Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[CH3:12].[C-:13]#[N:14].[Na+].[I-].[Na+].CCOCC>CN(C)C=O>[CH3:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:13]#[N:14]
Reactant: [C-]#N
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1c(CC#N)cccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
1-Chloromethyl-2-methyl-3-nitro-benzene (25g) was dissolved in 125 ml of N,N-dimethylformamide. To this mixture was added 10.89 g of sodium cyanide (Mallinckrodt, Paris, Ky.) and 0.4 g of sodium iodide (Mallinckrodt) and the heterogeneous mixture was heated to 80° C. for 21 hr. The reaction mixture was cooled to room temperature, poured into ether, washed several times with water, dried, and evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane, giving 16.83 g of (2-methyl-3-nitro-phenyl)-acetonitrile as a cream solid. ##STR103##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[O:25][C:26]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Reactant: Cc1oc(-c2ccccc2F)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2ccccc2F)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-{1-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-{1-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid as off-white solid.
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=[O:33])[C:7]([CH3:32])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][NH:21][C:20](=[O:23])[N:19]2[CH3:24])=[CH:11][CH:10]=1)C.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][C:36]=1[C:43]([F:46])([F:45])[F:44]>CN(C=O)C>[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][N:21]2[CH2:22][CH:18]([CH2:17][CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][C:7]([CH3:32])([O:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:6]([OH:5])=[O:33])=[CH:14][CH:13]=3)[N:19]([CH3:24])[C:20]2=[O:23])=[CH:37][C:36]=1[C:43]([F:44])([F:45])[F:46]
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc(F)c(C(F)(F)F)c2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.6 %

Procedure:
NaH (9.2 mg, 0.23 mmol, 60% w/w in mineral oil) is added to a cooled (0° C.) solution of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (82.0 mg, 0.19 mmol) in DMF (1 ml). After 5 minutes, the reaction mixture is removed from the cooling bath and stirred while warming to ambient temperature over one hour. After the solution is cooled again to 0° C., 4-fluoro-3-(trifluoromethyl)benzyl bromide (148 mg, 0.57 mmol) is added in a single portion, the cooling bath removed, and the mixture stirred for one hour. The reaction mixture is quenched with 1N HCl and extracted with ethyl acetate (2×). The organic extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil. The crude product is dissolved in methanol (5 ml), treated with 5N NaOH (0.5 ml), and stirred for 18 hours at ambient temperature. After concentration to remove methanol, the residue is partitioned between diethyl ether and water. The aqueous layer is adjusted to pH 2 with conc. HCl, then extracted with ethyl acetate (2×15 ml). The combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil which is purified by MS/LC to yield an oil (41 mg, 37%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=1)#[CH:2].C([Mg]Br)C.[CH3:14][C:15]([O:18][C:19]([N:21]1[C@H:25]([C:26](N(OC)C)=[O:27])[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])[CH3:16]>C1COCC1>[I:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:26]([C@@H:25]2[CH2:24][CH2:23][CH2:22][N:21]2[C:19]([O:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:20])=[O:27])=[CH:4][CH:5]=1
Reactant: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: C#Cc1ccc(I)cc1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C#Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
To a solution of 1-ethynyl-4-iodobenzene 6 (0.908 g, 3.98 mmol) in THF (20 mL) at −78° C. was added ethylmagnesium bromide (3M in ether, 1.39 mL, 4.18 mmol). After 10 minutes the cooling bath was removed and the solution was allowed to stir at room temperature for 1 hour. The reaction mixture was then re-cooled to 0° C. and added to a solution of N-(tert-butoxycarbonyl)-L-proline N′-methoxy-N′-methylamide 2 (0.970 g, 3.76 mmol) in THF (10 mL). The reaction mixture was warmed to room temperature and stirring was continued for 12 hours before the mixture was quenched with saturated NH4Cl. The mixture was diluted with ethyl acetate/H2O, the layers separated and the aqueous phase was re-extracted with ethyl acetate (2×). The combined organic layers were washed (H2O, brine), dried (Na2SO4), and filtered, and the solvent was removed in vacuo. The resulting residue was purified by flash chromatography (hexane:ethyl acetate, 4:1) to give (S)-tert-butyl 2-(3-(4-iodophenyl)propioloyl)pyrrolidine-1-carboxylate 7 (0.908 g, 71%) as a yellow oil which solidified on standing. 1H NMR (400 MHz, CDCl3) δ 7.72-7.76 (m, 2H), 7.26-7.30 (m, 2H), 4.49 (dd, J=8.8, 4.3 Hz, 0.3H), 4.29 (dd, J=8.5, 5.5 Hz, 0.7H), 3.59 (app t, J=6.7 Hz, 2H), 2.20-2.33 (m, 1H), 1.85-2.10 (m, 3H), 1.45, 1.40 (s, 9H, rotamers in 2:3 ratio). LCMS: Anal. Calcd. for C18H20INO3: 425. found: 326 (M+H-Boc)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Li]CCCC.CON(C)[C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1)=[O:18]>C1COCC1>[Cl:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1)=[O:18]
Reactant: Clc1cccc(Br)c1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1-bromo-3-chlorobenzene (15 g, 78.3 mmol) in anhydrous THF (150 mL) cooled to −78° C. was added dropwise a solution of 2.5 M n-BuLi in hexanes (31.3 mL, 78.34 mmol). The reaction mixture was stirred at −78° C. for 1 h and a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (17.8 g, 65.3 mmol) in anhydrous THF (50 mL) was added dropwise. After addition, the mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with satd aq NH4Cl (250 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether/EtOAc 5:95) to give (R)-tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate (12.9 g, 51%). 1H NMR (400 MHz, CDCl3): 1.45 (s, 9H), 1.54-1.73 (m, 2H), 1.75 (m, 1H), 2.00 (m, 1H), 2.71-2.78 (m, 1H), 2.93 (m, 2H), 3.30-3.35 (m, 1H), 4.22 (m, 1H), 7.39-7.42 (t, 1H), 7.52 (d, 1H), 7.89 (d, 1H), 7.90 (m, 1H). MS m/z 324 (M+H+).
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][N:9]1C(CC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reaction time: 2 h

Procedure:
To 1.20 g (2.86 mmol) of N-t-butyl-4-(1,1-dimethyl-ethoxy-carbonyl)-1 -(phenylmethylcarbonyl)piperazine-2(S)-carboxamide and 1.1 g (0.086 mmol) of 10% Pd/C was added 15 mL of methanol. The vessel was charged with hydrogen and the reaction stirred for 2 hours, filtered through Celite and washed with ethanol. The solvents were removed in vacuo to provide the title product as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:30]1([CH2:33][CH2:34][C:35]([OH:37])=O)[CH2:32][CH2:31]1>>[CH:30]1([CH2:33][CH2:34][C:35]([N:14]([CH:13]2[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12]2)[CH3:15])=[O:37])[CH2:31][CH2:32]1
Reactant: O=C(O)CCC1CC1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)CCC1CC1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 3-cyclopropyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-propionamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 3-cyclopropylpropionic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 534.3 [M]+.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34]CC1C=CC=CC=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>[Pd]>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[OH:34])[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Agent: [Pd]
Agent: Cl
Product: CC(=O)N[C@@H](Cc1ccc(O)c(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1

Procedure:
Following essentially the procedure of EXAMPLE 71, Step 3, the product from step 2, compound 19, (0.19 g, 0.32 mmol) is deprotected under 20 psi of H2 in the presence of 54 mg of 10% palladium on carbon in 3.5 h, affording, after filtration, concentration and treatment with ethereal HCl, 20 (0.16 g, 0.32 mmol, quant.) as a cream-white solid: 1H NMR (CDCl3+CD3OD drop) δ 7.43-7.27 (m, 4H), 6.86-6.77 (m, 3H), 3.95 (br, 1H), 3.8 (br, 1H), 2.93 (m, 2H), 2.6 (m, 4H), 2.4 (m, 1H), 2.06 (m, 2H), 1.85 (s, 3H), 1.8 (m, 2H), 1.59 (m, 1H), 1.5-1.3 (m, 3H), 1.27 (d, J=7 Hz, 6H); IR (diffuse reflectance) 3251, 3113, 3087, 3061, 3053, 3028, 2956, 2941, 2865, 2810, 1645, 1596, 1520, 1446, 1294 cm −1. MS (CI) m/z (rel intensity) 457 (MH+,99), 459 (5), 458 (25), 457 (99), 439 (3), 257 (7), 218 (5), 202 (3), 201 (9), 96 (4), 77 (3). HRMS (ESI) calcd for C27H37N2O3F+H1 457.2866, found 457.2855. Anal. Calcd for C27H37FN2O3.HCl.1.5 H2O: C, 62.35; H, 7.95; N, 5.39; Found: C, 62.63; H, 7.76; N, 5.47.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.Cl.CN(C1C=CC=CN=1)C.[Cl:29][C:30]([F:35])([F:34])[C:31](O)=[O:32]>ClCCl>[Cl:29][C:30]([F:35])([F:34])[C:31]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:32]
Reactant: O=C(O)C(F)(F)Cl
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: O=C(N=c1cccc[nH]1)C(F)(F)Cl
Reaction time: 8 h
Yield: 23.9 %

Procedure:
In 5 ml of dichloromethane, 200 mg (2.13 mmol) of 2-aminopyridine was dissolved. To this solution, 491 mg (2.55 mmol) of EDC-HCl, 311 mg (2.55 mmol) of dimethylaminopyridine, and 187 μl (2.23 mmol, 290 mg) of chlorodifluoroacetic acid were added in this order, followed by stirring overnight. After completion of the reaction, the reaction liquid was diluted with dichloromethane, washed with water and with 1% hydrochloric acid, and then dried over anhydrous magnesium sulfate. Thus, 105 mg of 2-chloro-2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide was obtained (Percentage Yield: 24%).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: O=C1CCC(O)(c2nccs2)CC1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(O)(c4nccs4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-thiazol-2-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)=[CH:11][C:12]2[C:13]([CH3:21])=[CH:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]C.[CH:34](=O)[CH2:35][CH3:36]>>[CH2:1]([O:8][C:9]1[C:10]([N:22]([CH2:34][CH2:35][CH3:36])[C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)=[CH:11][C:12]2[C:13]([CH3:21])=[CH:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCOc1cc2c(cc1Nc1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Reactant: CCC=O
Product: CCCCCCOc1cc2c(cc1N(CCC)c1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Yield: 100 %

Procedure:
Following General Procedure P, ethyl 4-(3-n-heptyloxy-5,5,8-trimethyl-5,6-dihydronaphthalen-2-ylamino)benzoate (Compound 113, 0.024 g, 0.05 mmol) was reacted with propionaldehyde to afford 0.026 g (100%) of the title compound as a yellow oil.
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]=1.[ClH:15]>Cl([O-])=O.[Na+]>[Cl:15][C:5]1[N:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:4]=1[I:3]
Reactant: Cl
Reactant: Ic1cnc(-c2ccccn2)[nH]1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Agent: [OH-]
Product: Clc1nc(-c2ccccn2)[nH]c1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
To 5% aqueous sodium chlorite solution (180 mL) was added sodium hydroxide (737 mg) and completely dissolved. To the reaction solution was added 2-(5-iodo-1H-imidazol-2-yl)pyridine (5.00 g), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was adjusted to pH 3 to 4 with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=30:70-100:0, volume ratio) to give the title compound (3.57 g, yield 63%) as colorless crystals. melting point 188-189° C.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:19][C:20]([CH3:27])=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:19][C:20]([CH3:27])=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)[CH2:7][C:6]([OH:28])=[O:5])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)oc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)O)oc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.7 %

Procedure:
A solution of methyl 2-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-5-methyl-1,3-oxazole-4-carboxylate (Preparation 173) (2.92 g, 7.43 mmol) in anhydrous dichloromethane (15 ml) was treated with trifluoroacetic acid (7.5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 24 hours. The solvent was removed under reduced pressure and the residue was azeotroped with dichloromethane (×3). The residue was purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate:pentane (0:100 to 40:60) to afford the title compound as a colourless oil (2.50 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:47])[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:23]=[C:24]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[CH:25]=[C:26]([CH2:28][OH:29])[CH:27]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:2].[H-].[Na+].I[CH2:51][CH3:52]>>[CH2:1]([O:3][C:4](=[O:47])[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:23]=[C:24]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[CH:25]=[C:26]([CH2:28][O:29][CH2:51][CH3:52])[CH:27]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(CO)cc(-c3ccc(S(C)(=O)=O)cc3)c2)c1CCC(=O)OCC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Product: CCOCc1cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)cc(-c2ccc(S(C)(=O)=O)cc2)c1
Yield: 42.7 %

Procedure:
A similar procedure as described in Example 24, step 1 was used, starting from 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-hydroxymethyl-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (250 mg, 0.37 mmol), sodium hydride (29.9 mg, 0.75 mmol), and iodoethane (116.7 mg, 0.75 mmol) to obtain 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-ethoxymethyl-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (110 mg, 42%) as a light brown oil: ES(+)-HRMS m/e calcd for C39H52O9S (M+Na)+ 719.3224, found 719.3227.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([CH2:30][CH2:31][N:32]4[C:33](=[O:42])[C:34]5[C:35](=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:36]4=[O:37])[S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCN3C(=O)c4ccccc4C3=O)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Yield: 7.7 %

Procedure:
Intermediate (6) was prepared by alkylation of Compound (1) (210 mg, 0.45 mmol) with N-(2-bromoethyl)phthalimide (230 mg, 0.90 mmol) according to the procedure in Method C, Step a. The crude material was purified by flash column chromatography eluting with EtOAc/hexane (5-80%) to afford 2-(4-bromophenyl)-5-cyclopropyl-6-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl](methylsulfonyl)amino}-N-methyl-2H-indazole-3-carboxamide (6) as an off-white solid (22 mg).
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([O:12][C@@H:13]([C:18]1[C:19]([CH3:60])=[N:20][C:21]2[N:22]([N:36]=[C:37]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:38]=2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)[CH:40]=2)[C:23]=1[C:24]1[C:25]([CH3:35])=[C:26]2[C:31](=[C:32]([F:34])[CH:33]=1)[O:30][CH2:29][CH2:28][CH2:27]2)[C:14]([O:16]C)=[O:15])([CH3:11])([CH3:10])[CH3:9].[Li+].[OH-]>O1CCOCC1>[C:8]([O:12][C@@H:13]([C:18]1[C:19]([CH3:60])=[N:20][C:21]2[N:22]([N:36]=[C:37]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:38]=2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)[CH:40]=2)[C:23]=1[C:24]1[C:25]([CH3:35])=[C:26]2[C:31](=[C:32]([F:34])[CH:33]=1)[O:30][CH2:29][CH2:28][CH2:27]2)[C:14]([OH:16])=[O:15])([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(-c3cccc(OCc4ccc(F)cc4)c3)c(-c3ccccc3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(-c3cccc(OCc4ccc(F)cc4)c3)c(-c3ccccc3)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 60 °C
Reaction time: 48 h
Yield: 50.7 %

Procedure:
To a solution of (2S)-methyl 2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-3-(3-((4-fluorobenzyl)oxy)phenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate TFA salt (10 mg, 0.014 mmol) in dioxane (0.5 mL) was added 1.0 N LiOH aqueous solution (0.5 mL, 0.5 mmol). The reaction mixture was stirred at 60° C. for 48 h. The reaction mixture was filtered and the filtrate was purified by preparative HPLC to afford (5 mg, 50%) of the title compound as the TFA salt. Preparative HPLC condition: Phenomenex Luna C18 30×100 mm S10, 50 to 100% B over 22 min gradient, 6 min hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA. Flow rate: 40 mL/min. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.087 (9H, br. s.), 1.88 (2H, br. s.), 2.51 (2H, br. s.), 2.71 (3H, br. s.) 2.82-2.96 (2H, m), 4.29 (2H, br. s.), 4.6 (1H, s), 5.02 (2H, s), 6.9 (1H, s), 7.14-7.47 (12H, m), 7.97 (1H, s).
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][C:21]([C:25]5C=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[N:31]1C=CC=CC=1C1C=CC2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)N=1>>[CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][C:21]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][N:31]=5)=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccn4)nc3c2)OC1(C)C
Reactant: Nc1ncnn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Product: Nc1ncnn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccn5)nc4c3)c12

Procedure:
7-Cyclobutyl-5-(2-pyridin-2-yl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine was prepared using the same procedures described as described for 7-Cyclobutyl-5-(2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine, except 2-pyridin-2-yl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline was used in place of 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline; 1H NMR (DMSO-d6, 400 MHz) δ 1.88-2.00 (m, 1H), 2.02-2.16 (m, 1H); 2.32-2.44 (m, 2H); 2.44-2.58 (m, 2H); 4.00-4.16 (m, 1H); 6.76 (brs, 2H); 7.45-7.59 (m, 1H); 7.94 (s, 1H); 7.94-8.05 (m, 2H); 8.13 (d, J=8.4 Hz, 1H); 8.24-8.32 (m, 1H); 8.51-8.68 (m, 3H); 8.72-8.80 (m, 1H); MS (ES+): m/z 394.08 (100) [MH+], HPLC: tR=3.14 min (MicromassZQ, polar—5 min).