBr
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-methyl-benzoic acid methyl ester (1.61 g, 5.0 mmol), 4-trifluoromethoxy-benzylamine (0.916 mL, 6.0 mmol), and K2CO3 (1.24 g, 9.0 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (1.21 g, 60%). GC-MS: m/z 399 (M)+, 316 (M−83)+.
Reaction SMILES: C(C1C=CC(CNC(=O)C(C2C(F)=CC=C(O)C=2F)OC)=CC=1)#N.[C:25]([C:27]1[CH:56]=[CH:55][C:30]([CH2:31][NH:32][C:33]([CH:35]([O:52][CH2:53]C)[C:36]2[C:37]([F:51])=[C:38]([O:43][S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])[CH:39]=[CH:40][C:41]=2[F:42])=[O:34])=[CH:29][CH:28]=1)#[N:26]>>[C:25]([C:27]1[CH:56]=[CH:55][C:30]([CH2:31][NH:32][C:33]([CH:35]([O:52][CH3:53])[C:36]2[C:37]([F:51])=[C:38]([O:43][S:44]([C:47]([F:49])([F:48])[F:50])(=[O:46])=[O:45])[CH:39]=[CH:40][C:41]=2[F:42])=[O:34])=[CH:29][CH:28]=1)#[N:26]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(OS(=O)(=O)C(F)(F)F)c1F
Agent: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(O)c1F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(OS(=O)(=O)C(F)(F)F)c1F

Procedure:
(RS)-Trifluoro-methanesulfonic acid 3-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-2,4-difluoro-phenyl ester was prepared from (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-hydroxy-phenyl)-2-methoxy-acetamide in analogy to (RS)-trifluoro-methanesulfonic acid 3-[(4-cyano-benzylcarbamoyl)-ethoxy-methyl]-2,4-difluoro-phenyl ester (example 217). Yellow oil. MS 482.3 ([M+NH4]+).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[C:12]2[CH:13]=[CH:14][O:15][C:11]=2[C:10]([CH3:16])=[CH:9][CH:8]=1.CN(C)[CH:19]=[O:20].C(OCC)(=O)C>O1CCCC1>[CH3:6][C:7]1[C:12]2[CH:13]=[C:14]([CH:19]=[O:20])[O:15][C:11]=2[C:10]([CH3:16])=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C)c2occc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c2oc(C=O)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under nitrogen atmosphere at −35° C., 18.4 ml of n-butyllithium (1.56M hexane solution) was added to 50 ml of a solution of 3.5 g of 4,7-dimethylbenzofuran in anhydrous tetrahydrofuran, and the resulting mixture was stirred for 15 minutes, followed by the dropwise addition thereto of 5.6 ml of N,N-dimethylformamide. The temperature of the resulting mixture was raised to room temperature, followed by the addition of ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting crude crystal was washed with n-hexane to give 2.3 g of the title compound as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: Brc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCN1CCC(c2cccc(Br)c2)CC1
Temperature: 25 °C

Procedure:
4-(3-Bromo-phenyl)-piperidine (1.2 g, 4.8 mmol) and 2-bromoethanol (0.72 mL, 10 mmol) were diluted with DMF (20 mL) and treated with potassium carbonate (2.7 g, 20 mmol). These were stirred at ambient temperature for 18 then poured onto water and extracted with ethyl acetate. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to clear oil (0.6 g, 44%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[OH-:26].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[Cl-].[NH4+]>O1CCOCC1.O.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(OCC)(=O)C>[OH:26][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(=O)C[C@H](c2ccc(O)cc2)c2ccccc2C)ccn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a white suspension of (R)-3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 142, step 2, 200 mg) and potassium hydroxide (62.6 mg) in 1,4-dioxane (1 mL) and water (0.6 mL) under argon were added 2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-biphenyl (17.2 mg) and tris(dibenzylideneacetone)dipalladium(0) (9.3 mg). The reaction mixture was heated to 100° C. and stirred for 3 hours. A saturated aq. solution of ammonium chloride and ethyl acetate were added, the phases were separated and the inorganic one was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (30% to 100% ethyl acetate in heptane) to yield the title compound as a light yellow semisolid (77%), MS (ESI+): m/z=332.1 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=O)=[N:7][CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.Cl.[CH2:34]1[C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][N:35]1[C@H:43]1[C:51]2[C:46](=[CH:47][C:48]([C:52]3[CH:53]=[CH:54][C:55]([C:58]#[N:59])=[N:56][CH:57]=3)=[CH:49][CH:50]=2)[CH2:45][CH2:44]1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:40]2[CH2:41][CH2:42][C:37]3([CH2:36][N:35]([C@H:43]4[C:51]5[C:46](=[CH:47][C:48]([C:52]6[CH:53]=[CH:54][C:55]([C:58]#[N:59])=[N:56][CH:57]=6)=[CH:49][CH:50]=5)[CH2:45][CH2:44]4)[CH2:34]3)[CH2:38][CH2:39]2)=[O:12])=[N:7][CH:8]=1
Reactant: COc1ccc(CC(=O)O)nc1
Reactant: N#Cc1ccc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)cn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-c5ccc(C#N)nc5)ccc42)C3)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
To a mixture of (5-methoxypyridin-2-yl)acetic acid (SM-1aa), 28 mg, 0.17 mmol) in dichloromethane (5 mL) was added 1,1′-carbonyldiimidazole (28 mg, 0.17 mmol) and the reaction was stirred for 2 hours at room temperature. In a separate flask, triethylamine (68 mg, 0.67 mmol) was added to a mixture 5-[(R)-1-(2,7-diaza-spiro[3.5]non-2-yl)-indan-5-yl]-pyridine-2-carbonitrile dihydrochloride (4-1d, 58 mg, 0.17 mmol) in dichloromethane (5 mL). The activated acid was added to the amine solution and the reaction was stirred at room temperature overnight. The reaction mixture was quenched by the addition of 10 mL of saturated NaHCO3 and diluted with 50 mL of dichloromethane. The organic solution was collected, washed with saturated brine, dried over MgSO4, filtered and concentrated. Purification by preparative HPLC (on Phenomenex Luna (2) C18 21.2×150 mm, 5% H20/95% MeOH (0.1% formic acid), 10.0 min, 28 mL/min) provided the title compound (7.5 mg, 9%) as a gum. MS (ES+) 494.1 (M+H)+ 1H NMR (CD3OD) δ 1.76-1.87 (m, 4H), 2.14-2.26 (m, 1H), 2.55 (dd, 1H), 3.00-3.12 (m, 1H), 3.18-3.27 (m, 1H), 3.54-3.60 (m, 4H), 3.81-3.85 (m, 4H), 3.86 (s, 1H), 4.04 (d, 2H), 4.18 (d, 2H), 4.94 (dd, 1H), 7.22-7.29 (m, 1H), 7.31-7.38 (m, 1H), 7.63-7.72 (m, 2H), 7.75 (s, 1H), 7.93 (dd, 1H), 8.13 (d, 1H), 8.23 (dd, 1H), 8.97 (d, 1H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:25])[CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21]Cl)=[C:14]([O:23][CH3:24])[CH:13]=2)[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[OH:35])=[CH:30][CH:29]=1.C(N(CC)CC)C.C(Cl)Cl.CO.[OH-].[NH4+]>C(O)C1C=CC=CC=1>[C:1]1([CH2:7][O:8][C:9](=[O:25])[CH:10]([OH:11])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:39]3[CH2:40][CH2:41][CH:36]([C:34]([C:42]4[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=4)([C:31]4[CH:30]=[CH:29][C:28]([F:27])=[CH:33][CH:32]=4)[OH:35])[CH2:37][CH2:38]3)=[C:14]([O:23][CH3:24])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: COc1cc(C(O)C(=O)OCc2ccccc2)ccc1OCCCCl
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: OCc1ccccc1
Product: COc1cc(C(O)C(=O)OCc2ccccc2)ccc1OCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 110 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
A mixture of 0.637 g (0.00175 mole) 4-(3-chloropropoxy)-3-methoxymandelic acid phenylmethyl ester, 0.545 g (0.00180 mole) of [α,α-bis(4-fluorophenyl)]-4-piperidinemethanol hydrochloride, and 0.3 ml (0.0025 mole) of triethylamine in 3 ml of benzyl alcohol was heated under nitrogen atmosphere at 110° C. for 7 hours while the reaction was monitored by TLC (silica gel, methylene chloride/methanol/ammonium hydroxide 90:10:1). The reaction mixture was concentrated in vacuo, ethyl ether (60 ml) and hexanes (40 ml) were added to the oily residue, and the solution was kept in the refrigerator for 2 hours. The solid that formed was filtered, washed with ether and dissolved in methylene chloride (40 ml). The methylene chloride solution was washed with water (3×10 ml) and dried (sodium sulfate), and the solvent was evaporated in vacuo to give 0.6 g of an oil. Final purification was done using 6 tapered silica gel plates 20×20 cm eluting with methylene chloride/methanol/ammonium hydroxide (90:5:0.5). The TLC sections containing the product were scraped off, and eluted with the above solvent system to give 0.4 g (34%) of the product as a light-amber oil. 1H NMR and mass spectral analysis support the structure assigned.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[O:10])=[C:7]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[Cl:32])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].IC.[C:37]([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([N:11]([CH3:37])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[O:10])=[C:7]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[Cl:32])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cccc(S(C)(=O)=O)c2)c(Oc2ccc(F)cc2Cl)c1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)c1ccc(C(C)(C)C)cc1Oc1ccc(F)cc1Cl)c1cccc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-tert-butyl-2-(2-chloro-4-fluorophenoxy)-N-(3-(methylsulfonyl)phenyl)benzamide (14 mg, 30 μmol) in 0.30 mL DMF was added NaH (60% suspension in mineral oil, 3 mg, 80 μmol). After 5 min, iodomethane (5 μL, 80 μmol) was added to the reaction, and it was stirred for 16 h at room temperature. The reaction was worked up by adding sat. NaHCO3(aq) and extracting with CH2Cl2. The organic layer was filtered through a pad of Na2SO4 and evaporated. The product, 4-tert-butyl-2-(2-chloro-4-fluorophenoxy)-N-methyl-N-(3-(methylsulfonyl)phenyl)benzamide, was purified using reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). LC/MS: m/z 490.2 (M+H)+ at 2.03 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).