Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH:16]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:17]([OH:19])=[O:18].[CH:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[N:33]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:34]=[C:35]([C:36]([O:38][CH3:39])=[O:37])[C:28]=12)=O>C(Cl)Cl>[C:43]([O:42][C:40]([N:33]1[C:29]2=[N:30][CH:31]=[CH:32][C:27]([CH2:25][NH:15][C@H:16]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:17]([OH:19])=[O:18])=[C:28]2[C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34]1)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: NC(CC(F)(F)F)C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@H](CC(F)(F)F)C(=O)O)c12
Reaction time: 0.5 h

Procedure:
To a 10 mL round bottom flask was added sodium triacetoxyborohydride (104 mg, 0.493 mmol), 2-amino-4,4,4-trifluorobutanoic acid (51.6 mg, 0.329 mmol) and DCM (2 mL). The reaction mixture was stirred for 30 min after which was added 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 2 h and then quenched with MeOH (3 drops). The mixture was concentrated to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C19H22F3N3O6, 446; found, 446.5.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([OH:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>>[F:1][C:2]1[C:10]([F:11])=[C:9]([OH:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(F)c1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To the 2,3-difluoro-4-hydroxybenzoic acid (800 mg, 5.1 mmol) dissolved in anhydrous methanol (50 mL) was added thionyl chloride (0.55 mL, 7.3 mmol). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgSO4 to give methyl 2,3-difluoro-4-hydroxybenzoate (540 mg, 62%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH3:13][S:14]([O:9][CH2:8][CH2:7][N:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=[C:2]1[CH3:1])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Solvent: c1ccncc1
Product: Cc1ncc([N+](=O)[O-])n1CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.9 %

Procedure:
Metronidazole (5.0 g, 29.2 mmol) was dissolved in pyridine (10 ml), and a pyridine solution (10 ml) of methanesulfonyl chloride (3.5 g, 30.7 mmol) was added dropwise to the solution. After the mixture was stirred at room temperature for 5 hours, the solvent was distilled off under reduced pressure, and the residue was washed with water-ethanol and dried to obtain 6.4 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([O:21][CH3:22])=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=2)[CH:3]=1.[CH:23]1([CH:26]=O)[CH2:25][CH2:24]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH:23]1([CH2:26][NH:1][C:2]2[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]3[CH:11]=[CH:12][C:13]([O:21][CH3:22])=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=3)[CH:3]=2)[CH2:25][CH2:24]1
Reactant: COc1ccc(-c2cc(N)c(=O)n(C)c2)cc1NS(C)(=O)=O
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(NCC3CC3)c(=O)n(C)c2)cc1NS(C)(=O)=O
Temperature: 30 °C
Yield: 13.2 %

Procedure:
To a solution of compound from Example 109 (64.6 mg, 0.2 mmol) in MeOH (3 mL) and AcOH (0.3 mL) was added cyclopropanecarbaldehyde (14.0 mg, 0.2 mmol) dropwise with stirring at 30° C. NaBH3CN (24.5 mg, 0.4 mol) was added in portions at 30° C. The reaction mixture was stirred for 2 h at 30° C. It was then quenched with saturated aqueous NH4Cl (5 mL), extracted with EtOAc (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (10.0 mg, 13.2%) as a light green solid. 1H NMR (Methanol-d4 400 MHz): δ 7.55 (d, J=2.4 Hz, 1H), 7.36 (dd, J=8.4, 2.4 Hz, 1H), 7.16-7.07 (m, 2H), 6.61 (d, J=2.4 Hz, 1H), 3.94 (s, 3H), 3.66 (s, 3H), 3.05 (s, 2H), 2.95 (s, 3H), 1.21-1.14 (m, 1H), 0.64-0.56 (m, 2H), 0.35-0.28 (m, 2H). LCMS (M+H)+ 378.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH:13]([NH:14][C:15]2=[O:16])[C:12](=NN)[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH:13]([NH:14][C:15]2=[O:16])[CH2:12][CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C23CCC(=NN)C(C2)NC3=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(C23CCCC(C2)NC3=O)c1
Yield: 90.9 %

Procedure:
A mixture of 21.73 g of 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-4,7-dione, 4.9 g of hydrazine hydrate and 170 ml of ethanol is refluxed for 1 hour. After cooling, the mixture is evaporated under reduced pressure to remove solvent. The residue thus obtained is dispersed in benzene and then filtered to give 21.64 g of 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-4,7-dione-4-hydrazone as crude crystals. A mixture of 21.64 g of 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-4,7-dione-4-hydrazone, 17.1 g of potassium tert.-butoxide and 400 ml of toluene is refluxed for 2 hours under heating. After cooling, water is added to the mixture, and the aqueous mixture is extracted with ether. The ether extract is washed with water, dried and then evaporated to remove solvent. The residue thus obtained is recrystallized from a mixture of ethylacetate and n-hexane. 17.54 g of 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-7-one are obtained. M.p. 109° - 111°C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[CH2:30]([O:32][CH2:33][CH2:34]O)[CH3:31].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH2:31][CH2:30][O:32][CH2:33][CH3:34])=[O:24])=[CH:21][CH:20]=1
Reactant: CCOCCO
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOCCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords the product as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[S:22])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: COc1nc(C)c(C(C)=O)cc1NC(=S)Oc1ccccc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3cc(C(C)=O)c(C)nc3OC)CC2)c1
Yield: 77 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11]N(C)C.[CH2:15]([O:17][C:18](=[O:28])[CH:19]([NH:25][CH:26]=[O:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:23]([O:22][C:20](=[O:21])[C:19]([CH2:11][C:7]1[C:6]2[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[NH:9][CH:8]=1)([NH:25][CH:26]=[O:27])[C:18]([O:17][CH2:15][CH3:16])=[O:28])[CH3:24]
Reactant: CN(C)Cc1c[nH]c2c(F)cccc12
Reactant: CCOC(=O)C(NC=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1c[nH]c2c(F)cccc12)(NC=O)C(=O)OCC
Yield: 101.9 %

Procedure:
A suspension of (7-fluoro-1H-indol-3-ylmethyl)-dimethyl-amine (550 mg, 0.0028 mol.), 2-formylamino-malonic acid diethyl ester (640 mg, 0.0031 mol.), and NaOH (30 mg) in toluene (20 mL) under argon was refluxed for 3 days. The reaction mixture was concentrated and purified by column chromatography on silica gel using 40% ethyl acetate-hexane to give 2-(7-Fluoro-1H-indol-3-ylmethyl)-2-formylamino-malonic acid diethyl ester (1.0 gm, 99%): mp 164-166° C., 1H NMR (500 MHz, CDCl3): 1.28 (t, J=7.5 Hz, 6H), 3.87 (s, 2H), 4.17-4.31 (m, 4H), 6.80 (s, 1H), 6.86-6.89 (dd, J=8.0 and 8.0 Hz, 1H), 6.97-7.01 (m, 2H), 7.27 (s, 1H), 8.18 (d, J=1.5 Hz, 1H), 8.27 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:19][CH:18]4[CH2:20][NH2:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:28][C:29]([F:35])([F:34])[CH2:30][C:31](O)=[O:32]>>[F:28][C:29]([F:35])([F:34])[CH2:30][C:31]([NH:21][CH2:20][CH:18]1[CH2:19][C:17]1([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:32]
Reactant: NCC1CC1(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: O=C(O)CC(F)(F)F
Product: O=C(CC(F)(F)F)NCC1CC1(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 85.6 %

Procedure:
(2-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropyl)methanamine (71 mg, 0.15 mmol) was coupled with 3,3,3-trifluoropropanoic acid (38 mg, 0.2 mmol) using General Coupling Method A to give 60 mg (86% yield) of 3,3,3-trifluoro-N-((2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropyl)methyl) propanamide. MS found: (M+H)+=468.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[CH3:24].C(N(CC)CC)C.Cl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([NH:7][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[N:4][C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[CH3:24]
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1ccc(Oc2cc(C)c(-c3nc(N)sc3Br)c(C)c2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Oc2cc(C)c(-c3nc(NC(=O)c4ccncc4)sc3Br)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of 5-bromo-4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (2-4, 325 mg, 0.70 mmol) in CH2Cl2 (10 ml) was added triethylamine (0.50 mL, 1.7 mmol) followed by isonicotinoyl chloride hydrochloride (302.5 mg, 3.4 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered, and dried under vacuum to give N-{5-bromo-4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl}isonicotinamide (2, 345 mg) as white solids in 99% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.3 (s, 1 H), 8.82 (m, 2 H), 7.98 (m, 2 H), 7.05 (d, J=9.0 Hz, 2 H), 6.99 (d, J=9.0 Hz, 2 H), 6.70 (s, 2 H), 3.76 (s, 3 H), 1.99 (s, 6 H); ESI-MS: m/z 509.6, 511.1 (M+H)+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][CH2:12][C@@H:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C.C(OC(C)C)(C)C>[ClH:1].[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][S:14][C@H:11]2[CH2:12][CH2:13][NH:9][CH2:10]2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CS[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@H]2CCNC2)cc1
Reaction time: 0.5 h

Procedure:
106 ml of a 4N ethyl acetate solution of hydrogen chloride were added, whilst ice-cooling, to a solution of 27.50 g of (3R)-1-t-butoxycarbonyl-3-(4-methoxybenzylthio)pyrrolidine [prepared as described in step (2) above] dissolved in 100 ml of ethyl acetate, and the mixture was stirred at 0° to 5° C. for 30 minutes and then at 25° C. for 2 hours. At the end of this time, the mixture was diluted with 200 ml of diisopropyl ether, and the crystals which precipitated were collected by filtration, to give 20.84 g of the title compound as colorless crystals, melting at 125°-126° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:28])=[C:11]([CH3:27])[C:12]3[O:16][C:15]([CH3:17])=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C:13]=3[C:25]=2[CH3:26])=O)=[CH:4][CH:3]=1>C(O)C>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:8][C:9]2[C:10]([CH3:28])=[C:11]([CH3:27])[C:12]3[O:16][C:15]([CH3:17])=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C:13]=3[C:25]=2[CH3:26])=[CH:4][CH:3]=1
Reactant: Cc1oc2c(C)c(C)c(NC(=O)c3ccc(F)cc3)c(C)c2c1-c1ccc(F)cc1
Solvent: CCO
Product: Cc1oc2c(C)c(C)c(NCc3ccc(F)cc3)c(C)c2c1-c1ccc(F)cc1
Yield: 66 %

Procedure:
By using 4-fluoro-N-[3-(4-fluorophenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-yl]benzamide, the title compound was synthesized according to Example 2b. Yield: 66%. Melting point: 107-109° C. (Ethanol);
Reaction SMILES: [ClH:1].FC1C=CC=C(F)C=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4C=NC=CC=4)=[CH:23][C:16]=23)=[C:10]([F:30])[CH:9]=1)=[O:6].Cl.FC1C=C(NC(=O)[CH2:66][C:67]([NH:69][C:70]2[CH:75]=[CH:74][C:73]([F:76])=[CH:72][CH:71]=2)=[O:68])C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=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>CN(C=O)C>[ClH:1].[F:30][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:66][C:67]([NH:69][C:70]2[CH:75]=[CH:74][C:73]([F:76])=[CH:72][CH:71]=2)=[O:68])[CH:13]=[CH:12][C:11]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:21][C:22]([CH3:24])=[CH:23][C:16]=12
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]c(-c4cccnc4)cc23)c(F)c1)c1c(F)cccc1F
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)ccnc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
To a mixture of 3-fluoro-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzenamine (20 mg, 0.078 mmol, Compound E of Example 292), 3-(4-fluorophenylamino)-3-oxopropanoic acid (20 mg, 1 mmol, Compound A of Example 25), and HATU (44 mg, 0.12 mmol) in DMF (0.5 mL) was added DIPEA (0.1 mL). The reaction mixture was stirred at rt for 2 h and concentrated in vacuo. The residue was purified by preparative HPLC to give the desired product (HCl salt, 12.5 mg, 34%) as a white solid. 1H NMR (CD3OD) δ 8.05 (d, 1H, J=7.2 Hz), 7.79 (dd, 1H, J=12.7, 2.8 Hz), 7.50-7.53 (m, 2H), 7.27-7.36 (m, 2H), 6.97 (m, 2H), 6.70 (d, 1H, J=6.6 Hz), 6.20 (s, 1H), 3.47 (s, 2H), 2.40 (s, 3H); LC/MS(ESI+) m/z 437 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:29][CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O.[C:42]([O-:45])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH:19]4[CH2:27][CH:23]5[CH2:22][CH:21]([CH2:26][CH:25]3[CH2:24]5)[CH2:20]4)=[O:16])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:29][CH2:30][N:12]1[CH2:13][CH2:42][O:45][CH2:10][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC3(CCN(C(=O)NC4C5CC6CC(C5)CC4C6)CC3)c3c(Br)cccc32)cc1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CC(CCN1CCOCC1)c1cccc(Br)c12
Temperature: 85 °C
Reaction time: 8 h
Yield: 18.4 %

Procedure:
To a solution of (±)-7-bromo-N-(2-adamantyl)-3-(2-(p-toluenesulfonyloxy)ethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (50 mg, 0.078 mmol) and K2CO3 (21.56 mg, 0.156 mmol) in anhydrous CH3CN (3 mL) was added NaI (3 mg, 0.020 mmol) at 0° C. Then the mixture was stirred overnight at 80-90° C. The mixture was concentrated to give the crude product which was purified by preparative HPLC to afford (±)-7-bromo-N-(2-adamantyl)-3-(2-morpholinoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (4 mg, 9%). LC-MS Method 5 tR=1.09 min, m/z=558; 1H NMR: (400 MHz, CDCl3): δ=1.43 (m, 2H), 1.56-1.69 (m. 3H), 1.75-1.85 (m, 9H), 1.94-2.05 (m, 3H), 2.45-2.59 (m, 4H), 2.91 (m, 2H), 3.12 (m, 5H), 3.25 (m, 2H), 3.56 (m, 3H), 3.91-4.16 (m, 6H), 4.20 (m, 2H), 7.12 (m, 2H), 7.40 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([I:9])[C:6]([F:10])=[CH:5][C:3]=1[NH:4][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(F)c(I)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(F)c(I)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
To a solution of 2,5-difluoro-4-iodoaniline (5.3 g, 19.4 mmol, Can. J. Chem., 2000(78), 1081-1088) in DCM (50 ml) was added methanesulfonyl chloride (1.65 ml, 21.3 mmol) and pyridine (4.7 ml, 58.2 mmol) at 0° C. The mixture was stirred for 24 hours at room temperature. The mixture was partitioned between EtOAc and 2 M HCl aqueous solution. The organic layer was separated and washed with 2 M aqueous HCl solution and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with gradually from hexane/EtOAc (4:1) to hexane/EtOAc (3:1) to give the title compound (5.6 g, 87%) as purple solids.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:15].Br[CH2:18][CH2:19][C:20]([OH:22])=[O:21]>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1([CH3:16])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:3]1[CH3:15]
Reactant: CC1=Nc2ccc3ccccc3c2C1(C)C
Reactant: O=C(O)CCBr
Solvent: Clc1ccccc1Cl
Product: CC1N(CCC(=O)O)c2ccc3ccccc3c2C1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 112.2 %

Procedure:
A mixture of 1,1,2-trimethyl-[1H]-benz[e]indole (10.0 g, 47.8 mmol) and 3-bromopropanoic acid (7.3 g, 47.8 mmol) in 1,2-dichlorobenzene (50 mL) was heated with stirring at 110° c. for 18 h. After the resulting mixture was cooled to room temperature, the precipitated was collected by filtration, triturated with DCM thoroughly, and dried under vacuum to afford 15.2 g of light brown powder (88%). ESI-MS: observed for [MH]+ 281.31.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.[NH2:18][C:19]1[N:20]=[CH:21][C:22]([C:34]2[N:38]([CH2:39][CH3:40])[N:37]=[C:36]([CH:41]3[CH2:46][CH2:45][N:44]([C:47](=[O:57])[CH2:48][CH2:49][O:50]C4CCCCO4)[CH2:43][CH2:42]3)[N:35]=2)=[N:23][C:24]=1[C:25]1[O:26][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[N:28][N:29]=1>CO>[NH2:18][C:19]1[N:20]=[CH:21][C:22]([C:34]2[N:38]([CH2:39][CH3:40])[N:37]=[C:36]([CH:41]3[CH2:42][CH2:43][N:44]([C:47](=[O:57])[CH2:48][CH2:49][OH:50])[CH2:45][CH2:46]3)[N:35]=2)=[N:23][C:24]=1[C:25]1[O:26][C:27]([C:30]([CH3:33])([CH3:31])[CH3:32])=[N:28][N:29]=1
Reactant: CCn1nc(C2CCN(C(=O)CCOC3CCCCO3)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: CO
Product: CCn1nc(C2CCN(C(=O)CCO)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
Pyridine 4-methylbenzenesulfonate (11.62 g, 46.24 mmol) was added to a suspension of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-one (128 g, 231.19 mmol) in methanol (1 L) under nitrogen. The mixture was stirred at 60° C. for 1.5 hours. The mixture was soluble after 5 minutes. The mixture was held at 50° C. overnight during which time a precipitate formed. The solid material was isolated by filtration and washed with water and acetonitrile. This material still contained minor impurities from the previous stage and required further purification. The material was dissolved in dichloromethane and purified by flash chromatography on silica gel (0% methanol/DCM to 10% methanol/DCM). The desired product, 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (Reference Example 1) (92 g, 85%), was thus isolated as a cream solid (Form A): 1H NMR Spectrum: (DMSO-d6) 1.4-1.51 (12H, m), 1.51-1.78 (2H, m), 1.89-2.05 (2H, n), 72-2.86 (1H, m), 2.91-3.05 (1H, m), 3.12-3.24 (1H, m), 3.64 (2H, q), 3.83-4.01 (1H, m), 4.29-4.41 (1H, m), 4.47 (1H, t), 4.58 (2H, q), 8.26 (2H, s), 8.85 (1H, s): Mass Spectrum [M+H]+=470.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:16]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:17](=[O:20])[O:18][CH3:19])[CH:5]=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:7]=1[F:8].[CH:30]1([N:33]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[C:34]2[C:39]3=[N:40][CH:41]=[C:42]([C:43]#[N:44])[N:38]3[N:37]=[C:36](S(C)(=O)=O)[N:35]=2)[CH2:32][CH2:31]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:43]([C:42]1[N:38]2[C:39]([C:34]([N:33]([CH:30]3[CH2:32][CH2:31]3)[CH2:49][C:50]3[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=3)=[N:35][C:36]([NH:1][C:2]3[CH:3]=[C:4]([N:16]([CH2:21][C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)[C:17](=[O:20])[O:18][CH3:19])[CH:5]=[C:6]([N:9]4[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]4)[C:7]=3[F:8])=[N:37]2)=[N:40][CH:41]=1)#[N:44]
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: COC(=O)N(Cc1ccc(OC)cc1)c1cc(N)c(F)c(N2CCN(C)CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1ccc(OC)cc1)c1cc(Nc2nc(N(Cc3ccc(OC)cc3)C3CC3)c3ncc(C#N)n3n2)c(F)c(N2CCN(C)CC2)c1
Yield: 103.7 %

Procedure:
methyl (3-amino-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate (50 mg, 0.093 mmol), 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (44.6 mg, 0.112 mmol) and Cs2CO3 (91 mg, 0.280 mmol) in DMF (1 ml) were heated at 45° C. for 14 hours. LCMS showed product formation (m/e+=721, [M+H]+). The mixture was poured onto a Phenomenex Strata XC cation exchange resin (2 g adsorbent). The cartridge was washed with MeOH and CH3CN. The product was eluted with a 1:1 mixture of CH3CN and a 2 molar solution of NH3 in MeOH. Evaporation to dryness gave crude methyl (3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate (69.5 mg). The material was used in the following PMB deprotection reaction without further purification.