Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([C:6]2[C:7]([CH:15]3[CH2:17][CH2:16]3)=[N:8][N:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=23)=O)CC1.C(O)CO>C1C=CC=CC=1>[CH:15]1([C:7]2[CH:6]=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH2:17][CH2:16]1
Reactant: O=C(c1c(C2CC2)nn2ccccc12)C1CC1
Solvent: OCCO
Solvent: c1ccccc1
Product: c1ccn2nc(C3CC3)cc2c1
Temperature: 25 °C

Procedure:
Cyclopropyl(2-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)methanone (1.0 g, 4.42 mmol) was heated in benzene (80 ml) to reflux in a Dean-Stark apparatus, in the presence of TsOH monohydrate (0.8 g, 4.21 mmol, 0.95 eq.), for 10 minutes. Freshly distilled ethylene glycol (2.0 g, 32.24 mmol, 7.3 eq.) was added and the biphasic solution maintained at reflux for a further 12 hours. The reaction was cooled to rt and extracted with a saturated NaHCO3 solution (25 ml×3). The organic phase was dried over Na2SO4, filtered and concentrated in-vacuo. Purification by column chromatography (4:1 hexane:ethyl acetate) provided 2-cyclopropylpyrazolo[1,5-a]pyridine as a faintly yellow oil (0.61 g, 3.85 mmol, 87%).
Reaction SMILES: C([N:4]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:5]1[C:6]([OH:8])=[O:7])(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH:4]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:5]1[C:6]([OH:8])=[O:7]
Reactant: CC(=O)N1CCCC[C@@H]1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)C1CCCCN1

Procedure:
(R)-N-acetylpipecolic acid was placed in 10 volumes of toluene and heated, with stirring, to reflux. On attaining reflux, a catalytic amount of 4-toluenesulphonic acid was added to the solution which was then left to reflux for two hours with stirring. After this time had elapsed, the toluene was removed by rotary evaporation. To the residual solid was added 10 volumes of distilled water; this was then extracted with methyl ethyl ketone (MEK) (3×10 vols) to leave the sulphonic acid in the aqueous layer with any pipecolic acid formed. The MEK extracts were then concentrated down to a solid on the rotary evaporator to give racemic-N-acetylpipecolic acid, with 97% recovery.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][O:22][CH2:23][C:24]2[NH:26][C:8](=[O:10])[C:7]3[CH:6]=[CH:5][C:4]([F:11])=[N:3][C:2]=3[N:25]=2)=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: N=C(N)COCCc1ccc(Cl)cc1
Agent: Cl
Product: O=c1[nH]c(COCCc2ccc(Cl)cc2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(4-chloro-phenyl)-ethoxy]-acetamidine hydrochloride (example 83.2). Off-white solid. MS: m/e=334.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[N:3]=1.[NH2:16][CH2:17][CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][NH:16][C:13]([C:4]1[N:3]=[C:2]([Cl:1])[C:11]2[C:6]([C:5]=1[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:15]
Reactant: O=C(O)c1nc(Cl)c2ccccc2c1O
Reactant: NCCO
Product: O=C(NCCO)c1nc(Cl)c2ccccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid from example A-1 d) and 2-amino-ethanol in analogy to example 2; MS-(−)-ion: M−1=265.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH2:31][S:30][CH2:29][C:16]=3[N:17]=[C:18]([C:20]3[CH:25]=[C:24]([F:26])[C:23]([Cl:27])=[CH:22][C:21]=3[F:28])[N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32].O1CCOCC1.[OH-].[Na+].C(OCC)C>CO>[ClH:27].[ClH:32].[Cl:27][C:23]1[C:24]([F:26])=[CH:25][C:20]([C:18]2[N:19]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15]3[CH2:31][S:30][CH2:29][C:16]=3[N:17]=2)=[C:21]([F:28])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3c2CSC3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: C1COCCO1
Product: Fc1cc(-c2nc3c(c(N4CCNCC4)n2)CSC3)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 503 mg of 1-tert-butoxycarbonyl-4-[2-(4-chloro-2,5-difluorophenyl)-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperazine, 2 ml of MeOH, and 6 ml of 4M HCl-dioxane solution was stirred at ambient temperature for 1 hour. To the reaction mixture were added 15 ml of 1M aqueous sodium hydroxide and 2 ml of diethyl ether, and the precipitate was collected by filtration, washed with water and then diethyl ether, and dried under reduced pressure. The solid obtained was dissolved in 5 ml of MeOH, here was added 2 ml of 4M HCl-dioxane solution, and the solvent was then distilled off under reduced pressure. The residue obtained was washed with EtOH-EtOAc and dried under reduced pressure to yield 423 mg of 2-(4-chloro-2,5-difluorophenyl)-4-piperazin-1-yl-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride.
Reaction SMILES: ClC1C(OC)=NN=NC=1OC.[NH2:12][C:13]1[NH:14][C:15](=[O:33])[C:16]2[CH:21]([CH2:22][CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[CH2:20][NH:19][C:17]=2[N:18]=1.CN1CCOCC1.Cl.[CH2:42]([O:44][C:45](=[O:55])[C@H:46]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[NH2:47])[CH3:43]>CN(C)C=O>[CH2:42]([O:44][C:45](=[O:55])[C@H:46]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[NH:47][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([CH2:23][CH2:22][CH:21]2[C:16]3[C:15](=[O:33])[NH:14][C:13]([NH2:12])=[N:18][C:17]=3[NH:19][CH2:20]2)=[CH:25][CH:26]=1)[CH3:43]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: Nc1nc2c(c(=O)[nH]1)C(CCc1ccc(C(=O)O)cc1)CN2
Agent: COc1nnnc(OC)c1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCC2CNc3nc(N)[nH]c(=O)c32)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
1.12 Grams (6.36 mmol) of chlorodimethoxytriazine was added to a solution of 1.91 grams (6.36 mmol) of 4-(2-[2-amino-4,5,6,7-tetrahydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl)benzoic acid and 0.63 grams (6.3 mmol) of N-methylmorpholine (NMM) in 20 ml of dimethylformamide (DMF) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. Next, an additional 0.3 grams (2.97 mmol) of NMM and 0.22 grams (1.25 mmol) of chlorodimethoxytriazine was added to the solution and the mixture stirred for an additional 30 min. Then, 0.64 grams (6.3 mmol) of NMM and 1.52 grams (6.3 mmol) of diethyl-L-glutamate hydrochloride was added to the mixture. After stirring overnight at room temperature, the resulting suspension was mixed with 30 grams of silica gel and dried under vacuum. The residue was added to a column of 70 grams silica gel and eluted with 500 ml of CH2Cl2 -EtOH 90:10 followed by CH2Cl2 -EtOH 80:20. 1.62 Grams (52%) of purified N-[4-[2-(2-amino-4,5,6,7-tetrahydro-4-oxo 3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester was obtained as a colorless powder. Selected data: 1H NMR (DMSO-d6) δ 9.55 (s, 1H), 8.60 (d, J=7.4 Hz, 1H), 7.73 (d, J=8.3 Hz, 2H) 7.27 (d, J=8.3 Hz, 2H), 6.28 (s, 1H), 6.20 (s, 2H), 4.38 (m, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.40 (m, 1H), 3.02 (m, 2H), 2.65 (t, J=7.6 Hz, 2H), 2.39 (t, J=7.5 Hz, 2H), 2.00 (m, 3H), 1.54 (m, 1H), 1.13 (t, J =7.1 Hz, 3H), 1.11 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[OH:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([N:15]2[CH2:16][CH2:17][CH:13]([OH:12])[CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: OC1CCNC1
Product: OC1CCN(c2cccc(C(F)(F)F)c2)C1
Yield: 54 %

Procedure:
The title compound (2.67 g, yield 54%) was obtained from 3-(trifluoromethyl)phenyl bromide and 3-hydroxypyrrolidine by a method similar to that in Reference Example 1.
Reaction SMILES: O[CH:2]([C:13]1[C:14]([O:22]C)=[N:15][C:16]([CH3:21])=[C:17]([CH2:19][CH3:20])[CH:18]=1)[CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.Cl.N1C=CC=CC=1>>[O:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=[C:4]1[CH:3]=[CH:2][C:13]1[C:14](=[O:22])[NH:15][C:16]([CH3:21])=[C:17]([CH2:19][CH3:20])[CH:18]=1
Reactant: CCc1cc(C(O)Cc2nc3ccccc3o2)c(OC)nc1C
Agent: Cl
Solvent: c1ccncc1
Product: CCc1cc(C=Cc2nc3ccccc3o2)c(=O)[nH]c1C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
A mixture of 2-[2(R/S)-hydroxy-2-(2-methoxy-5-ethyl-6-methylpyridin-3-yl)ethyl]benzoxazole (72 mg, 0.23 mmol) and pyridine hydrochloride (133 mg, 1.2 mmol), under a nitrogen atmosphere, was placed in a preheated oil bath (165° C.) for 5 minutes. The reaction flask was removed, cooled, and water added to give a solid. This crude product was extracted into chloroform, dried (MgSO4) and the solvent evaporated to yield 49 mg (75%) of pure product. Recrystallization from methanol gave 15 mg of analytically pure product, mp 262°-264° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:28][C:29]2[N:36]=[CH:35][CH:34]=[CH:33][C:30]=2[CH:31]=O)[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25].COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[CH3:15][O:14][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[CH:31][C:30]2[C:29]([NH:28][C:20]3[CH:21]=[C:22]([O:26][CH3:27])[C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=3)=[N:36][CH:35]=[CH:34][CH:33]=2)[CH:9]=[C:8]([O:10][CH3:11])[C:7]=1[O:12][CH3:13]
Reactant: COc1cc(Nc2ncccc2C=O)cc(OC)c1OC
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1cc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
To a solution of 3,4,5-trimethoxyacetophenone (145 mg, 0.693 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes. Then added 2-(3,4,5-trimethoxyphenylamino)nicotinaldehyde (200 mg, 0.693 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (6v) (289 mg, 87% yield).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]([NH:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH:5]([CH3:8])[CH2:6][CH3:7].C1COCC1.[Li+].[OH-].Cl>CO.O>[CH3:8][CH:5]([CH2:6][CH3:7])[CH:4]([NH:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[C:3]([OH:18])=[O:2]
Reactant: CCC(C)C(NC(=O)c1cccnc1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)C(NC(=O)c1cccnc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
To a solution of 3-methyl-2-[pyridine-3-carbonyl-amino]-pentanoic acid methyl ester (1.5 g, 5.9 mmol), in methanol (10 mL), THF (9 mL), was added LiOH (1.25 g, 29.9 mmol) dissolved in water (3 mL). The mixture was allowed to stir at room temperature (25° C.) over 3 h. Methanol and THF was stripped off from the reaction mass, acidified the reaction mass using 1.5N HCl (pH=2-3). Extracted the reaction mass with ethyl acetate (100 mL) thrice and dried over sodium sulphate and concentrated to obtain product as pale yellow solid (0.7 g, 50%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][CH2:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH3:20])[CH3:19])=[N:14][CH:15]=2)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:28][NH2:29]>C(O)CC>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]([CH3:20])([CH3:19])[CH2:17][NH:16][C:13]2[N:12]=[CH:11][C:10]([C:7]3[CH:6]=[C:3]4[C:2](=[CH:9][CH:8]=3)[NH:29][N:28]=[C:4]4[NH2:5])=[CH:15][N:14]=2)=[CH:26][CH:25]=1
Reactant: NN
Reactant: CC(C)(CNc1ncc(-c2ccc(F)c(C#N)c2)cn1)c1ccc(F)cc1
Solvent: CCCO
Product: CC(C)(CNc1ncc(-c2ccc3[nH]nc(N)c3c2)cn1)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To a 5 mL microwave reaction vessel was added 2-fluoro-5-(2-(2-(4-fluorophenyl)-2-methylpropylamino)pyrimidin-5-yl)benzonitrile (220 mg, 0.6 mmol), hydrazine (500 μL), and propanol (5 mL). The reaction was heated to 120° C. and stirred for 3 h. The reaction was concentrated and purified by reverse phase column chromatography to give 95 mg (42%) of 5-(2-(2-(4-fluorophenyl)-2-methylpropylamino)pyrimidin-5-yl)-1H-indazol-3-amine as a white solid (m/z [M+H]=377.1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:43](Cl)(=[O:46])[CH2:44][CH3:45].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:43](=[O:46])[CH2:44][CH3:45])[CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(=O)N1CCC(C(=O)N2C[C@H](c3ccc(Cl)c(Cl)c3)[C@@H](N(C)C(=O)Oc3ccc(F)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
To a solution of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (200 mg, 0.41 mmol) in THF (2 mL) was added N,N-diisopropyl ethyl amine (208 μl, 1.21 mmol). After stirring for a period of 5 min propionyl chloride (53 μl, 0.61 mmol) was added. After stirring for 3 h at ambient temperature the reaction mixture was treated with an aqueous solution of sodium carbonate (1 M, 10 mL). The organic layer was separated and washed with brine (10 mL) and the aqueous layers were extracted with ethyl acetate (20 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, ethyl acetate:methanol=100:0 to 80:20) afforded the title compound (88 mg, 40%) as a white solid. MS m/e: 550.3 [M]+.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:15](I)([CH3:17])[CH3:16].O>CN(C=O)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: Nc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Nc1ccc(I)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
A mixture of 4-iodoaniline (4.38 g, 20.0 mmol), Cs2CO3 (16.3 g, 50.0 mmol), isopropyliodide (3.0 mL, 30.0 mmol) in DMF (20 mL) was stirred in a sealed tube at 70° C. for 24 h. The mixture was cooled to room temperature and poured into water (200 mL). The organic layer was separated and washed with water and brine and purified on silica gel (CH2Cl2/hexanes, 1:1) to provide (4-iodophenyl)-isopropylamine (3.26 g, 63%).
Reaction SMILES: BrC1C(C)=CC2C(C)(C)CCC(C)(C)C=2C=1.C([N:20](C(C)C)[C:21]([C:23]1[C:28](C(=O)C)=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:22])(C)C>>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]([NH2:20])=[O:22]
Reactant: CC(=O)c1cccnc1C(=O)N(C(C)C)C(C)C
Agent: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Product: NC(=O)c1ccccn1
Yield: 80 %

Procedure:
2-Bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene 33 (620 mg, 2.2 mmol) and the acetylpyridineamide 36a (500 mg, 2 mmol) were converted by a similar method as described above to obtain the intermediate 34 in over 80% yield. To a solution of the pyridine amide 34 (432 mg, 1 mmol) in 5 mL of THF at −78° C. was added 1.5 M DIBAL toluene solution (0.7 mL, 1.05 mmol) and the resulting yellow clear solution was warmed up to −20° C. slowly in 60 min. and then was quenched with water. Removal of solvent and chromatography of the crude mixture afforded the pyridinealdehyde 35 in 83% yield as a white solid. 1H-NMR (CDCl3) δ 1.25 (s, 2(CH3)), 1.29 (s, 2(CH3)), 1.70 (s, 2(CH2)), 1.96 (s, CH3), 5.47 (s, ═CH), 5.92 (s, ═CH), 7.10 (s, Ar—CH), 7.11 (s, Ar—CH), 7.70 (d, J=8.0 Hz, Pyr-CH), 7.88 (d, J=8.0 Hz, Pyr-CH), 8.72 (s, Pyr-CH), 10.06 (s, CHO).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[N:33][CH:32]=1>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:33][CH:32]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1ccc(CCl)nc1
Product: COC(=O)c1ccc(COCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)nc1

Procedure:
The title compound was prepared in analogy to Example 26, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 6-chloromethyl-nicotinic acid methyl ester (commercially available) to give the title compound after purification by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane and ethyl acetate (100:0 to 60:40) as a light yellow solid (10%). MS (Turbo Spray): m/z=540.4 [M+H].
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:31]=[C:32](O)[CH:33]=[CH:34][C:35]=1[Cl:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[Cl:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][C:35]=1[Cl:36])[O:1][C@@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3ccc(Cl)c(Cl)c3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.6 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 3,4-dichlorophenol (8.20 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (5.20 mg, 39.7% yield) as a thick oil: 1H NMR (CDCl3) δ 7.70-7.63 (m, 2H), 7.55 (m, 1H), 7.47-7.43 (m, 3H), 7.40-7.19 (m, 3H), 7.00-6.50 (m, 2H), 6.69 (dd, 1H, J=2.2, 8.8 Hz), 5.25 (m, 1H), 3.20 (m, 2H), 2.70 (m, 2H), 2.53 (m, 2H), 2.40-2.20 (m, 4H), 2.10-1.80 (m, 4H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 525.4 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]#[N:28])[CH:23]=[CH:24][CH:25]=1.[H-].[Na+]>CN(C=O)C>[CH:1]1([CH2:6][CH:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=2)[C:27]#[N:28])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(C#N)CC2CCCC2)c1
Yield: 50.1 %

Procedure:
By working in a way similar to that described in example 2 but using toluen-4-sulphonic acid cyclopentylmethyl ester (5.09 g, 20 mmoles), obtained as described in example 6, 3-methoxy-phenyl-acetonitrile (2.94 g, 20 mmoles), NaH (55-65%, 880 mg, 22 mmoles) and DMF (25 ml), 2.3 g of the title compound were obtained (yield: 50.1%).
Reaction SMILES: C([N:8]1[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([C:15]([F:18])([F:17])[F:16])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C@H:10]1[O:11][C@@H:12]([CH3:14])[CH2:13][NH:8][CH2:9]1
Reactant: [H][H]
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H](C(F)(F)F)O1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CNC[C@@H](C(F)(F)F)O1
Yield: 76.7 %

Procedure:
N-benzyl-cis-2-trifluoromethyl-6-methylmorpholine [679839-97-5] (6.2 g, 23.91 mmol) was added to a suspension of Pd/C 10% (1 g) in methanol (150 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere until 1 equivalent of hydrogen was absorbed. The catalyst was removed by filtration over diatomaceous earth. The solvent was evaporated, yielding 3.1 g (77%) of Intermediate 29 as an oil that was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccn1Cc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1cccn1Cc1ccccc1
Reaction time: 0.33 h
Yield: 68.8 %

Procedure:
To a mixture of (1-benzyl-1H-pyrrol-2-yl)-methanol (3.08 g, 16.4 mmol) and powdered 4 Å molecular sieves (3.0 g) in DCM (33 mL) was added NMO (2.89 g, 24.7 mmol) along with tetrapropylammonium perruthenate (TPAP) (289 mg, 0.822 mmol). The mixture turned black and exothermed. After 20 min, the crude mixture was filtered through a plug of silica gel (EtOAc) to give a red solution. The solution was concentrated in vacuo and the resulting oil was chromatographed over silica gel (0 to 35% EtOAc in heptane over 35 min) to give 1-benzyl-1H-pyrrole-2-carboxaldehyde as a colorless oil (2.09 g, 69%). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.58 (s, 1H) 7.24-7.35 (m, 3H) 7.16 (dd, J=7.7, 1.1 Hz, 2H) 6.98 (d, J=3.5 Hz, 2H) 6.26-6.31 (m, 1H) 5.58 (s, 2H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[C:38]([CH3:44])=[N:39][N:40]([CH3:43])[C:41]=1[CH3:42]>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[C:38]([CH3:44])=[N:39][N:40]([CH3:43])[C:41]=3[CH3:42])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cc1nn(C)c(C)c1Br
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1nn(C)c(C)c1-c1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1,3,5-trimethyl-1H-pyrazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI+): m/z=462 [M+H]+.