Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[C:6]([OH:17])[C:5]([N+:18]([O-])=O)=[CH:4][CH:3]=1.[H][H]>[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:18])=[C:6]([OH:17])[C:7]=1[S:8]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)(=[O:9])=[O:10]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCOCC2)c1O
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCOCC2)c1O
Yield: 94.6 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, 6-chloro-2-hydroxy-1-(4-morpholinylsulfonyl)-3-nitrobenzene (210 mg, 0.65 mmol) was reduced with hydrogen and Pd/C (100 mg) to form the desired product (180 mg, 95%). 1H NMR (MeOD-d4): δ 6.28 (mn, 2H), 3.68 (t, 4H), 3.30 (t, 4H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:38]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26](OS(C(F)(F)F)(=O)=O)[CH:27]=[CH:28][CH:29]=5)[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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:26]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:27]=[CH:28][CH:29]=[C:24]([C:23]2[N:18]3[N:17]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)=[CH:10][CH:11]=4)[N:38]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH:25]=1
Reactant: O=S(=O)(Oc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1)C(F)(F)F
Reactant: OB(O)c1ccccc1
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+]
Product: c1ccc(-c2cccc(-c3cccc4nc(Nc5ccc(OCCN6CCCC6)cc5)nn34)c2)cc1
Temperature: 150 °C

Procedure:
A microwave vial was charged with trifluoro-methanesulfonic acid 3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-phenyl ester (50 mg, 0.09 mmol), benzeneboronic acid (15 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium (10 mg, 0.009 mmol), potassium phosphate (0.5M in water, 0.36 ml, 0.18 mmol) and N,N′-dimethylacetamide (1 ml). The reaction was heated to 150° C. for 10 minutes under microwave irradiation. The mixture was then filtered through a plug of silica, washed with methanol and concentrated in vacuo. The product was purified by preparatory LCMS to yield the desired product. RT: 2.96 min, MI: 476.22, Method: 2
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:14]=[C:13]3[C:9]([N:10]=[CH:11][N:12]3[CH:15]([CH3:17])[CH3:16])=[C:8]([NH:18][CH2:19][CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=4)[NH:23][CH:22]=3)[N:7]=2)[C:3]2[CH:31]=[CH:32][CH:33]=[CH:34][C:2]1=2.[C:35]([O:39][C:40]([NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48](O)=[O:49])=[O:41])([CH3:38])([CH3:37])[CH3:36].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:35]([O:39][C:40]([NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:20][CH2:19][NH:18][C:8]1[N:7]=[C:6]([C:4]2[C:3]3[CH:31]=[CH:32][CH:33]=[CH:34][C:2]=3[S:1][CH:5]=2)[N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[CH:15]([CH3:17])[CH3:16])=[O:49])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(O)cc34)nc(-c3csc4ccccc34)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(OC(=O)CCCCCNC(=O)OC(C)(C)C)cc34)nc(-c3csc4ccccc34)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)-1H-indol-5-ol (55.5 mg, 0.119 mmol) and 6-(tert-butoxycarbonylamino)hexanoic acid (30 mg, 0.113 mmol) in DMF (3 ml) was added Et3N (24 mg, 0.237 mmol) and HATU (90 mg, 0.237 mmol). The mixture was stirred at rt for 16 hr, and then was concentrated. Water was added and the reaction mixture was extracted with ethyl acetate. The organic fractions were combined, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (0 to 5% MeOH in DCM eluant) to afford the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](O)=[O:11])=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH3:16].B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH3:16]
Reactant: COc1c(Br)ccc2oc(C(=O)O)c(C)c12
Agent: B
Solvent: C1CCOC1
Product: COc1c(Br)ccc2oc(CO)c(C)c12
Yield: 81.1 %

Procedure:
A solution of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid (286 mg, 1.0 mmol, 1 eq, Example 119, Step 3)) in 5 mL of THF under a nitrogen atmosphere was placed in a water bath. To this solution, 1.4 mL of BH3.THF (1.0 M in THF, 1.4 mmol, 1.4 eq) was added dropwise. After 24 h the reaction mixture was quenched with water, and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium carbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give (5-bromo-4-methoxy-3-methyl-benzofuran-2-yl)-methanol (220 mg) in 81% yield. 1H NMR (400 MHz, CDCl3) δ ppm 2.4 (s, 3 H) 3.9 (s, 3 H) 4.7 (s, 2 H) 7.1 (d, J=8.6 Hz, 1 H) 7.4 (d, J=8.8 Hz, 1 H).
Reaction SMILES: CN(C)C=O.[NH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]1=[O:16].[H-].[Na+].Br[CH2:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1>C(OCC)(=O)C.O>[O:22]1[CH2:23][CH2:24][O:25][CH:21]1[CH2:20][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]1=[O:16]
Reactant: BrCC1OCCO1
Reactant: O=c1ccc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1ccc2ccccc2n1CC1OCCO1
Temperature: 52.5 °C
Reaction time: 0.33 h

Procedure:
To 11.5 mL of an N,N-dimethylformamide solution containing 1.15 g of quinolin-2(1H)-one, 0.35 g of 60% sodium hydride was added, and the mixture was stirred at 50 to 55° C. for 20 minutes. Thereto was added 0.90 mL of 2-bromomethyl-1,3-dioxolane, and the reaction mixture was stirred at 85 to 95° C. for 30 minutes. The reaction mixture was further added with 0.35 g of 60% sodium hydride and 0.90 mL of 2-bromomethyl-1,3-dioxolane, and stirred for 1 hour. The mixture was further added with 0.35 g of 60% sodium hydride and 0.90 mL of 2-bromomethyl-1,3-dioxolane, and stirred for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate 2:1] to obtain 0.89 g of a yellow oily substance, 1-(1,3-dioxolan-2-ylmethyl)quinolin-2(1H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[CH:5]=O.[C:22]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH2:22])[CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Temperature: 100 °C
Yield: 79.5 %

Procedure:
To a stirred solution of 3-chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (2.8 g, 8.2 mmol) in 1,4-dioxane (30 mL) were added K2CO3 (1.68 g, 12.24 mmol) and methyl triphenyl phosphonium bromide (4.37 g, 12.24 mmol) at ambient temperature. Then the resultant reaction mixture was heated at 100° C. for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 20% EtOAc in n-Hexane) to afford the title compound as a white solid (1.94 g, 70%): mp 141-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.70 (m, 2H), 7.41 (m, 1H), 7.21 (m, 2H), 6.71 (dd, J=17.6, 10.8 Hz, 1H), 5.72 (d, J=17.6 Hz, 1H), 5.23 (d, J=10.8 Hz, 1H), 4.92 (s, 2H); ESIMS m/z 298.10 ([M−H]−).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([C:27](OCC)=O)=NC(OCC)=O.[CH2:32]([N:39]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C@H:40]1[CH2:45][CH2:44][C@@H:43]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:42][C@H:41]1[CH2:54]O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CC(C)(O)C#N>C1COCC1>[C:27]([CH2:54][C@H:41]1[C@@H:40]([N:39]([CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:45][CH2:44][C@@H:43]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:42]1)#[N:20]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)[C@H](CO)C1
Agent: CC(C)(O)C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)[C@H](CC#N)C1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
Examples 11p and 11q, Step 4: To a solution of triphenylphosphine (4.47 g, 17.04 mmoles) in 50 ml of anhydrous THF at −20° C. was added 7.41 ml of 40% solution of diethyl azodicarboxylate in THF (17.04 mmoles) dropwise, and the mixture was stirred for 20 minutes at −20° C. Then to the mixture was added a solution of tert-butyl (1R,3R,4S)-4-(dibenzylamino)-3-(hydroxymethyl)cyclohexylcarbamate (1.81 g, 4.26 mmoles) in 20 ml of anhydrous THF, and it was stirred for 20 minutes at −20° C. At the end of the stirring was added 20 ml of anhydrous THF followed by acetone cyanohydrine (1.56 ml, 17.04 mmoles), and it was continued to stir for 1.5 hours while gradually raising the temperature to 8° C. The reaction was quenched by several drops of methanol, and the solvent was evaporated off. The residue was purified by column chromatography (silica gel, 25:75 EtOAc and hexane) to give 1.87 g of tert-butyl (1R,3S,4S)-3-(cyanomethyl)-4-(dibenzylamino)cyclohexylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(Nc2cc(Cl)nc(Cl)n2)n[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
A mixture of 2,4,6-trichloropyrimidine (1.0 g, 5.4 mmol), 3-amino-5-methyl-1H-pyrazole (0.53 g, 5.4 mmol), and sodium carbonate (0.57 g, 5.4 mmol) in ethanol (25 ml) was stirred at ambient temperature for 18 hours. Water was added and the resulting precipitate was collected by filtration washed with water and a small amount of methanol, and dried to give the title compound (1.15 g, 88%) as a colourless crystalline solid.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:10]=[C:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[CH2:27][NH:28][CH2:29][CH2:30][CH3:31])([O-])=O.S1C=CC=C1.O=[Si]=O>CO.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:10]=[C:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[CH2:27][NH:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCNCc1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=[Si]=O
Solvent: c1ccsc1
Solvent: CO
Product: CCCNCc1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1N

Procedure:
A mixture of N-[3-(4-nitro-3-propylaminomethyl-phenoxy)-phenyl]-benzenesulfonamide (0.0045 mol) in methanol (100 mL) was hydrogenated with 10% Pd/C (0.5 g) as a catalyst in the presence of thiophene solution (1 mL). After uptake of H2 gas (3 equiv.), the reaction mixture was filtered over Dicalite and the filtrate was evaporated to yield the title compound as a residue.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]([CH3:24])([S:15]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[CH3:14])[O:8][N:7]=1)([CH3:5])[CH:3]=O.CN.[C:28]([BH3-])#[N:29]>C1COCC1>[CH3:1][C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]([CH3:14])([S:15]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[CH3:24])[O:8][N:7]=1)([CH3:5])[CH2:3][NH:29][CH3:28]
Reactant: CC(C)(C=O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Reactant: [BH3-]C#N
Agent: CN
Solvent: C1CCOC1
Product: CNCC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of N-[3-(1,1-Dimethyl-2-oxo-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (50 mg, 0.13 mmol) (see Amide Method G) in THF (0.5 mL) is added methylamine (2M solution in THF, 0.25 mL, 0.5 mmol) and 2.44 mmol/g of MP-cyanoborohydride (137 mg, 0.34 mmol). The reaction mixture is placed on a shaker for 2 h. After this time, more methylamine (2 M solution in THF, 0.13 mL, 0.26 mmol) and 2.44 mmol/g of MP-cyanoborohydride (137 mg, 0.34 mmol) are added to the reaction mixture and the stirring is continued for 18 hs. After this time, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. Purification by preparative HPLC provides the title compound. Yield: 21%; m/z 388 [M+H].
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[N:18]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[N:17]=[N:16][C:15]=2[C@H:26]([NH:28][C:29](=[O:41])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[C:31]=2[Cl:40])[CH3:27])(=O)=O)=CC=1.[H-].[Na+]>C1COCC1>[Cl:40][C:31]1[C:32]([C:36]([F:39])([F:37])[F:38])=[CH:33][CH:34]=[CH:35][C:30]=1[C:29]([N:28]1[CH2:12][CH2:13][C:14]2[N:18]([C:19]3[N:20]=[CH:21][C:22]([F:25])=[CH:23][N:24]=3)[N:17]=[N:16][C:15]=2[C@H:26]1[CH3:27])=[O:41]
Reactant: Cc1ccc(S(=O)(=O)OCCc2c([C@@H](C)NC(=O)c3cccc(C(F)(F)F)c3Cl)nnn2-c2ncc(F)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1c2nnn(-c3ncc(F)cn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Temperature: 60 °C
Yield: 72.2 %

Procedure:
To the solution of Intermediate 244 (12.9 g, 21.04 mmol, 1.0 equiv.) in THF (150 mL) was added NaH (60 wt % in mineral oil, 4.5 g, 112.38 mmol, 5.3 equiv.). The reaction solution was heated to 60° C. for 3 hours and then cooled to room temperature. The reaction was quenched with cold H2O and EtOAc. The organic layer was separated, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography to afford Example 344: (R)-(2-chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-4-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone (6.70 g, 15.20 mmol, 72% yield) as a white solid. MS-ESI (m/z): [M+H]+ calcd for C18H13ClF4N6O, 440.79. found, 440.90. CHN analysis calcd for C18H13ClF4N6O: 49.04% C, 2.98% H, 19.05 N. found, 48.93% C, 3.25% H, 19.02 N. Chiral HPLC analysis: Chiral Pak AD-H column, 0.4 mL/min, 80% EtOH 20% hexane, major isomer 12.56 min, minor isomer 11.28 min.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][C@@H:30]([CH2:33][F:34])[CH2:29]3)=[CH:21][CH:20]=1)[C:13]([C:35]1[CH:40]=[CH:39][C:38]([O:41]CC3C=CC=CC=3)=[CH:37][CH:36]=1)=[C:12]2[CH3:49])C1C=CC=CC=1.N#N>C(OCC)(=O)C.C(O)C.C(OCC)(=O)C.[Pd]>[F:34][CH2:33][C@@H:30]1[CH2:31][CH2:32][N:28]([CH2:27][CH2:26][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][N:14]3[C:15]4[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=4)[C:12]([CH3:49])=[C:13]3[C:35]3[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=3)=[CH:20][CH:21]=2)[CH2:29]1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCN3CC[C@@H](CF)C3)cc2)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCN3CC[C@@H](CF)C3)cc2)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.1 %

Procedure:
A solution of (R)-5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-1-(4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)benzyl)-3-methyl-1H-indole (263 mg, 0.40 mmol) in ethyl acetate/ethanol (4:1, 6 mL) was degassed with three vacuum/N2 cycles. To this solution was added 10% Pd on carbon (120 mg, 0.11 mmol) and then the needle of a H2 balloon was placed into the reaction flask. The mixture was stirred at room temperature for 15 hrs then diluted with ethyl acetate, filtered through Celite and concentrated. The residue was dried further on high vacuum to give 171 mg of (R)-1-(4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)benzyl)-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 9.67 (s, 1H), 8.69 (s, 1H), 7.16 (d, 2H), 7.06 (d, 1H), 6.85 (d, 2H), 6.80 (d, 1H), 6.75 (s, 4H), 6.57 (dd, 1H), 5.10 (s, 2H), 4.35-4.30 (m, 1H), 4.23-4.18 (m, 1H), 3.94 (t, 2H), 2.70 (t, 2H), 2.62 (t, 1H), 2.56-2.40 (m, 3H), 2.38-2.31 (m, 1H), 2.10 (s, 3H), 1.87-1.76 (m, 1H), 1.40-1.31 (m, 1H). LCMS: 475.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:31][CH2:30][C:28]2[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(O[C@@H]2CCOC2)c(-c2ccc(Cl)cc2)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(O[C@@H]2CCOC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using (R)-5-(4-chlorophenyl)-6-(tetrahydrofuran-3-yloxy)nicotinic acid (example CJ) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 94.6%, 469.1 (M+H)+.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:49]=[C:50]2[C:56]3([CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]3)[CH2:55][N:54]([C:69]3[C:70]4[C@H:77]([CH3:78])[CH2:76][CH2:75][C:71]=4[N:72]=[CH:73][N:74]=3)[C:51]2=[CH:52][CH:53]=1.[Cl:79][C:80]1[CH:81]=[C:82]([NH2:86])[CH:83]=[CH:84][CH:85]=1.C1(C)C=CC=CC=1>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:79][C:80]1[CH:81]=[C:82]([NH:86][C:48]2[CH:49]=[C:50]3[C:56]4([CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]4)[CH2:55][N:54]([C:69]4[C:70]5[C@H:77]([CH3:78])[CH2:76][CH2:75][C:71]=5[N:72]=[CH:73][N:74]=4)[C:51]3=[CH:52][CH:53]=2)[CH:83]=[CH:84][CH:85]=1
Reactant: Nc1cccc(Cl)c1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Br)ccc43)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Nc5cccc(Cl)c5)ccc43)c21
Temperature: 95 °C
Yield: 59.5 %

Procedure:
A pear-shaped flask was charged with Pd(OAc)2 (0.9 mg, 0.004 mmol) and rac-BINAP (81 mg, 0.13 mmol) and purged with N2. To the flask was added (R)-tert-butyl 5-bromo-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (20 mg, 0.040 mmol), 3-chlorobenzenamine (10 mg, 0.080 mmol), NaOBut (7.7 mg, 0.080 mmol) and toluene (0.5 mL). The mixture was heated at about 95° C. for 2 days. After cooling to about room temperature, the reaction was diluted with EtOAc, filtered through Celite, and concentrated. The crude product was purified by column chromatography (DCM:MeOH, 80:1) to give (R)-tert-butyl 5-(3-chlorophenylamino)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (13 mg, 59%) as a yellow oil. LCMS (APCI+) m/z 546 [M+H]+; Rt=4.24 min.
Reaction SMILES: [N+]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])([O-])=O.NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.C(N(CC)CC)C.C(Cl)(=O)C1C=CC=CC=1>ClCCl>[CH3:29][O:28][C:20]1[CH:19]=[C:18]([NH:17][C:14]2[N:15]=[N:16][C:11]([CH:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH3:10])=[CH:12][N:13]=2)[CH:23]=[C:22]([O:24][CH3:25])[C:21]=1[O:26][CH3:27]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3)nn2)cc(OC)c1OC

Procedure:
In a similar manner as described for Intermediate 10, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.28 g, 0.92 mmol), triethylamine (0.28 mL, 2.0 mmol) and benzoyl chloride (0.14 g, 1.0 mmol) in dichloromethane (10 mL) gave N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.30 g) as a white solid. MS m/z 410, (M+1).
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[S:12][C:11]([CH:13]=[CH:14][C:15](O)=[O:16])=[CH:10][CH:9]=1)#[N:7].C(Cl)(=O)C(Cl)=O.[BH4-].[Na+]>CCOCC.O1CCCC1>[C:6]([C:8]1[S:12][C:11]([CH:13]=[CH:14][CH2:15][OH:16])=[CH:10][CH:9]=1)#[N:7]
Reactant: N#Cc1ccc(C=CC(=O)O)s1
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=CCO)s1
Reaction time: 2 h

Procedure:
Dimethylformamide (0.1 ml) was added to a stirred suspension of 3-(5-cyano-2-thiphenyl)-propenoic acid (3.7 g) in dry ether (100 ml) and dry tetrahydrofuran (100 ml) containing oxalyl chloride (2.2 ml). The mixture was stirred for 2 hours then the clear solution was decanted from a little dark tar and evaporated to give the crude acid chloride as a pale solid. A solution of this acid chloride in ether (50 ml) and tetrahydrofuran (50 ml) was added rapidly to a stirred suspension of sodium borohydride doped alumina (3.5 g sodium borohydride on 35 g alumina) in ether (100 ml) with cooling to keep at 15°-20° C. The mixture was stirred for 1 hour and then filtered. The filtrate was evaporated and the residue was chromatographed on silica-gel eluting with ether to give the product as a pale solid.
Reaction SMILES: [O:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[O:1]([C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([N:20]3[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]3)=[CH:24][CH:25]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]3)=[CH:31][CH:30]=2)=[CH:7][CH:8]=1
Reactant: Nc1ccc(Oc2ccc(N)cc2)cc1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Product: O=C(Nc1ccc(Oc2ccc(NC(=O)c3ccc(N4CCC(O)CC4)cc3)cc2)cc1)c1ccc(N2CCC(O)CC2)cc1

Procedure:
Compound 914 was prepared according to the procedure described in Scheme IV from 4,4′-oxydianiline and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C36H38N4O5: 607.28; found 607.21.