Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H][H]>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COc1ccc(Cl)c(NC(=O)COCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(NCCOCc2ccccc2)c1
Yield: 101.7 %

Procedure:
2-Benzyloxy-N-(2-chloro-5-methoxy-phenyl)acetamide (2) (18.9 g, 62.0 mmol) in THF (100 mL) was stirred and lithium aluminum hydride (4.9 g, 130.0 mmol) was added slowly over 15 min. There was a rapid evolution of hydrogen gas as the first of the lithium aluminium hydride was added. The reaction was then heated to reflux for 4 h and allowed to stand at RT over the weekend. The reaction was then quenched by the dropwise addition of water (50 mL) to the stirred solution. There was a violent evolution of hydrogen causing the reaction mixture to reflux. The reaction was then concentrated in vacuum to a slurry. Water (200 mL) and ethyl acetate (200 mL) were added and the mixture vigorously shaken. The reaction was then filtered through celite to remove the precipitated aluminium hydroxide and the ethyl acetate solution was separated, dried over magnesium sulfate and concentrated in vacuo to afford 18.4 g (quantitative) of (2-Benzyloxy-ethyl)-(2-chloro-5-methoxyphenyl) amine (3) as a gum. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 43.3, 55.3, 68.2, 73.0, 98.1, 1018, 111.6, 127.6, 127.7, 128.4, 129.3, 137.9, 144.8, and 159.5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=O)[C:14]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[N:13]([CH:23]3[CH2:25][CH2:24]3)[C:12]2=[O:26])=[CH:7][CH:6]=1)[CH3:2].[BH4-].[Na+]>C1COCC1.CO>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C:14]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[N:13]([CH:23]3[CH2:25][CH2:24]3)[C:12]2=[O:26])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2C(=O)N(C3CC3)C3(CCCCCC3)C2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1ccc(N2CC3(CCCCCC3)N(C3CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
To 228 mg (0.61 mmol) of 4-(1-Cyclopropyl-2,4-dioxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid ethyl ester dissolved in 4 ml THF/Methanol 1:1 was added under ice-cooling 70 mg (1.84 mmol) of sodium borohydride. The reaction mixture was stirred for 2 h at RT and then additional 70 mg of sodium borohydride was added and the stirring was continued over night. The whole was concentrated under reduced pressure to dryness and the residue was dissolved in 2 ml of trifluoroacetic acid. To this ice-chilled solution was added again 70 mg of sodium borohydride. The reaction mixture was stirred for 1 h at RT and then the trifluoroacetic acid was removed under reduced pressure. The residue was taken up in EtOAc and washed with sodium bicarbonate solution and water. The crude product was purified by chromatography over silica gel with DCM/EtOAc 9:1 to give 103 mg of pure 4-(1-Cyclopropyl-2-oxo-1,3-diaza-spiro[4.6]undec-3-yl)-benzoic acid ethyl ester. MS (ESI): 357.3 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[O:14][C:13]2[C:12]([NH2:15])=[N:11][N:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.[N+:30]([C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36])([O-:32])=[O:31]>O1CCCC1>[CH2:1]([O:4][C:5]([C:7]1[O:14][C:13]2[C:12]([NH:15][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[N+:30]([O-:32])=[O:31])=[N:11][N:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCOC(=O)c1cc2c(o1)c(N)nn2C(=O)OCC
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCOC(=O)c1cc2c(o1)c(NC(=O)c1ccccc1[N+](=O)[O-])nn2C(=O)OCC
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
To a solution of 3-amino-furo[3,2-c]pyrazole-1,5-dicarboxylic acid 1-ethyl ester 5-propyl ester (500 mg, 1.606 mmol) and diisopropylethylamine (DIEA, 0.824 mL, 4.818 mmol) in tetrahydrofuran (THF, 20 mL) at 0° C., 2-nitro-benzoyl chloride (0.318 mL, 2.409 mmol) was added. The reaction mixture was kept at the same temperature for 10 minutes then allowed to reach room temperature and let react overnight. The solvent was removed under vacuum, the residue was dissolved in dichloromethane (DCM) and washed with a 10% solution of acetic acid (AcOH), water, saturated NaHCO3 and brine. The crude was purified on silica gel (eluant dichloromethane/methanol 96/4) yielding 512 mg (69%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:5][CH2:6][C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)COc1ccc(OC)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(OCC(=O)O)cc1Cl

Procedure:
The above ethyl 3-chloro-4-methoxyphenoxyacetate (700 mg) was hydrolysed with 1M aq. NaOH in THF-MeOH (30 mL, 2:1) to provide the title compound as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.CS(O[CH2:16][C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH2:16][C:17]23[CH2:26][CH:21]4[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]4)[CH2:24]2)[CH2:18]3)=[C:4]([Cl:10])[CH:3]=1
Reactant: Oc1cc(Cl)c(Br)cc1Cl
Reactant: CS(=O)(=O)OCC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Clc1cc(OCC23CC4CC(CC(C4)C2)C3)c(Cl)cc1Br
Temperature: 125 °C
Reaction time: 48 h

Procedure:
A mixture of 4-bromo-2,5-dichlorophenol (1.35 g, 5.58 mmol), adamantan-1-ylmethyl methanesulfonate (Fr. Demande, 2909090, May 30, 2008) (1.5 g, 6.14 mmol), and potassium carbonate (0.85 g, 6.14 mmol) in N,N-dilmethylformamide (10 mL) was stirred at 65° C. for 16 h and at 125° C. for 48 h. The reaction mixture was cooled down to ambient temperature, diluted with water (40 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 5% to 10% gradient of ethyl acetate in hexanes to afford 1-((4-bromo-2,5-dichlorophenoxy)methyl)adamantine as a colorless solid (1.7 g, 71%): MS (ES+) m/z 391.3 (M+1);
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]#[CH:14])[CH:12]=[C:6]2[C:5]=1[NH:15][C@H:16]1[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17]1)(=[O:3])[NH2:2].[N:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[N+:31]=[N-:32]>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[N:32]=[N:31][N:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:15][C@H:16]1[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:17]1)(=[O:3])[NH2:2]
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C#Cc1cc2c(N[C@@H]3CN(C(=O)OC(C)(C)C)C[C@@H]3CC)c(C(N)=O)cnn2c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cn(-c4ccccc4)nn3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To a solution of (3S,4S)-tert-butyl 3-((3-carbamoyl-6-ethynylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate from Step 2 of Example 292 (71 mg, 0.179 mmol) in toluene (2 mL) and DMF (0.2 mL) was added azidobenzene (149 mg, 1.250 mmol). The flask was purged with nitrogen, and the reaction solution was stirred at room temperature for 1 hour, then warmed to 95° C. After stirring over two nights, the reaction was cooled to room temperature. The volatiles were removed in vacuo and the residue was diluted with 3 mL DMF and purified by via preparative HPLC with the following conditions: Column: Phenomenex Luna C18, 21.5×250 mm, 5-μm particles; Mobile Phase A: 10:90 methanol:water with 0.1% trifluoroacetic acid; Mobile Phase B: 90:10 methanol:water with 0.1% trifluoroacetic acid; Gradient: 30-100% B over 14 minutes, then a 2-minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and concentrated via centrifugal evaporation to remove the methanol. The solution was neutralized with 1N NaOH, and was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate. Filtration and evaporation afforded the title compound (41 mg, 42% yield). MS (ES+) m/z: 517.1 (M+H); LC retention time: 3.385 min (analytical LCMS Method J).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:11]=2[O:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])=[C:4]([F:26])[CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:21][C:19]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]2[CH:24]=[CH:25][C:2]([Br:1])=[CH:3][C:4]=2[F:26])[CH:20]=1
Reactant: [H][H]
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc(Br)cc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OCC(=O)O)c(C(=O)NCc2ccc(Br)cc2F)c1
Yield: 72.1 %

Procedure:
[2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-nitro-phenoxy]-acetic acid (1.10 g, 2.76 mmol) was dissolved in ethyl alcohol (40 mL, 0.1 M), treated with 10% Pd on carbon (Degussa, 0.10 g) and placed under a balloon of hydrogen for 12 h. The reaction was filtered through Celite and concentrated to give a crude solid which was recrystallized from heptane and ethyl acetate to give [4-amino-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid (0.79 g, 66%): mp 204° C (dec.); Rf 0.10 (10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 9.16 (br t, J=6.3 Hz, 1H), 7.85 (d, J=2.7 Hz, 1H), 7.46-7.11 (m, 5H), 4.91 (s, 2H), 4.57 (br d, J=3.6 Hz, 2H). ESI-LC/MS m/z calcd for C16H14BrFN2O4: 396.0 found 395.0 (M−1)−. Anal. calcd for C16H14BrFN2O4: C, 48.38; H, 3.55; N, 7.05. Found C, 48.05; H, 4.02; N, 6.94.
Reaction SMILES: [CH3:1][N+:2]([CH3:4])=[CH2:3].[I-].C(Cl)(=O)C.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=[O:12]>C(#N)C>[CH3:3][N:2]([CH3:4])[CH2:1][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=[O:12]
Reactant: COc1cccc(C(C)=O)c1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: COc1cccc(C(=O)CCN(C)C)c1
Reaction time: 20.5 h
Yield: 93 %

Procedure:
The Eschenmoser salt was produced by reacting 232 g (2.27 mol, 1 equivalent) tetramethyl diaminomethane with 187 g (2.14 mol, 0.95 equivalent) acetyl chloride in 1200 ml acetonitrile. 328 g (2.17 mol, 0.96 equivalent) 3-methoxyacetophenone were then added within 115 minutes at a temperature of from +3° C. to +11° C. and then stirred at from +20° C. to +25° C. for 20 to 21 hours. The resulting hydrochloride salt of the 3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one (II) was filtered out. The residue was suspended in 1600 ml water and 190 ml sodium hydroxide solution (36% by weight) (pH 11-12) and extracted with 1000 ml ethyl acetate. The organic phase was separated off and dried over 50 g sodium sulfate. Once the organic solvent had been evaporated, the free base of the 3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one (II) was obtained as a colorless oil (93% yield, 96% purity ascertained by HPLC).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[CH:11](OCC)(OCC)OCC>C(O)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][CH:11]=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: Fc1cc2nc[nH]c2cc1F
Temperature: 100 °C

Procedure:
A stirred mixture of 4,5-difluorobenzene-1,2-diamine (1.40 g, 9.7 mmol) from the previous step, formic acid (2.0 mL), and triethyl orthoformate (20 mL) was heated at 100° C. for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 5% MeOH in DCM to afford 5,6-difluoro-1H-benzo[d]imidazole as (1.12 g, 75%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.44 (m, 2H); LCMS (ESI) m/z 155 (M+H)+.
Reaction SMILES: O.[NH2:2][C:3]1[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[C:6]([OH:14])=[CH:5][CH:4]=1.[CH:15](=O)[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18]>C(OCC)(=O)C>[CH3:13][C:10]1([CH3:12])[CH2:9][C:8]2[C:3]([N:2]=[CH:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[OH:18])=[CH:4][CH:5]=[C:6]([OH:14])[C:7]=2[O:11]1
Reactant: O=Cc1ccccc1O
Reactant: CC1(C)Cc2c(N)ccc(O)c2O1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)Cc2c(N=Cc3ccccc3O)ccc(O)c2O1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
To a 500 milliliter round bottom flask equipped with a water collector, water condenser, magnetic stirrer and drying tube was added 5.38 grams (0.030 moles) of 4-amino-2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuran, 3.91 grams (0.032 moles) of salicylaldehyde and 300 milliliters of ethyl acetate. The resulting reaction mixture was heated to reflux with removal of the first 50 milliliters of distillate, and the remaining mixture allowed to reflux for 1 additional hour with continuous stirring. After the stirring and refluxing period, the reaction mixture was cooled to room temperature, filtered, dried over magnesium sulfate and concentrated under reduced pressure to give 6.15 grams (0.022 moles) of 2,3-dihydro-2,2-dimethyl-4-(2-hydroxybenzylideneamino)benzofuran-7-ol in the form of a dark red oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([C@H:8]1[CH2:17][NH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2cnc3ccccc3n2)cc1
Solvent: Cc1ccccc1
Product: c1ccc(C[C@H]2CNc3ccccc3N2)cc1
Temperature: 40 °C
Reaction time: 29 h
Yield: 96.4 %

Procedure:
To an argon-purged pressure-resistant glass vessel (100 mL) equipped with a magnetic stir bar, RuCl[(R)-daipena][(R)-dm-segphos] (1.1 mg, 0.94 μmol) and KO(t-Bu) (5.4 mg, 0.048 mmol) were added, and the vessel was purged with argon again. To this vessel, a toluene (0.9 mL) solution containing 2-benzylquinoxaline (207.4 mg, 0.942 mmol) and being degassed by the freeze-pump-thaw technique in advance was added by pressure transfer using a cannula. An operation in which hydrogen was introduced into the pressure-resistant vessel up to 0.8 MPa and then released was repeated 10 times to completely substitute the inside with hydrogen. Then, hydrogen was introduced up to 2.0 MPa, and the vessel was stirred in a water bath at 40° C. for 29 hours. After hydrogen was released, the solution was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (hexane:ethyl acetate=3:1) to obtain (S)-2-benzyl-1,2,3,4-tetrahydroquinoxaline (203.7 mg, 97%). A result of an analysis was conducted by high performance liquid chromatography (column: CHIRALCEL OD-H, mobile phase: hexane:IPA=90:10, 1 mL/min) showed that the optical purity of this product was 98% ee.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[O:15]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>CO.[Cl-].[Na+].O>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][N:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:28][CH:27]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Oc2ccccc2)cc1
Yield: 68.4 %

Procedure:
To 2.0 g of 4-chloro-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 50 mL of methanol was added 2.2 g of 4-phenoxyaniline. After stirring the reaction under an inert atmosphere for 18 hr, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals filtered and washed with water. The product was then recrystallized from chloroformhexanes. Drying in vacuo yielded 2.35 g (69%) of 6-fluoro-4-(4-phenoxy-phenylamino)-[1.7]naphthyridine-3-carbonitrile as yellow needles: melting point 211-213° C.; mass spectrum (m/e): M+H 356.9.
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[O:10]=[C:11]1[C:23]2[C:18](=[N:19][C:20](C#N)=[C:21]([C:24]#[N:25])[N:22]=2)[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2>[OH-].[Na+].C1COCC1>[F:2][C:3]1([F:9])[CH2:8][CH2:7][N:6]([C:20]2[N:19]=[C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11](=[O:10])[C:23]3=[N:22][C:21]=2[C:24]#[N:25])[CH2:5][CH2:4]1
Reactant: N#Cc1nc2c(nc1C#N)-c1ccccc1C2=O
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1nc2c(nc1N1CCC(F)(F)CC1)-c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
4,4-Difluoropiperidine hydrochloride (249 mg, 1.58 mmol) was dissolved in 1N NaOH (5 ml) and extracted with CH2Cl2 (2×5 ml). Organic phase was dried over Na2SO4, filtered and evaporated. The residue was dissolved in THF (2 ml) and this solution was added to a solution of 1 (185 mg, 0.79 mmol) in THF (2 ml); the mixture was stirred at room temperature for 48 hours. The solvent was evaporated, the crude solid washed with EtOH and dried under vacuum, affording 8 (245 mg, 95%) as yellow-brown solid.
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[CH:29]=O)[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C@H:31]12[CH2:37][C@H:34]([NH:35][CH2:36]1)[CH2:33][N:32]2[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[C:1]1([C:7]2([N:14]3[CH2:15][CH2:16][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[CH2:29][N:35]4[CH2:36][CH:31]5[CH2:37][CH:34]4[CH2:33][N:32]5[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:18][CH2:19]3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: O=Cc1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC2CC1CN2Cc1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Reaction time: 24 h
Yield: 98 %

Procedure:
To a stirred solution of 1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazole-2-carbaldehyde (this was prepared in preparation 10, 159 mg, 0.396 mmol) and t-butyl (1S,4S)-(−)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (86 mg, 0.436 mmol) in 1,2-dichloroethane (4 ml) was added NaBH(OAc)3 (117 mg, 0.554 mmol) and acetic acid (48 μl, 0.832 mmol) at room temperature. After 24 hour stirring, the reaction mixture was quenched with NaHCO3 solution and extracted with CH2Cl2. The extracts combined were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (1 mm thick plate×2, acetone/n-hexane:1/3) to afford 227 mg (98%) of title compound as colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[F:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(/C=C/c2cccc(F)c2)cc1
Product: O=C(O)C1CC(=O)N(c2ccc(/C=C/c3cccc(F)c3)cc2)C1
Temperature: 130 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A mixture of 600 mg (2.8 mmol) of (E)-4-[2-(3-fluoro-phenyl)-vinyl]-phenylamine and 366 mg (2.8 mmol) of itaconic acid is heated to 130° C. After 1 hour, the molten material is cooled to RT and, thereafter, the resulting solid is triturated with ethyl acetate to yield 568 mg (62% of theory) of (RS)-(E)-1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as a fine yellow powder; MS: m/e=324 (M−H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:8]=2[NH2:9])[CH2:3][CH2:2]1.[C:18](Cl)(Cl)=[S:19]>O1CCOCC1.O>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][C:8]=2[N:9]=[C:18]=[S:19])[CH2:5][CH2:6]1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCOCC1
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(N2CCOCC2)c(N=C=S)c1

Procedure:
Reaction of 2-morpholino-5-trifluoromethylaniline (12 g) with thiophosgene (8.6 g) in dioxan (30 ml) and water (100 ml) at 0° C. for 30 minutes and then at room temperature for 2 hours yielded a residue which was extracted with dichloromethane to give 2-morpholino-5-trifluoromethylphenyl isothiocyanate as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH3:35])[CH2:30][C:29]2=[O:36])[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:18][P:16]([CH3:19])([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:21][C:22]4[CH:23]=[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH2:34][CH3:35])[CH2:30][C:29]5=[O:36])[CH:25]=[CH:26][CH:27]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)=[O:17]
Reactant: CCN1CCN(c2cccc(N)c2)C(=O)C1
Reactant: CP(C)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CCN1CCN(c2cccc(Nc3nc4c(-c5ccc(P(C)(C)=O)cc5)cccn4n3)c2)C(=O)C1

Procedure:
1-(3-{8-[4-(Dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-phenyl)-4-ethyl-piperazin-2-one was prepared from 2-chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3271 mmol) and 1-(3-amino-phenyl)-4-ethyl-piperazin-2-one (79.0 mg, 0.360 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (28.0 mg, 0.0512 mmol) as the ligand in a manner analogous to Example 2d. MP=205-207° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (d, J=6.6 Hz, 1H), 8.13 (d, J=7.9 Hz, 2H), 7.92-7.85 (m, 2H), 7.68 (s, 1H), 7.63 (d, J=7.2 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.04-6.97 (m, 2H), 6.93 (d, J=7.5 Hz, 1H), 3.80-3.75 (m, 2H), 3.35 (s, 2H), 2.88-2.83 (m, 2H), 2.57 (q, J=7.0 Hz, 2H), 1.80 (s, 3H), 1.77 (s, 3H), 1.18 (t, J=7.0 Hz, 3H). MS=489 (MH)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:22]O>>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:22])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1NCCO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCCO

Procedure:
2-(2-Hydroxyethylamino)-3-nitrobenzoic acid (5.14 g, 22.7 mmol) was dissolved in methanol (200 mL) and concentrated H2SO4 (10 mL) was added. The mixture was heated at reflux for 2.5 h. The solvent was removed at reduced pressure. The residue was treated with water (100 ml) and extracted with ethyl acetate (3×150 mL). The combined organic phase was dried and concentrated. Purification by column chromatography on silica using heptane ethyl acetate 1:1 as an eluent afforded methyl 2-[(2-hydroxyethyl)amino]-3-nitrobenzoate, 3.92 g (72%). MS NISI) m/z 241 [M+H]. 1H NMR (400 MHz, CDCI3) δ ppm 3.12 (t, J=5.10 Hz, 2H), 3.84 (t, J=5.15 Hz, 2H), 3.91 (s, 3H), 6.69 (t, J=7.96 Hz, 1H), 7.95 (dd, J=8.34, 1.52 Hz, 1H), 8.08 (dd, J=7.83, 1.52 Hz, 1H).