Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[CH2:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:16].[N+:26]([C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1)([O-:28])=[O:27].[OH-].[Na+].[Cl-].[Na+]>ClCCl>[CH2:15]([C:17]1[NH:18][C:19]2[C:24]([C:25]=1[CH2:33][C:32]1[CH:35]=[CH:36][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:16]
Reactant: CCc1cc2ccccc2[nH]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1[nH]c2ccccc2c1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
In an ice water bath, trifluoroacetic acid (4.4 g, 38.6 mmol), triethylsilane (9.02 g, 77.6 mmol), dichloromethane 15 mL were added into a reaction vessel. After stirring for 5 min, a dichloromethane solution dissolving 2-ethyl-1H-indole (3.74 g, 25.8 mmol) and p-nitro benzaldehyde (4.29 g, 28.4 mmol) was added dropwise slowly into the reaction vessel. After completion of dropwise addition it was reacted maintaining this temperature for 1 h, adjusted to pH=8-9 with 2 M solution of sodium hydroxide. An aqueous solution of sodium chloride was added, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, concentrated to dryness to obtain a red brown solid, washed with a small amount of diethyl ether to obtain a yellow powdered solid 3 g, at a yield of 41.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]#[C:10][C:11]([OH:13])=O.C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.[NH2:43][C:44]1[CH:45]=[C:46]([NH:50][C:51]2[N:59]=[C:58]([NH:60][CH:61]3[CH2:66][CH2:65][CH:64]([OH:67])[CH2:63][CH2:62]3)[N:57]=[C:56]3[C:52]=2[N:53]=[CH:54][N:55]3[CH2:68][CH3:69])[CH:47]=[CH:48][CH:49]=1>CN(C=O)C.C(#N)C>[CH2:68]([N:55]1[CH:54]=[N:53][C:52]2[C:56]1=[N:57][C:58]([NH:60][C@H:61]1[CH2:66][CH2:65][C@H:64]([OH:67])[CH2:63][CH2:62]1)=[N:59][C:51]=2[NH:50][C:46]1[CH:45]=[C:44]([NH:43][C:11](=[O:13])[C:10]#[C:9][C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:49]=[CH:48][CH:47]=1)[CH3:69]
Reactant: CCn1cnc2c(Nc3cccc(N)c3)nc(NC3CCC(O)CC3)nc21
Reactant: O=C(O)C#Cc1c(Cl)cccc1Cl
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCn1cnc2c(Nc3cccc(NC(=O)C#Cc4c(Cl)cccc4Cl)c3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4.3 g (0.02 mol) (2,6-dichlorophenyl)-propargylic acid (M. S. Reich et al., Bull. Soc. Chim. Fr. 21, 217-225 (1917)) in 120 ml DMF and 120 ml acetonitrile are added at RT 4.23 ml (0.025 mol) N,N-di-isopropyl-N-ethylamine, followed by a solution of 5.94 g (0.02 mol) TPTU (O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, Fluka, Buchs, Switzerland) in 100 ml DMF. The resulting solution is stirred at RT for 5 minutes and then added dropwise to a solution of 7.36 g (0.02 mol) 4-[6-(3-amino-phenylamino)-9-ethyl-9H-purin-2-ylamino]-cyclohexanol (example 77, stage 1.2) in a 1:1 mixture of DMF and acetonitrile (240 ml). The addition takes 1.25 hrs and stirring at RT is continued for an additional hour. A second portion of preactivated (2,6-dichlorophenyl)-propargylic acid [prepared by adding 2.0 g (0.0066 mol) TPTU in 30 ml DMF to a solution of 1.3 g (0.0066 mol) (2,6-dichlorophenyl)-propargylic acid in 30 ml DMF and 30 ml acetonitrile and stirring for 5 minutes at RT] was then added dropwise over 30 minutes. After stirring for another 1.5 hrs the solvent is evaporated under reduced pressure and the residue taken up in a mixture of ethyl acetate and 10% aqueous citric acid. The aqueous phase is extracted with ethyl acetate and the combined organic layers are washed with water, saturated sodium bicarbonate solution and brine. After drying (anhydrous sodium sulfate) the ethyl acetate solution is concentrated until the product crystallises. It is collected by filtration, re-suspended in a small amount of ethyl acetate, filtered and vacuum dried. N-{3-[9-Ethyl-2-(trans-4-hydroxy-cyclo-hexylamino)-9H-purin-6-yl-amino]-phenyl}-3-(2,6-dichlorophenyl)-propargylic acid amide (7.0 g, 60%), is obtained as a colourless solid.
Reaction SMILES: C([O:5][C:6]([C:8]1(C(OC(C)(C)C)=O)[C:17]2[C:12]3=[C:13]([C:21](=[O:29])[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:23][N:11]3[N:10]([CH3:30])[CH2:9]1)[C:14]([F:20])=[C:15]([F:19])[C:16]=2[F:18])=[O:7])(C)(C)C.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[F:18][C:16]1[C:15]([F:19])=[C:14]([F:20])[C:13]2[C:21](=[O:29])[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:23][N:11]3[C:12]=2[C:17]=1[CH:8]([C:6]([OH:7])=[O:5])[CH2:9][N:10]3[CH3:30]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)C(C(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)CN2C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)C(C(=O)O)CN2C
Temperature: 60 °C
Yield: 95.3 %

Procedure:
1.0 g of the compound (196) obtained in Example 67 was dissolved in 2 ml of trifluoroacetic acid, and the solution was heated at 60° C. for 2 hours. The reaction solution was added to 50 ml of isopropyl ether, and deposited solids were filtered off to obtain 0.67 g of the subject compound (197) in a 99% yield.
Reaction SMILES: [H-].[K+].[C:3]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:24]([O:27][C:28]1[C:33]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:32][C:31]([CH3:38])=[CH:30][C:29]=1[Si:39](Cl)([CH3:41])[CH3:40])[CH:25]=[CH2:26].C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.O1CCCC1.C1(C)C=CC=CC=1>[CH2:24]([O:27][C:28]1[C:33]([C:34]([CH3:35])([CH3:36])[CH3:37])=[CH:32][C:31]([CH3:38])=[CH:30][C:29]=1[Si:39]([CH:10]1[C:9]2[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][C:13]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:15]=2)([CH3:40])[CH3:41])[CH:25]=[CH2:26]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)C1c2cc(C(C)(C)C)ccc2-c2ccc(C(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
There was washed 3.00 g (22.45 mmol) of potassium hydride having a purity of 30% by weight with each 6 mL of hexane three times in an atmosphere of nitrogen, and 32 mL of tetrahydrofuran (referred to as “THF” hereinafter) was added thereto. To the obtained THF slurry of potassium hydride, 5.00 g (17.96 mml) of 2,7-di-tert-butylfluorene was added dropwise at 0° C. using 32 mL of a THF solution thereof. The obtained mixture was stirred for 2.5 hours at a room temperature, and then 5.33 g (17.96 mmol) of (2-allyloxy-3-tert-butyl-5-methylphenyl)chlorodimethylsilane was added dropwise at −78° C. using 6 mL of a toluene solution thereof. The temperature of the obtained liquid reaction mixture was raised up to a room temperature, and the mixture was stirred for 2.5 hours. The mixture was added dropwise at 0° C. to a mixture of 32 mL of a 10% aqueous solution of sodium hydrogen carbonate and 32 mL of a 10% aqueous solution of sodium carbonate, and the resultant mixture was extracted with 20 mL of toluene. The obtained extract was dried over sodium sulfate, and the solvent contained therein was distilled away under a reduced pressure, thereby obtaining quantitatively (2-allyloxy-3-tert-butyl-5-methylphenyl)(2,7-di-tert-butylfluoren-9-yl)dimethylsilane.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([C:22]4([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24][CH2:23]4)=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[Cs+].[Cs+]>CCO.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>[CH3:15][C:14]1[N:13]=[C:12]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24][CH2:23]3)=[N:17]2)[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)[CH:7]=1
Reactant: Cc1nc(-n2nc(C3(C(F)(F)F)CCC3)[nH]c2=O)ccc1Oc1ccnc(Cl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: Cc1nc(-n2nc(C3(C(F)(F)F)CCC3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 100 °C
Yield: 4.9 %

Procedure:
To a suspension of 1-(5((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-1H-1,2,4-triazol-5(4H)-one (0.240 g, 0.564 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.250 g, 1.202 mmol), Cs2CO3 (0.500 g, 1.535 mmol) and Pd(PPh3)4 (0.030 g, 0.026 mmol) in EtOH (20 mL) was heated at 100° C. The solvent from the reaction mixture was completely evaporated and the residue was partitioned between DCM (30 mL) and water (30 mL). The organic layer was separated and the aqueous layer saturated with solid sodium chloride and extracted with DCM (2×20 mL). The combined organics were dried, concentrated in vacuo, and purified by silica gel chromatography (0-40% THF/EtOAc) to provide 1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-1H-1,2,4-triazol-5(4H)-one (0.013 g, 4.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.48 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 6.67 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.61 (m, 4H), 2.35 (s, 3H), 2.03 (t, J=8.2 Hz, 2H); MS (ESI) m/z: 472.2 (M+H+).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN(C)CCN(C)CCN(C)C.CN([CH:39]=[O:40])C>C1COCC1>[Si:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13]([F:18])=[C:14]([CH:15]=[CH:16][CH:17]=1)[CH:39]=[O:40])([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccccc1F
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCc1cccc(C=O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl(3-(2-fluorophenyl)propoxy)dimethylsilane [Aromatic Intermediate 24, step b] (4.4 g) was added dropwise over 5 min to a solution of sec-butyllithium (1.4M in cyclohexane, 11.7 mL) and 1,1,4,7,7-pentamethyldiethylenetriamine (3.4 mL) in THF (25 mL) at −78° C. The resulting mixture was stirred for 2 h, then DMF (6.4 mL) was cautiously added and the resulting mixture allowed to warm to RT and stirred overnight. The reaction was quenched with water (100 mL) and then ethyl acetate (250 mL) was added. The phases were separated and the organic phase washed with water (2×100 mL), aqueous HCl (2M, 2×50 mL), and brine (100 mL), then dried over magnesium sulphate, filtered and evaporated. Purification was by silica gel chromatography eluting with isohexane to 10% ether in isohexane gradient. The fractions containing product were combined and evaporated to give the titled compound as a clear oil. Yield 1.0 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)=[O:18])=[C:15]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(-c3cccnc3)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccc(OC)cc3)c(-c3cccnc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
4-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridyl)benzoic acid (44 mg, 0.1119 mmol) was dissolved in methylene chloride (10 ml), then p-anisidine (28 mg, 0.2276 mmol), triethylamine (23 mg, 0.2277 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (38 mg, 0.1982 mmol) were added thereto at room temperature and the mixture was stirred for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (33 mg, 0.0662 mmol, 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[S:25]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>N1C=CC=CC=1.C(OCC)(=O)C>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:31](=[O:32])[CH2:30][C:27]1[CH:28]=[CH:29][S:25][CH:26]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: O=C(O)Cc1ccsc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccsc1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (55 mg, 0.16 mmol) produced in Example 16(vi) was dissolved in pyridine (2.0 mL), thiophen-3-ylacetic acid (45 mg, 0.32 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (120 mg, 0.32 mmol) were added, and the mixture was stirred at 80° C. for 12 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), and washed successively with 5% aqueous ammonium chloride solution (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate/heptane to give the title compound (51 mg, 68%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13]([S:16](Cl)(=[O:18])=[O:17])[CH2:14][CH3:15]>N1C=CC=CC=1>[CH2:13]([S:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH2:14][CH3:15]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc(C(=O)O)cc1

Procedure:
In a manner similar to Preparation 9 react ethyl 4-aminobenzoate with 1-propanesulfonyl chloride and pyridine to obtain the title compound.
Reaction SMILES: CC1(C)[O:6][CH:5]2[CH:7]([N:12]3[C:16]4[N:17]=[C:18]([S:31][CH2:32][CH2:33][CH3:34])[N:19]=[C:20]([NH:21][CH:22]5[CH2:24][CH:23]5[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:15]=4[N:14]=[N:13]3)[CH2:8][CH:9]([CH2:10][OH:11])[CH:4]2[O:3]1>CO.Cl>[OH:11][CH2:10][CH:9]1[CH2:8][CH:7]([N:12]2[C:16]3[N:17]=[C:18]([S:31][CH2:32][CH2:33][CH3:34])[N:19]=[C:20]([NH:21][CH:22]4[CH2:24][CH:23]4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:15]=3[N:14]=[N:13]2)[CH:5]([OH:6])[CH:4]1[OH:3]
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CO)C4OC(C)(C)OC43)c2n1
Agent: Cl
Solvent: CO
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CO)C(O)C3O)c2n1

Procedure:
A solution of the product from step (a) (18.5 g) in methanol (1 L) and 2N HCl (150 ml) was stirred at room temperature for 2 hours and concentrated in vacuo. Water (500 ml) was added and the product was collected by filtration and dried (16.7 g).
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[C:35]1([C:41]2([NH2:44])[CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Br:45][C:46]1[C:54]2[C:49](=[N:50][CH:51]=[C:52]([C:55]3[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=3)[C:58](O)=[O:59])[CH:53]=2)[O:48][C:47]=1[C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1>CN(C=O)C.CCOC(C)=O>[Br:45][C:46]1[C:54]2[C:49](=[N:50][CH:51]=[C:52]([C:55]3[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=3)[C:58]([NH:44][C:41]3([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:43][CH2:42]3)=[O:59])[CH:53]=2)[O:48][C:47]=1[C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1
Reactant: O=C(O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reactant: NC1(c2ccccc2)CC1
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1(c2ccccc2)CC1)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reaction time: 1 h
Yield: 62.5 %

Procedure:
DIEA (286 μL, 1.64 mmol) was added to a stirring solution of HATU (311 mg, 0.819 mmol), 1-phenylcyclopropanamine hydrochloride (111 mg, 0.655 mmol), and 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (225 mg, 0.546 mmol) in DMF (6 mL) at room temperature. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-N-(1-phenylcyclopropyl)benzamide (180 mg, 0.341 mmol, 63% yield) consistent by LCMS. LC-MS retention time: 1.89 min; m/z (MH+): 529. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])C.C(OC(C1(NC(C2CC(OC3C4C(=CC(OC)=CC=4)N=C(C4C=CC=CC=4)C=3)CN2C(=O)NC([C:82](=[O:94])[NH:83][CH:84]2[C:92]3[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=3)[CH2:86][CH:85]2[OH:93])C(C)(C)C)=O)CC1C=C)=O)C.C1C2C(=CC=CC=2)[C@H](N)[C@@H]1O.OC1CC2C(=CC=CC=2)C1NC(C(N1CC(OC2C3C(=CC(OC)=CC=3)C=C(C3C=CC=CC=3)C=2)CC1C1(C(O)=O)CC1C=C)C(C)(C)C)=O>>[OH:93][C@@H:85]1[CH2:86][C:87]2[C:92](=[CH:91][CH:90]=[CH:89][CH:88]=2)[C@@H:84]1[NH:83][C:82]([N:15]1[CH2:16][C@H:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:21]=2)[CH2:18][C@H:14]1[C:12]([NH:11][C@:6]1([C:4]([OH:3])=[O:5])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:13])=[O:94]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)OCC
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Agent: C=CC1CC1(C(=O)O)C1CC(Oc2cc(-c3ccccc3)cc3cc(OC)ccc23)CN1C(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Agent: N[C@H]1c2ccccc2C[C@H]1O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(=O)O

Procedure:
Compound 12 was treated as described for the preparation of 13 but with the use of (1S,2R)-cis-1-amino-2-indanol instead of 2-amino-N-(2-hydroxyindan-1-yl)-3,3-dimethyl butyramide followed by ester hydrolysis as described for the preparation of compound 14 which gave the title compound. Purity by HPLC>95%. M+H+649.1.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCOCC1>[CH3:3][C@@H:2]([NH:1][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:4]([OH:6])=[O:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Yield: 83.9 %

Procedure:
Under ice cooling, commercially available D-alanine (6.00 g, 73.5 mmol) was dissolved in an aqueous solution (225 mL) of sodium carbonate (21.45 g, 202 mmol), and a dioxane (60 mL) solution of benzyl chloroformate (Z—Cl) (10.5 mL, 73.5 mmol) was slowly added dropwise thereto. After completion of the dropwise addition, the reaction liquid was returned to room temperature, and continuously stirred overnight. The reaction liquid was transferred to a separating funnel, and excess Z—Cl was removed by diethyl ether extraction. Citric acid was added to the aqueous layer to adjust the pH to 3, and then the mixture was extracted three times with ethyl acetate. The combined organic layer was washed once with a saturated saline solution, and the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and then the concentrated residue was recrystallized by ethyl acetate-hexane to obtain a colorless crystal Z-D-alanine (13.77 g, 91.6%).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[CH:23]=[C:22]([Cl:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[N:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[Cl:24][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([N:25]2[CH2:26][CH2:27][CH:28]([OH:31])[CH2:29][CH2:30]2)=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:23]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(Cl)c2ccccc2c1N1CCC(O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2ccccc2c1N1CCC(O)CC1

Procedure:
A mixture of 6-bromo-9H-purine (0.096 g, 0.48 mmol), 1-[2-(1-aminoethyl)-4-chloro-1-naphthyl]piperidin-4-ol (0.074 g, 0.24 mmol), and N,N-diisopropylethylamine (0.084 mL, 0.48 mmol) in ethanol (0.8 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried and evaporated to dryness. The resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product as the free base. LCMS calculated for C22H24ClN6O (M+H)+: m/z=423.2; Found: 423.2.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:9]=[O:10])[CH2:3][CH2:2]1.S(=O)(=O)([OH:20])N.[Cl-].[Na+]>C(O)(=O)C.O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:16])[F:17])[C:9]([OH:20])=[O:10])[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (12 g, 50 mmol) and sulfamic acid (7.3 g, 75 mmol) are dissolved in glacial acetic acid (50 mL) and a solution of sodium chloride (8.2 g, 75 mmol) in water (15 mL) is added. The reaction mixture is stirred at room temperature for 1 hour, then water (300 ml) is added to obtain the precipitation of the desired product that is filtered and dried at 40° C. under vacuum (12 g).