Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[Se:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[B:19](OC)([O:22]C)[O:20]C.Cl>CCOCC>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[Se:6][C:5]=2[C:4]([B:19]([OH:22])[OH:20])=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)[se]c1ccccc12
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: OB(O)c1cccc2c1[se]c1ccccc12
Temperature: -78 °C
Reaction time: 8 h

Procedure:
4.0 g (17.3 mmol) of dibenzoselenophene and 150 mL of dry ether were added in a 250 mL three necked flask under nitrogen. To the mixture, 11.5 mL of BuLi (1.6 M in hexane) was added slowly at room temperature. The reaction mixture was then heated to reflux for 5 hours. The reaction mixture was cooled to −78° C. and 5 mL of trimethyl borate was added. It was then left to stir at room temperature for overnight. About 50 mL of 1 M HCl was added to the reaction mixture. The organic phase was extracted with ethyl acetate and dried with sodium sulfate. The combined organic phase was evaporated to dryness and 100 mL of 30% ethyl acetate in hexane was added to the solid with stirring at room temperature for 8 hours. The suspension was filtered, the solids were washed with hexane and dried, yielding 2 of white solids as the product which was confirmed by NMR
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([CH:19]=[O:20])=[CH:12][C:11]=1[O:21][CH3:22].CCOC(C)=O>C1COCC1>[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([CH2:19][OH:20])=[CH:12][C:11]=1[O:21][CH3:22]
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(C=O)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(CO)cc1OC
Yield: 64.2 %

Procedure:
Sodium borohydride (2.69 g, 71.3 nmol) was added to a stirred solution of the ester (49)(10.0 g, 33.6 mmol) in THF (50 mL) under an N2 atmosphere at room temperature. Effervescence was observed upon addition of the reducing agent. TLC (EtOAc) after 16 hours revealed the complete loss of starting material. The solution was concentrated and redissolved in EtOAc (100 mL). The organic layer was washed with sat. NH4Cl (5×100 mL) and concentrated in vacuo. Purification by flash chromatography (1% MeOH/CHCl3) yielded the product (50) as a yellow solid (6.46 g, 64%). MP=98-102° C. 1H NMR (250 MHz, CDCl3) δ 7.70 (s, 1H), 7.16 (s, 1H), 4.95 (d, J=6.5 Hz, 2H), 4.12 (t, J=6.2 Hz, 2H), 3.98 (s, 3H), 3.70 (s, 3H), 2.71 (t, J=6.5 Hz, 1H), 2.56 (t, J=7.1 Hz, 2H), 2.19 (pent, J=6.7 Hz, 2H). 13C NMR (67.8 MHz, CDCl3) 173.9 (C12), 154.6 (Cquat.), 147.3 (Cquat.), 139.6 (Cquat.), 133.2 (Cquat.), 111.0 (C6), 109.8 (C3), 68.6 (C9), 62.7 (C1), 56.7 (C8), 52.1 (C13), 30.7 (C11), 24.6 (C10). IR (cm−1) 3286, 2937, 2881, 1737, 1577, 1533, 1368, 1332, 1282, 1162, 1008, 979, 950, 872, 821, 755, 651. MS (M+) 299.0. Anal. Calcd for C13H17NO7: C, 52.17; H, 5.73; N, 4.68. Found: C, 52.41; H, 5.86; N, 4.67.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:17]([O:19][C:20]3[C:27]([CH3:28])=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[CH3:29])=[N:16][C:15](F)=[N:14][C:13]=2[CH:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[N:32]1[C:36](=O)[CH2:35][CH2:34][CH2:33]1>O>[CH2:3]([N:10]1[C:18]2[C:17]([O:19][C:20]3[C:27]([CH3:28])=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[CH3:29])=[N:16][C:15]([NH:10][C:3]3[CH:33]=[CH:34][C:35]([C:36]#[N:32])=[CH:5][CH:4]=3)=[N:14][C:13]=2[CH:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(F)nc2ccn(Cc3ccccc3)c12
Reactant: CN1CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccn(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred suspension of NaH (101 mg, 4.21 mmol) in dry NMP (4 mL) was added 4-aminobenzylnitrile (299 mg, 2.53 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 4-(5-benzyl-2-fluoro-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (314 mg, 0.84 mmol) in dry NMP (4.4 mL) and stirred at room temperature for 2 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc×3. The combined organic layers were washed with water, NH4Cl, water×2, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with 1% MeOH:CH2Cl2, producing the product as a tan solid (320 mg, 80%).
Reaction SMILES: CC1C=CN=C(NC2C=CC=C(C3OC(C4C=CC=CC=4)=NC=3)N=2)C=1.I[C:27]1[O:28][C:29]([C:32]2[N:37]=[C:36]([NH:38][C:39]3[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][N:40]=3)[CH:35]=[CH:34][CH:33]=2)=[CH:30][N:31]=1.[CH3:46][O:47][C:48]1[C:53](B(O)O)=[CH:52][CH:51]=[CH:50][N:49]=1.C([O-])([O-])=O.[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.O.C1COCC1>[CH3:46][O:47][C:48]1[C:53]([C:27]2[O:28][C:29]([C:32]3[N:37]=[C:36]([NH:38][C:39]4[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][N:40]=4)[CH:35]=[CH:34][CH:33]=3)=[CH:30][N:31]=2)=[CH:52][CH:51]=[CH:50][N:49]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(I)o3)n2)c1
Reactant: COc1ncccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccnc(Nc2cccc(-c3cnc(-c4ccccc4)o3)n2)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ncccc1-c1ncc(-c2cccc(Nc3cc(C)ccn3)n2)o1

Procedure:
Prepared as for (4-methyl-pyridin-2-yl)-[6-(2-phenyl-oxazol-5-yl)-pyridin-2-yl]-amine above using [6-(2-iodo-oxazol-5-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine, 2-methoxy-pyridine-3-boronic acid, K2CO3 and Pd(PPh3)4 in a 2:1 mixture by volume of THF and water to give {6-[2-(2-methoxy-pyridin-3-yl)-oxazol-5-yl]-pyridin-2-yl}-(4-methyl-pyridin-2-yl)-amine as a yellow solid. 1-1 NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.46-8.31 (m, 2H), 8.12 (d, J=5.0 Hz, 1H), 7.87-7.82 (m, 2H), 7.82-7.75 (m, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.34 (d, J=7.3 Hz, 1H), 7.21 (dd, J=7.5, 5.0 Hz, 1H), 6.78 (d, J=5.0 Hz, 1H), 4.04 (s, 3H), 2.33 (s, 3H). (ESI+) m/z 360 (M+H)+. Retention time=2.54 mins (method 1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1Br
Reactant: C#Cc1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccccc2C=O)cc1
Temperature: 50 °C
Yield: 88.9 %

Procedure:
To a solution of 2-bromobenzaldehyde (1.85 g, 10 mmol) and 4-methoxyphenyl acetylene (1.58 g, 12 mmol) in 40 mL of triethylamine were added dichlorobis(triphenylphosphine)palladium(II) (140 mg, 2 mol %) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and the ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure. Purification of the crude compound by column chromatography (silica gel 230-400 mesh; 10% ethyl acetate in hexanes as eluent) afforded 2-(4-methoxyphenylethynyl)benzaldehyde (2.1 g, 89%). The above compound (2.06 g, 8.73 mmol) and t-butylamine (3.83 g, 52.4 mmol) were stirred under nitrogen for 24 h at room temperature. The resulting mixture was extracted with ether and the organic layer was dried over anhydrous Na2SO4, and concentrated to give the imine (2.4 g, 94%), which was used in the next step without further purification. To a solution of the above imine (2.39 g, 8.2 mmol) in 100 mL anhydrous DMF was added (0.156 g, 0.82 mmol) copper (I) iodide, and the solution was flushed with nitrogen. The reaction mixture was heated at 100° C. for 4 h. The mixture was cooled to room temperature, and diluted with ether (200 mL). The organic layer was washed with saturated aqueous ammonium chloride (3×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give the crude compound as a dark colored solid. Purification by column chromatography (silica gel 230-400 mesh; 10% ethylacetate in hexanes as eluent) afforded 3-(4-methoxyphenyl)isoquinoline (1.064 g, 55%), as a white solid. The 3-(4-methoxyphenyl)isoquinoline (1.05 g, 4.47 mmol) was suspended in 30 mL hydroiodic acid and 12 mL of acetic acid was added. The reaction mixture was stirred at 110° C. for 2 h, then cooled to room temperature. The precipitate formed was filtered off, washed with acetic acid (2×5 mL) and dried under vacuum, to give a yellow solid. The crude compound was purified by triturating with 5% methanol in ether to give 4-isoquinolin-3-yl-phenol (0.83 g, 84%) as a white powder. Selected data: MS (ES) m/z: 222.89, 221.86; MP 218-219° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1([C:6]2[O:10][N:9]=[C:8]([NH2:11])[CH:7]=2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>ClCCl>[F:13][C:2]([F:1])([F:12])[C:3]1([C:6]2[O:10][N:9]=[C:8]([NH:11][C:21](=[O:22])[O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:7]=2)[CH2:4][CH2:5]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C2(C(F)(F)F)CC2)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Nc1cc(C2(C(F)(F)F)CC2)on1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a stirred mixture of 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine (687 mg, 3.58 mmol) and potassium carbonate (987 mg, 7.0 mmol) in dry dichloromethane (30 mL) at 0° C., was added a solution of phenyl chloroformate (848 mg, 5.42 mmol) in anhydrous dichloromethane (5 mL). The reaction mixture was warmed to room temperature and stirred for a further 15 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give an oil. Purification via silica gel flash chromatography afforded phenyl 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-ylcarbamate (727 mg, 65%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 11.34 (brs, 1H), 7.40-7.47 (m, 2H), 7.20-7.31 (m, 3H), 6.80 (s, 1H), 1.45-1.56 (m, 4H); LC-MS (ESI) m/z 313 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[C:26]([CH3:27])=[N:25][C:24]([CH3:28])=[CH:23][N:22]=1)=[C:19]=[S:20]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:21]1[C:26]([CH3:27])=[N:25][C:24]([CH3:28])=[CH:23][N:22]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: Cc1cnc(N=C=S)c(C)n1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ncc(C)nc2C)c1NCCCO
Temperature: 60 °C
Reaction time: 6 h
Yield: 52.3 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (500 mg, 1.94 mmol) and 2-isothiocyanato-3,5-dimethylpyrazine (866 mg, 5.24 mmol) in tetrahydrofuran (4.0 mL) was stirred at 60° C. for 6 hr. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give methyl 4-chloro-3-{[(3,5-dimethylpyrazin-2-yl)carbamothioyl]amino}-2-[(3-hydroxypropyl)amino]benzoate as a yellow solid (430 mg).
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([O:36][CH2:37][CH3:38])([CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[C:18](=[O:33])[N:17]2[CH3:34])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH2:37]([O:36][C:5]([CH3:35])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:26][CH:27]=3)[C:18](=[O:33])[N:17]2[CH3:34])=[CH:11][CH:12]=1)[C:4]([OH:39])=[O:3])[CH3:38]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(OC(F)(F)F)cc3)C(=O)N2C)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(C)(Cc1ccc(OCCC2CN(Cc3ccc(OC(F)(F)F)cc3)C(=O)N2C)cc1)C(=O)O
Temperature: 25 °C
Yield: 32 %

Procedure:
A solution of 2-ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester and 5N NaOH (0.3 mL) in ethanol (3 mL) is refluxed for 1 h, cooled to ambient temperature, and concentrated. The residue is diluted with CH2Cl2, dried, and concentrated in vacuo to provide the title compound (0.022 g, 32% after two steps). 1H NMR (400 MHz, CDCl3): δ 7.24-7.19 (m, 1H), 7.09 (d, 2H, J=8.3 Hz), 6.83-6.78 (m, 3H), 6.69 (d, 2H, J=8.3 Hz), 4.38, 4.28 (ABq, 2H, J=14.8 Hz), 3.94-3.91 (m, 3H), 3.77 (s, 3H), 3.60-3.53 (m, 3H), 3.36 (t, 1H, J=9.0 Hz), 3.04-2.92 (m, 1H), 1.89-1.83 (m, 1H), 1.40 (s, 3H), 1.23 (t, 3H, J=6.9 Hz). MS [EI+] 525 (M+H)+, [EI−] 523 (M−H)+. Rf=0.27 in 10% CH3OH in CH2Cl2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-])=O)[CH:3]=1>[OH-].[NH4+].O.S([O-])([O-])(=O)=O.[Fe+2].[NH4+]>[NH2:11][C:4]1[CH:3]=[C:2]([Br:1])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: Nc1cc(Br)ccc1C(=O)O
Temperature: 25 °C

Procedure:
A mixture of Example 125A (5.1 g, 20.7 mmol) in concentrated ammonium hydroxide (102 mL) was treated with a solution of ammonium iron (II) sulfate (49 g, 125.1 mmol) in water (102 mL) over 5 minutes, heated to reflux for 2 minutes, cooled to room temperature, filtered through diatomaceous earth (Celite®), acidified to pH 1 with concentrated HCl, and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (ESI(−)) m/e 214, 216 (M−H)−, 1H NMR (300 MHz, DMSO-d6) δ 7.59 (d, 1H), 6.97 (d, 1H), 6.63 (dd, 1H), 3.32 (br s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.CN(C=O)C.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1F)[CH:21]=[O:22]>C(OCC)(=O)C.O>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[CH:21]=[O:22]
Reactant: c1c[nH]cn1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(-n2ccnc2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
Potassium carbonate (1.71 g) and imidazole (847 mg) were added to a DMF (20 mL) solution of 3,4-difluorobenzaldehyde (2.0 g). The reaction solution was agitated at 100° C. overnight, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent:hexane:ethyl acetate=1:1→ethyl acetate), and 1.11 g of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)[C:7]([CH3:18])=[CH:6]2)#[N:2].[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[NH:33])[NH:31]O)=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CC#N>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:33]=[C:13]([C:12]([N:8]3[C:9]4[C:5](=[C:4]([C:19]([F:21])([F:22])[F:20])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH3:18])([CH3:17])[CH3:16])[O:15][N:31]=2)=[CH:26][CH:25]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)(C)C(=O)O
Reactant: N=C(NO)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)(C)c1nc(-c2ccc(F)cc2)no1

Procedure:
Synthesized as described in Example 37 from 2-[5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]-2-methylpropanoic acid and 4-fluoro-N-hydroxybenzenecarboximidamide using MeCN as the solvent, and HATU (1.05 eq), DIEA (1.05 eq), instead of EDCl, for the first coupling step: MS (ES) m/z 429 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][OH:22])[O:12]1.C[Si](Cl)(C)C.[Br:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.N>N1C=CC=CC=1.O>[Br:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:1][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[C@H:11]2[C@H:15]3[C@H:14]([O:18][C:17]([CH3:19])([CH3:20])[O:16]3)[C@@H:13]([CH2:21][OH:22])[O:12]2)=[O:34])=[CH:31][CH:30]=1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(N)ncnc21
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(NC(=O)c3ccc(Br)cc3)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol (0.400 g, 1.30 mmol) was dried by co-evaporation with pyridine, then suspended in dry pyridine (6.5 mL). TMSCl (0.330 mL, 2.60 mmol) was added and the mixture was stirred for 15 min. 4-Bromobenzoylchloride (0.342 g, 1.56 mmol) was added to the mixture and stirred for 2 h. The solution was cooled to 0° C. and 1 mL of H2O was added. After 5 min a 29% NH3 aq solution (0.847 mL) was added and the reaction mixture was stirred for 30 min while warming to r.t. The mixture was then concentrated and the residue was diluted with H2O (40 mL). The product was extracted with EtOAc (60 mL) and concentrated. The crude material was purified by flash chromatography (65 to 100% EtOAc/hexanes) to afford the title compound (0.305 g, 49%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[F:23]C1C=C2C(=CC=1)NC(=O)[C@]12C[C@H]1C1C=C2C(C=NN2)=CC=1>>[F:23][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:22])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([I:1])=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Reactant: O=C1Nc2ccc(F)cc2[C@]12C[C@H]2c1ccc2cn[nH]c2c1
Product: O=C1Nc2ccc(F)cc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Yield: 57 %

Procedure:
The title compound was prepared in a manner similar to the method of (1R,2S)-2-(3-iodo-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one using (1R,2S)-5′-fluoro-2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (240 mg, 0.818 mmol). Purification using Biotage Isolera with SNAP 25 g column with 5-90% EtOAc in hexane yielded the title compound as a cream solid (195 mg, 57%; 97% e.e.) with the major (1R,2S) enantiomer eluting at 3.7 min (Phenomenex Lux 5μ Cellulose-2 (150×4.6 mm); isocratic 25% EtOH in n-hexane; 1.5 mL/min; 24° C.; Detection: 254 nm). From the racemic reference standard, the retention time of the (1S,2R) enantiomer was 3.2 min using this method. NMR (400 MHz, CD3OD) δ 7.47 (s, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 6.88 (dd, J=8.8, 4.4 Hz, 1H), 6.79 (t, J=8.8 Hz, 1H), 5.69 (d, J=8.4 Hz, 1H), 3.38 (t, J=8.8 Hz, 1H), 2.28 (dd, J=8.8, 4.2 Hz, 1H), 2.21 (dd, J=9.2, 4.4 Hz, 1H); MS ESI 420.0 [M+H]+, calcd for [C17H11FIN3O+H]+ 420.0.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([N:8]([CH2:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[C:9](=[O:18])[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([CH3:31])=[N:4]1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([N:3]1[CH:7]=[C:6]([N:8]([CH2:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)[C:9](=[O:18])[C@@H:10]([OH:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]([CH3:31])=[N:4]1)[CH3:2]
Reactant: CCn1cc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)C(=O)c2ccccc2)c(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCn1cc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](O)c2ccccc2)c(C)n1
Temperature: 0 °C
Reaction time: 12 h
Yield: 115.6 %

Procedure:
A solution of N-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-2-oxo-2-phenyl-N-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-acetamide (145 mg, 0.34 mmol) was dissolved in MeOH (4 mL), cooled to 0° C. and treated with NaBH4 (38 mg, 1 mmol) and stirred for 12 h at ambient temperature. The reaction mixture was quenched with aqueous K2CO3 (2 M, 1 mL), concentrated, then redissolved in EtOAc (15 mL) and washed with aqueous K2CO3 (2 M, 3×15 mL). The combined aqueous layers were extracted with EtOAc (3×15 mL) and the combined organic layers dried over sodium sulfate. Concentration afforded the racemic compound (170 mg, >100%) as a light yellow oil. Separation by chromatography on a chiral column provided the title compound as a colourless oil (38 mg, 26%) MS m/e: 433.2 [M+H]+ which crystallized upon standing.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH:13]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH:13]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)c1cn(CCCN2C(=O)c3ccccc3C2=O)c2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)c1cn(CCCN2C(=O)c3ccccc3C2=O)c2ccccc12
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
2-(N-tert-butoxycarbonylamino)-1-{1-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-propyl]-3-indolyl}-1-ethanone (0.30 g, 0.65 mmol) was dissolved in dry THF (7.5 ml) and cooled to −10° C., sodium bis(trimethylsilyl)amide (0.65 ml, 1 M in THF, 0.65 mmol) was added and the resulting yellow solution stirred for 15 minutes. Benzylbromide (0.16 ml, 1.30 mmol) was added and the stirring continued for 15 minutes at −10° C., the cooling bath was removed and stirring continued for 4 hours. Saturated NH4Cl(aq) was added followed by removal of the aqueous phase. The organic solvent was evaporated in vacuum and the residue chromatographed furnishing the sub-title product (0.28 g, 79%).
Reaction SMILES: C([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]2[O:24][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[N:26][N:27]=2)[CH:9]=1)(=O)C(C)(C)C.[OH-].[Na+].O.Cl>CO.C1COCC1>[C:28]([C:25]1[O:24][C:23]([C:10]2[CH:9]=[C:8]([OH:7])[CH:13]=[CH:12][C:11]=2[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[N:27][N:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COc1ccc(F)c(-c2ccc(OC(=O)C(C)(C)C)cc2-c2nnc(C(C)(C)C)o2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(O)cc2-c2nnc(C(C)(C)C)o2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.1 %

Procedure:
To a solution of 2-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl pivalate (405 mg) in methanol (3.0 mL) and THF (3.0 mL) was added 1N aqueous sodium hydroxide solution (3.0 mL), and the mixture was stirred at room temperature for 4 hr. Water and hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (114 mg) as a white amorphous solid.