Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[C:14]([O:18][C:19]([C@@:21]1([CH2:35][C:36](=[CH2:39])[CH:37]=[O:38])[CH2:25][C:24](=[O:26])[N:23]([C@@H:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:28])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>C(O)C>[C:14]([O:18][C:19]([C@@:21]1([CH2:35][C:36](=[CH2:39])[CH2:37][OH:38])[CH2:25][C:24](=[O:26])[N:23]([C@@H:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:28])[CH2:22]1)=[O:20])([CH3:16])([CH3:15])[CH3:17]
Reactant: C=C(C=O)C[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: C=C(CO)C[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Yield: 120.2 %

Procedure:
Ethanol (43.9 ml) was added to sodium borohydride (644 mg, 17.0 mmol) in a nitrogen atmosphere, and the mixture was cooled with ice-acetone. Cerium chloride heptahydrate (6.55 g, 17.6 mmol) and (3S)-3-(3-oxo-2-methylene-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (3.14 g, 6.55 mmol) were added under cooling. The mixture was stirred under cooling for one hour, and then cerium chloride heptahydrate (1.64 g, 4.40 mmol) and sodium borohydride (166 mg, 4.39 mmol) were added. The mixture was stirred under cooling for 30 minutes and then ice-cooled. A saturated ammonium chloride solution (150 ml) was added to the reaction solution. The mixture was concentrated under reduced pressure and ethanol was removed. The mixture was extracted with ethyl acetate (150 ml×1, 100 ml×1). The organic layer was washed with brine (200 ml) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→66:34→50:50→34:66→25:75→17:83→5:95) to give 2.83 g of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:25])([CH3:24])[CH2:3][CH2:4][O:5][C:6](=[O:23])[C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH3:26][C:27]1[O:31][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:29][C:28]=1[CH2:38][CH2:39]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:25][Si:2]([CH3:24])([CH3:1])[CH2:3][CH2:4][O:5][C:6](=[O:23])[C:7]1[CH:12]=[C:11]([O:13][CH2:39][CH2:38][C:28]2[N:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:31][C:27]=2[CH3:26])[CH:10]=[CH:9][C:8]=1[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1C(=O)OCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(C(=O)OCC[Si](C)(C)C)c1
Temperature: 55 °C
Reaction time: 12 h
Yield: 78.1 %

Procedure:
To a solution of 2-(2-tert-butoxycarbonyl-ethyl)-5-hydroxy-benzoic acid 2-trimethylsilanyl-ethyl ester (4.30 g, 11.7 mmol) and toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (4.61 g, 12.9 mmol) in DMF (30 mL) was added Cs2CO3 (4.59 g, 14.1 mmol). The suspension was stirred at 55° C. for 12 h. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (3×100 mL). The combined organics were dried (Na2SO4) and concentrated to a residue, which was purified using silica gel chromatography (hexanes/EtOAc 9/1 to 8/2) to afford the title compound as a colorless oil (5.04 g, 78%). 1H NMR (400 MHz, CDCl3): δ 0.06 (s, 9H), 1.11 (t, 2H, J=8.8 Hz), 1.40 (s, 9H), 2.36 (s, 3H), 2.51 (t, 1H, J=7.8 Hz), 2.97 (t, 2H, J=6.8 Hz), 3.12 (t, 1H, J=7.8 Hz), 4.24 (t, 2H, J=6.8 Hz), 4.35 (t, 2H, J=8.8 Hz), 6.88 (dd, 1H, J=3.0, 8.3 Hz), 7.15 (d, 1H, J=8.3 Hz), 7.37-7.44 (m, 4H), 7.97 (d, 2H, J=7.8 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[CH3:22][CH:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(NCCCC)CCC>>[CH3:22][CH:23]([NH:30][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(N)c1ccccc1
Reactant: Cc1cccn2cc(-c3ccc(OCCCCl)cc3)nc12
Solvent: CCCCNCCCC
Product: Cc1cccn2cc(-c3ccc(OCCCNC(C)c4ccccc4)cc3)nc12

Procedure:
This compound was prepared according to the procedure described in Example 1 of U.S. Pat. No. 4,727,145. using 2-(4-chloropropoxyphenyl)-8-methylimidazo[1,2-a]pyridine and alpha-methylbenzylamine instead of 2-(4-chloropropoxyphenyl)-imidazo[1,2-a]pyridine and dibutylamine respectively. Analysis: Calc'd for C25H27N3O 3HCl; C, 6.11; H, 60.8; N, 8.49. Found: C, 6.51; H, 60.43; N, 8.36.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[CH2:22](O)CCC>C(OCC)(OCC)OCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:22]=[N:13][N:12]=[C:10]3[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=CC1
Reactant: CCCCO
Solvent: CCOC(OCC)OCC
Product: Fc1ccccc1C1=CCc2nncn2-c2ccc(Cl)cc21

Procedure:
12.1 g of 7-chloro-5-(2-fluorophenyl)-2-hydrazino-3H-1-benzazepine are heated to boiling under reflux for 2 hours in a mixture of 330 ml of n-butanol and 110 ml of triethyl orthoformate. The mixture is evaporated in vacuo. The residue is crystallized from hexane, there being obtained crude 8-chloro-6-(2-fluorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine as reddish coloured crystals. This material is purified by chromatography on 121 g of silica gel. Impurities are eluted with benzene/methanol (99:1). The product is subsequently eluted with benzene/methanol (98.5:1.5 and 98:2). After crystallization of the resulting material from ether, there is obtained 8-chloro-6-(2-fluorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine of melting point 180°-182°.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:4]=2[N:3]=1.C(N(CC)CC)C.Cl[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28].O>ClCCl>[Cl:1][C:2]1[N:6]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:5]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:4]=2[N:3]=1
Reactant: FC(F)(F)c1ccc2[nH]c(Cl)nc2c1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CCOCn1c(Cl)nc2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-chloro-5-trifluoromethyl-1H-benzoimidazole (1 g, 4.52 mmol, Example 1c), triethylamine (1.3 mL, 9.04 mmol, Aldrich) and (2-chloromethoxy-ethyl)-trimethyl-silane (881 μL, 4.98 mmol, Aldrich) in dichloromethane (30 mL) was stirred at room temperature for 16 h. Water (150 mL) was added, and the mixture was extracted with dichloromethane (2×150 mL). The combined organic extracts were dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with hexane/EtOAc (10:1) to give the title compound as an orange solid. MS (ESI, positive ion) m/z: 351 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4](=[O:13])[C:3]=1[C:14]#[N:15].[N:16]1([C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[N:7][CH:8]=1)[NH:5][C:4](=[O:13])[C:3]([C:14]#[N:15])=[C:2]2[N:19]1[CH2:20][CH2:21][N:16]([C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:17][CH2:18]1
Reactant: N#Cc1c(Cl)c2cc(F)cnc2[nH]c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O
Yield: 79 %

Procedure:
This compound was prepared from 4-chloro-6-fluoro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (96) and piperazin-1-yl-thiophene-2-yl-methanone according to general procedure E to yield 4.85 g (79%) of 6-fluoro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (98) as yellow solids. MP 244° C.; 1H-NMR (DMSO-d6): δ 3.72 (m, 4H), 3.91 (m, 4H), 7.16 (dd, J=3.6, 4.8 Hz, 1H), 7.49 (d, J=3.6 Hz, 1H), 7.80 (d, J=5.2 Hz, 1H), 8.05 (dd, J=2.8, 7.2 Hz, 1H), 8.70 (d, J=2.8 Hz, 1H); EIMS: 384 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:30])[CH2:2][CH3:3].Br[CH2:32][CH:33]1[CH2:35][CH:34]1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:9]([C:22]3[CH:26]=[N:25][N:24]([CH2:32][CH:33]4[CH2:35][CH:34]4[C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:43])([F:44])[F:45])[CH:37]=4)[CH:23]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:30])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Reactant: FC(F)(F)c1cccc(C2CC2CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC4CC4c4cccc(C(F)(F)F)c4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 52.5 °C
Yield: 379.1 %

Procedure:
A mixture of 1,3-dipropyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.100 g, 0.23 mmol), 1-(2-bromomethyl-cyclopropyl)-3-trifluoromethyl-benzene (0.64 g, 0.23 mmol), K2CO3 (0.063 g, 0.46 mmol) and acetone (10 ml) were heated at 50-55° C. for 16 hrs. Reaction mixture was cooled to 20-25° C. and filtered off. The filtrate was evaporated and residue was purified by column chromatography to afford 1,3-dipropyl-8-{1-[2-(3-trifluoromethyl-phenyl)-cyclopropylmethyl]-1H-pyrazol-4-yl}-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.55 g, 58%).
Reaction SMILES: [CH3:1][S-:2].[Br:3][C:4]1[CH:9]=[C:8]([CH2:10]Br)[C:7]([F:12])=[CH:6][C:5]=1[O:13][CH3:14].O.C(OCC)(=O)C>CN(C=O)C>[Br:3][C:4]1[CH:9]=[C:8]([CH2:10][S:2][CH3:1])[C:7]([F:12])=[CH:6][C:5]=1[O:13][CH3:14]
Reactant: C[S-]
Reactant: COc1cc(F)c(CBr)cc1Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(F)c(CSC)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
Thiomethoxide (1.19 g, 17.0 mmol) was added to a solution of 1-bromo-5-(bromomethyl)-4-fluoro-2-methoxybenzene (4.9 g, 16.4 mmol) in anhydrous DMF (25 mL) at 0° C. The mixture was stirred at room temperature for 5 h, and then poured into water (40 mL). Extractive work up with ethyl acetate gave the title compound (4.3 g, 99.0%) as colorless oil which was carried on without purification. 1H NMR (CDCl3, 400 MHz) δ 7.50 (d, J=8.0 Hz, 1H), 6.64 (d, J=11.2 Hz, 1H), 3.88 (s, 3H), 3.63 (s, 2H), 2.04 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH:6]=[N:5]2.[H-].[Na+].[CH3:23]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH3:23])[CH:6]=[N:5]2
Reactant: Fc1ccc(CNc2cnc3cc(Br)ccc3n2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(F)cc1)c1cnc2cc(Br)ccc2n1
Temperature: 7.5 °C
Reaction time: 0.25 h
Yield: 115.5 %

Procedure:
(6-Bromo-quinoxalin-2-yl)-(4-fluoro-benzyl)-amine (0.35 g, 1.0 mmol) was added to a suspension of sodium hydride (0.037 g, 1.5 mmol) in DMF (5 mL) at room temperature and it was stirred for 15 minutes. The reaction mixture was cooled down to 5-10° C. and methyl iodide (0.17 g, 1.2 mmol) was added at 5-10° C. and this was maintained for 30 minutes. After completion of the reaction, the reaction mixture was gradually poured into ice cold water (30 mL) and stirred for a further 30 minutes. The precipitated product was filtered and washed by water and dried under vacuum to afford the title compound (0.4 g) which was used directly for the next step.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:28][CH2:29][C:30]1([CH3:35])[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:28][CH2:29][C:30]1([CH3:35])[CH2:34][CH2:33][N:32]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH3:16])[C:10]=2[F:15])[CH2:31]1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC1(CNC(=O)OC(C)(C)C)CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(F)c(N2CCC(C)(CN)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
A mixture of 0.61 g (2.18 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.56 g (2.61 mmol) of 3-[(t-butoxycarbonyl)aminomethyl]-3-methylpyrrolidine, 0.66 g (6.54 mmol) of triethylamine, and 25 ml of acetonitrile was refluxed for six hours, then stirred overnight at room temperature. The precipitate was filtered and washed with acetonitrile and ether. The crude product was suspended in 20 ml of 6N hydrochloric acid and 20 ml of glacial acetic acid and was stirred at room temperature for three hours. The solution was concentrated and the residue was triturated with ether. The solid was filtered and washed with ether to give 0.61 g of the title compound as the hydrochloride, mp 250°-252° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12](=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=1.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl.O.[OH-].[NH4+]>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:12]2[NH:1][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=3[N:11]=2)=[CH:15][CH:16]=1)[CH3:22]
Reactant: CCOc1ccc(CC(=O)Nc2cc([N+](=O)[O-])ccc2N)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3[nH]2)cc1
Temperature: 25 °C

Procedure:
N-(2-Amino-5-nitro-phenyl)-2-(4-ethoxy-phenyl)-acetamide 41 (590 mg, 1.871 mmol), Phosphorous pentachloride (390 mg, 1.871 mmol) were dissolved in anhydrous chloroform (20 mL) in a small, argon purged flask fitted with an condenser and magnetic stirbar. The solution was heated to reflux in an oil bath for 4 hours and cooled to room temperature overnight. The mixture was diluted with H2O and chloroform and 2M ammonium hydroxide solution added to adjust pH to 9-10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with chloroform and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated to afford crude. The product was purified using dry silica gel column chromatography eluting with 20 mL portions of solvent system (2.5% 2M NH3 in methanol/95% dichloromethane) to afford a yellow residue 42 2-(4-Ethoxy-benzyl)-5-nitro-1H-benzimidazole. 1H NMR (DMSO) δ: 1.30 (t, 3H, J=6.5), 3.87 (q, 2H, J=7.3), 4.11 (s, 2H), 6.88 (d, 2H, J=8.0), 7.25 (d, 2H, J=7.9), 7.65 (d, 1H, J=8.9), 8.07 (d, 1H, J=9.0), 8.36-8.40 (m, 1H); MS (ESI): 298 (MH+, 100%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](I)=[CH:15][N:16]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.Br[C:19]1[CH:20]=[C:21]([NH:25][C:26]([NH:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[O:27])[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14]([C:23]4[CH:22]=[C:21]([NH:25][C:26]([NH:28][CH2:29][C:30]([F:31])([F:32])[F:33])=[O:27])[CH:20]=[CH:19][CH:24]=4)=[CH:15][N:16]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(Br)c1
Reactant: Fc1ccc(-c2ccn3c(I)cnc3c2)cc1
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: [Na+]
Solvent: COCCOC
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ccc(F)cc4)ccn23)c1
Temperature: 80 °C
Yield: 76.8 %

Procedure:
A mixture of 7-(4-fluoro-phenyl)-3-iodo-imidazo[1,2-a]pyridine (10.1 g, 29.8 mmol), 1-(3-bromo-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (12.3 g, 35.8 mmol) and 2M sodium carbonate (120 mL) in dimethoxyethane (595 mL) was deoxygenated by evacuation/refill with N2 (×3). Tetrakis(triphenylphosphine)palladium (1.72 g, 1.49 mmol) was added, the resulting mixture was deoxygenated again (×3) and then heated at 80° C. under N2 overnight. The reaction was allowed to cool to RT, and solvents were removed under reduced pressure. The crude mixture was diluted with water (100 mL), EtOAc (100 mL) and DCM (100 mL) with stirring. The resulting slurry was filtered, the solid was washed with EtOAc and dried under vacuum to give the title compound (9.8 g). 1H NMR (400 MHz, DMSO-d6) δ 8.98 (1H, s), 8.61 (1H, d), 7.99 (1H, s), 7.96-7.87 (2H, m), 7.79 (2H, s), 7.45 (2H, d), 7.41-7.30 (3H, m), 7.30-7.23 (1H, m), 6.87 (1H, bt), 4.00-3.89 (2H, m). MS: [M+H]+ 429
Reaction SMILES: O[CH2:2][C@H:3]([NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)=[O:8])[CH3:4].C(P(CCCC)CCCC)CCC>CCOC(C)=O>[CH3:2][C@@H:3]1[CH2:4][N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:7](=[O:8])[CH2:6][NH:5]1
Reactant: C[C@H](CO)NCC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2cccc([N+](=O)[O-])c2)C(=O)CN1

Procedure:
To a solution of N2-[(1R)-2-hydroxy-1-methylethyl]-N1-(3-nitrophenyl)glycinamide (2.0 g, 7.9 mmol) and tributylphosphine (2.7 mL, 15.8 mmol) in EtOAc (21 mL) was slowly added a solution of di-t-butylazodicarboxlate, (3.6 g, 15.8 mmol) in EtOAc 10 mL. The inside temperature was kept between 25° C. to 30° C. The reaction was followed by HPLC. The crude material was purified a silica gel column chromatography (2% to 5% MeOH in CH2Cl2). The compound (5R)-5-methyl-1-(3-nitrophenyl)-2-piperazinone was isolated as solid (690 mg, 37% yield) MS: M(C11H13N3O3)=235.24 (M+H)+=236.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[CH:7][C:6]=1[N:13]1[CH2:17][CH2:16][O:15]C1=O.O>C(O)(=O)C>[CH3:11][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[C:6]([NH:13][CH2:17][CH2:16][OH:15])=[CH:7][C:8]=1[OH:12]
Reactant: COc1cc(C)c(O)cc1N1CCOC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C)c(O)cc1NCCO
Temperature: 70 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
10 ml of 5N sodium hydroxide was heated to 70° C., and 2.76 g (12.4 mmol) of N-(2-methoxy-4-methyl-5-hydroxyphenyl)-1,3-oxazolidin-2-one was added thereto, and then the resulting mixture was stirred at 70° C. for 1 hour. After allowing to cool, 40 ml of water was poured into the reaction mixture, and acetic acid was added thereto until no further crystals were precipitated. The crystals were filtered, washed with water and recrystallized from the solvent mixture of water/ethanol (4:1, by volume). Thus, 1.10 g (5.6 mmol) of 2-methyl-4-methoxy-5-(β-hydroxyethylamino)phenol was obtained. The yield was 45%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[CH2:10]([S:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=O)[CH2:11][CH3:12]>C(Cl)Cl>[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[CH:14][S:13][CH2:10][CH2:11][CH3:12]
Reactant: c1c[nH]cn1
Reactant: CCCSCC(=O)c1ccccc1O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCSC=C(c1ncc[nH]1)c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.08 g of imidazole and 30 ml of dry methylene chloride, 1.78 g of thionyl chloride was added with ice-cooling. The resultant mixture was stirred for 30 minutes, followed by an addition of 2.10 g of 2-n-propylthio-2'-hydroxyacetophenone. The thus-obtained mixture was stirred at room temperature for 2 hours. Ice water was then added to the reaction mixture, followed by its extraction with methylene chloride. The methylene chloride extract was then subjected to a post treatment in the same manner as in Example 5. The reaction product was separated by column chromatography, thereby obtaining 0.2 g of Isomer A (Compound 18) and 1.0 g of Isomer B (Compound 19) of 1-(2-hydroxyphenyl)-1-imidazolyl-2-n-propylthioethylene as colorless crystals respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6]2.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>CN(C)C=O.[Cu]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]([C:12]([OH:14])=[O:13])=[CH:6]2
Reactant: Brc1ccccc1
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: O=[Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(C(=O)O)n2-c1ccccc1
Temperature: 0 °C
Yield: 97 %

Procedure:
A mixture of 60.0 g (0.32 mole) of 5-methoxy-1H-indole-2-carboxylic acid, 35.0 ml (52.2 g; 0.32 mole) of bromobenzene, 36.0 g (0.64 mole) of potassium hydroxide, and 10.0 g (0.13 mole) of copper (II) oxide in 750 ml of N,N-dimethylformamide was stirred and heated at reflux under a nitrogen atmosphere for six hours. The cooled reaction mixture was added to 1.5 kg of ice/water and filtered through a bed of Celite filter-aid. Acidification of the filtrate with dilute hydrochloric acid precipitated the product. The solid was filtered and washed with water to yield 83.0 g (95% yield) of crude acid product. A sample recrystallized from ether/hexane was analytically pure, mp 197°-204° C.
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: COC(=O)N(Cc1ccc(OC)cc1)c1cc(N)c(F)c(N2CCN(C)CC2)c1
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
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.