Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(C1C=CC(C)=CC=1)(=O)=O.[CH3:30][NH2:31]>O1CCCC1>[CH3:30][NH:31][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCC(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Product: CNCCOCCOCCOCCC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Into a 250-mL sealed bottle, was placed a solution of tert-butyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (14 g, 32.41 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), and CH3NH2 (66.9 g, 712.16 mmol, 21.98 equiv, 33% in ethanol). The resulting solution was stirred overnight at 50° C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 150 mL of dichloromethane. The resulting mixture was washed with 2×150 mL of water and 1×150 mL of brine, dried over sodium sulfate, and concentrated under vacuum. This resulted in 8.2 g (87%) of product as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[SH:14])([O-:3])=[O:2].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Cl:22]>>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][S:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: ClCCCCCCBr
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1SCCCCCCCl

Procedure:
Following the procedures of Preparation 1, the title compound is prepared from 2-nitro-4-trifluoromethylthiophenol and 1-bromo-6-chlorohexane.
Reaction SMILES: [C:1]([C:3]1([C:21]([O:23]CC)=[O:22])[CH2:8][CH2:7][N:6]([CH:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[N:2].[Li+].[OH-].Cl>CO>[C:1]([C:3]1([C:21]([OH:23])=[O:22])[CH2:4][CH2:5][N:6]([CH:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]2)[CH2:7][CH2:8]1)#[N:2]
Reactant: CCOC(=O)N1CCCC(N2CCC(C#N)(C(=O)OCC)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N1CCCC(N2CCC(C#N)(C(=O)O)CC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 1053.4 %

Procedure:
Ethyl 4-[4-cyano-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (0.067 g, 0.182 mmol) was dissolved in methanol (4 mL) at rt and 1M LiOH sol. (0.2 mL) was added. The reaction mixture was stirred at rt for 1.5 h. The pH was carefully adjusted to pH 6 by addition of concentrated hydrochloric acid, the solvents were removed in vacuo, to give 4-cyano-1-[1-(ethoxycarbonyl)azepan-4-yl]piperidine-4-carboxylic acid, (0.62 g), Intermediate 9, as a yellow oil which was used directly without further purification.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH:4]([CH3:9])[C:5]([O:7][CH3:8])=[O:6].N[CH2:11]C1(C(O)=O)CC1>>[ClH:1].[NH2:2][CH2:3][C:4]1([C:5]([O:7][CH3:8])=[O:6])[CH2:11][CH2:9]1
Reactant: NCC1(C(=O)O)CC1
Reactant: COC(=O)C(C)CN
Agent: Cl
Product: COC(=O)C1(CN)CC1

Procedure:
The title compound was prepared in analogy to Compound W in Example 20 by using 1-(aminomethyl)cyclopropanecarboxylic acid (CAS number: 139132-50-6, J&K; for its synthesis, please refer to: Mertin A., et al. Synlett, 1991, 2, 87-9) instead of DL-3-aminoisobutyric acid.
Reaction SMILES: [CH3:1][S+:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.[CH3:11][O:12][S:13]([O-:16])(=[O:15])=[O:14].[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>C(#N)C>[CH3:11][O:12][S:13]([O-:16])(=[O:15])=[O:14].[CH3:1][S+:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([CH2:18][C:17]([OH:19])=[O:12])=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: C[S+](C)c1ccc(O)cc1
Agent: COS(=O)(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[S+](C)c1ccc(CC(=O)O)cc1

Procedure:
In 30 ml of acetonitrile was dissolved 2.6 g of p-dimethylsulfoniophenol methylsulfate, and 0.8 ml of acetyl chloride and 1.4 ml of triethylamine were dropwise added thereto. The reaction mixture was filtered to remove the deposited triethylamine hydrochloride. The filtrate was concentrated under reduced pressure and the residue was crystallized by adding ether.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[OH:13][CH:14]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[OH:13][CH:14]([C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCCCCC(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: CCCCCC(O)c1cccc(OCc2ccc3ccccc3c2)c1

Procedure:
A suspension of 2-bromomethyl naphthalene (5 g, 0.023 mol), 3-(1-hydroxyhexyl)phenol (5 g, 0.026 mol), powdered potassium carbonate (4.5 g, 0.033 mol), sodium iodide (0.4 g, 0.0023 mol) and cesium carbonate (0.7 g, 0.0021 mol) in dry acetone (75 ml) was refluxed overnight (14 hours). The reaction mixture was filtered, the filtrate was concentrated, dissolved in ether, and then washed successively with 1N NaOH solution 6N HCl solution, water and brine. After drying the organics over anhydrous MgSO4, all volatiles were removed. The crude product (5 g) was further purified by chromatography, using 8% ethylacetate in hexanes on silica gel, to yield 3.5 g of the pure desined compound as a colorless liquid.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[NH:30][C:31](=[NH:36])[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][C:31]1[N:36]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:30]=1
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: COCCC(=N)NO
Product: COCCc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 300 mg (0.720 mmol) of the compound from Example 45A and 93.6 mg (0.792 mmol) of N-hydroxy-3-methoxypropanimidamide were reacted Yield: 231 mg (63% of theory, approx. 15% trans isomer)
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:18][O:19][C:20](=[O:40])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]OS(C)(=O)=O>>[CH3:18][O:19][C:20](=[O:40])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCc1ccccc1OCCCCCOS(C)(=O)=O
Product: CCCCCc1c(OCCCCCOc2ccccc2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 98 %

Procedure:
Using the procedure of example 11 and starting with 1.25 g (5.34 mmol) of 2,3-dihydro-7-hydroxy-8-pentyl-4H-1-benzopyran-4-one (from example 117) and 1.64 g (4.76 mmol) of 2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]benzenepropanoic acid methyl ester (from example 72), 2-[5-[(3,4-dihydro-4-oxo-8-pentyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid methyl ester was obtained in 98% yield (2.52 g) as a pale-yellow oil. This diester (5.18 mmol) was saponified with 7.8 mL of 3N aqueous lithium hydroxide in 25 mL of tetrahydrofuran, at room temperature, for 48 hr. Work-up as in example 4 gave 2-[5-[(3,4-dihydro-4-oxo-8-pentyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid as an oil. This material was flash chromatographed on silica gel eluting with ethyl acetate-hexane mixtures giving 0.69 g (28.5%) of pure acid as a solid. Recrystallization from acetonitrile gave a colorless solid, mp 86°-87° C.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6](=[CH:11]OS(C1C=CC(C)=CC=1)(=O)=O)[C:7]([O:9][CH3:10])=[O:8].[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>COC(C)(C)C>[CH3:11][C:6](=[CH:5][S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Sc1ccccc1
Reactant: COC(=O)C(C)=COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: COC(C)(C)C
Product: COC(=O)C(C)=CSc1ccccc1
Temperature: 50 °C
Reaction time: 9 h
Yield: 76.7 %

Procedure:
To chloroform (100 mL) were added methyl 2-methyl-3-(p-toluenesulfonyloxy)acrylate (11.0 g) and thiophenol (6.3 g), and then added dropwise triethylamine (33 mL), and the mixture was stirred at 50° C. for 9 hours. To the reaction mixture were added tert-butyl methyl ether, and then a 1N aqueous sodium hydroxide solution, thereby layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain methyl 2-methyl-3-(phenylthio)acrylate (6.5 g).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([O:19]CC)=[O:18])[N:16]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1csc(CNC(=O)OC(C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.8 %

Procedure:
A 20 ml portion of a 2N aqueous sodium hydroxide solution was added to 100 ml of an ethanol solution containing 5.727 g of ethyl 2-(N-t-butoxycarbonylamino)methylthiazol-4-carboxylate, and the mixture was then stirred at room temperature for 45 minutes. After adjustment to pH 5 with 2N hydrochloric acid, the solvent was evaporated under reduced pressure. Further, the solution was dissolved in 300 ml of ethanol under heating, and after the removal of a salt by filtration, the solvent was evaporated under reduced pressure to obtain 4.228 g of 2-(N-t-butoxycarbonylamino)methylthiazol-4-carboxylic acid as a milky white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:33]=[CH:32][N:31](COCC[Si](C)(C)C)[N:30]=4)=[C:25]([F:42])[CH:24]=3)=[C:16]2[N:15]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:33]=[CH:32][NH:31][N:30]=4)=[C:25]([F:42])[CH:24]=3)=[C:16]2[N:15]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccccc5Cl)nc34)cc2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC[C@H](c2ccccc2Cl)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.3 %

Procedure:
To (S)-4-(2-chlorophenyl)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (20 mg, 0.033 mmol) in DCM (5 mL) was added TFA (1 mL) and the reaction was stirred at ambient temperature for 6 hours. The reaction was concentrated to dryness and the residue dissolved in MeOH/ammonia (7N). After stirring at ambient temperature for 30 minutes, the reaction was concentrated then purified by reverse phase chromatography (SP4, 12M, water/CH3CN 100:0 to 0:100, 20 column volumes) to yield (S)-4-(2-chlorophenyl)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (9 mg, 57% yield) as a pale yellow solid. LCMS (APCI+) m/z 476.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[C:25]([Cu])#[N:26]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2cccc(Oc3ccc(F)cc3)c2c1O
Reactant: N#C[Cu]
Product: COC(=O)c1nc(C#N)c2cccc(Oc3ccc(F)cc3)c2c1O

Procedure:
The title compound was synthesized from 1-bromo-5-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester and CuCN in analogy to example 3a; MS-(−)-ion: M−1=337.4.
Reaction SMILES: [CH2:1]([C@H:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:7](=O)[C@H:6]([CH3:19])[NH:5][C:4]1=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[K+]>C1COCC1>[CH2:1]([C@@H:3]1[CH2:4][NH:5][C@@H:6]([CH3:19])[CH2:7][N:8]1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH3:2]
Reactant: CC[C@@H]1C(=O)N[C@@H](C)C(=O)N1Cc1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H]1CN[C@@H](C)CN1Cc1ccc(OC)cc1
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a mixture of (3S,6R)-6-ethyl-1-(4-methoxy-benzyl)-3-methyl-piperazine-2,5-dione (5.34 g) in 130 ml of THF was added 160 ml of a 1 M solution of lithium aluminium hydride in THF. The mixture was stirred overnight and then heated to reflux for 4 h. At 0° C. 5 ml of water, followed by 16 ml of 1 M aqueous KOH-solution were added. The resulting suspension was stirred for 30 min at r.t. and filtered by suction over Celite. The filtrate was concentrated in vacuo and freeze-dried. 3.68 g (77%) of the title compound were obtained and used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20](/[CH:23]=[CH:24]/[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[S:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1csc(/C=C/c2ccccc2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: C(=C/c1nc(COc2ccc(CCCn3ccnc3)cc2)cs1)\c1ccccc1
Yield: 58 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-[(E)-2-phenylethenyl]thiazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]thiazole. The yield was 58%. Recrystallization from ethyl acetate gave colorless prisms, mp 129-130° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O.I[CH2:37][C:38]([NH2:40])=[O:39]>C(#N)C>[C:16]([C:10]1([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14][N:13]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:12][CH2:11]1)#[N:17]
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCNCC1
Reactant: NC(=O)CI
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CCN(CC(N)=O)CC1
Reaction time: 8 h
Yield: 109.9 %

Procedure:
4-(4-Nitro-phenyl)-piperidine-4-carbonitrile (0.795 g, 3.44 mmol) and MP-Carbonate resin (3.16 mmol/g loading; 2.18 g, 6.88 mmol) were combined in Acetonitrile (24.0 mL) and Iodoacetamide (0.720 g, 3.70 mmol) was then added and then stirred overnight. After 24 h, conversion was not complete, so additional MP-Carbonate resin (1.21 g, 3.82 mmol), Iodoacetamide (0.405 g, 2.08 mmol) and Acetonitrile (30.0 mL, 574 mmol) were added. After 8 h, the reaction was complete. Solubilize the precipitated product with DCM:MeOH, filter off resin and wash with DCM:MeOH. Conc. onto 10 g silica gel. ISCO (40 g, 0-20% MeOH:EtOAc) to afford 2-[4-Cyano-4-(4-nitro-phenyl)-piperidin-1-yl]-acetamide (1.09 g; Yield=100) as a white solid. 1H-NMR (DMSO-d6): 8.31 (d, 2H, J=8.7 Hz), 7.87 (d, 2H, J=8.7 Hz), 7.35 (br s, 1H), 7.18 (br s, 1H), 2.97 (m, 4H), 2.50 (m, 2H), 2.22 (m, 2H), 2.13 (m, 2H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([C:17]#[N:18])[CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[NH2:26][C@@H:27]([CH2:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[C:44]([F:49])[CH:43]=1)[C@H:28]([OH:40])[CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH3:39])[CH:33]=1>C(Cl)Cl>[CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([C:17]#[N:18])[CH:10]=[C:11]([C:14]([NH:26][C@@H:27]([CH2:41][C:42]3[CH:43]=[C:44]([F:49])[CH:45]=[C:46]([F:48])[CH:47]=3)[C@H:28]([OH:40])[CH2:29][NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH3:39])[CH:33]=3)=[O:16])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCn1ccc2c(C#N)cc(C(=O)O)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1ccc2c(C#N)cc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a mixture of 1-butyl-4-cyano-1H-indole-6-carboxylic acid (0.29 g) in methylene chloride (10 mL) was added 1,1-carbonyldiimidazole (0.194 g) and triethylamine (0.267 g). The mixture was stirred at room temperature for 45 minutes at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.5 g) dissolved in methylene chloride (10 mL) was added. The mixture was stirred at room temperature for 18 h then poured into methylene chloride (50 mL), washed with water followed by brine, dried over anhydrous magnesium sulfate and concentrated under vacuum. Column chromatography on silica gel (100 mL) using 5% methanol in methylene chloride as eluent to give 0.47 g of the title compound: MS (ESI+) for C33H36F2N4O2 m/z 559.0 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[F:20][C:21]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:21]=2[F:20])[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2ccccn2)c1F
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccn2)c1F

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 2-fluoro-3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 421.00 g/mol.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1>>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:16]=1
Reactant: ClCc1ccccn1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: Cl
Product: CCOC(=O)c1ccc(OCc2ccccn2)cc1
Yield: 83.7 %

Procedure:
2-Chloromethylpyridine hydrochloride (500 mg) and ethyl 4-hydroxybenzenecarboxylate (506 mg) were processed in the same manner as in Production Example 1-1 to obtain the entitled compound (656 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.[OH-:11].[NH4+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:7]([C:8]([NH2:9])=[O:11])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: Cc1ccnc(Cl)c1C#N
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: Cc1ccnc(Cl)c1C(N)=O
Temperature: 0 °C
Yield: 69 %

Procedure:
A solution of 6.33 g of 2-chloro-4-methyl-3-pyridine carbonitrile (9) in 6 mL concentrated H2SO4 was stirred at 100° C. for one hour, added ice water, made alkaline with ammonium hydroxide and extracted with ethyl acetate. The extract was dried and the solvent removed to leave a crystalline residue. Recrystallization from ethyl acetate gave 4.9 g (69%) of (10).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=1)([CH3:3])[CH3:2].P(OCC)(OCC)OCC.[CH3:26][O:27][CH:28]=[C:29]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40]Br)[C:30]([O:32][CH3:33])=[O:31].COC=C(C1C=CC=CC=1CN1C(=O)C=C(C(F)(F)F)N=C1OC(C)C)C(OC)=O>CCCCCCCC.[Cu-]=O.CC(C)=O.O>[CH3:26][O:27][CH:28]=[C:29]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][O:11][C:9]1[CH:8]=[C:7]([C:12]([F:14])([F:15])[F:13])[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[N:10]=1)[C:30]([O:32][CH3:33])=[O:31]
Reactant: CC(C)Oc1nc(O)cc(C(F)(F)F)n1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: O=[Cu-]
Agent: CCOP(OCC)OCC
Agent: COC=C(C(=O)OC)c1ccccc1Cn1c(OC(C)C)nc(C(F)(F)F)cc1=O
Solvent: O
Solvent: CC(C)=O
Solvent: CCCCCCCC
Product: COC=C(C(=O)OC)c1ccccc1COc1cc(C(F)(F)F)nc(OC(C)C)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.22 g of 2-isopropoxy-6-trifluoromethyl-4-hydroxypyrimidine and 0.86 g of copper(I) oxide were suspended in 50 ml of octane. The suspension was refluxed until no water was recognized to form, while formed water was being taken into a quantitative water receiver. 1.86 g of triethyl phosphite was added, and, 30 minutes later, 3.65 g of methyl 3-methoxy-2-(2-bromomethylphenyl)acrylate was added at an instance. The reaction was carried out for 6 hours at reflux of octane. The solution was cooled down to room temperature. 20 ml of acetone was added to it. Insoluble matter was filtrated and washed with 10 ml of acetone twice. The mixed solution of the obtained filtrate and washings was analyzed with high-performance liquid chromatography. Yields were 82.1% for the target compound, and as for byproducts 3.1% for methyl 3-methoxy-2-[2-(2-isopropoxy-6-trifluoromethylpyrimidin4-on-3-ylmethyl)phenyl]acrylate and 14.8% for 4-(α-methoxy)methylen-2H-chromen-3(4H-one.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Br:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH:41]=O.[Cl-].[NH4+]>C1COCC1>[Br:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH:41]=[CH:2][O:3][CH3:4]
Reactant: O=Cc1ccc2ccccc2c1Br
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccc2ccccc2c1Br
Reaction time: 1 h
Yield: 86.7 %

Procedure:
A solution of (methoxymethyl)triphenyl phosphonium chloride (32.0 g, 93.3 mmol) in THF (100 mL) at −78° C. was treated with potasium tert-butoxide (9.90 g, 88.1 mmol), stirred cold for 1 hour, treated with a solution of 1-bromo-2-naphthaldehyde (12.1 g, 51.7 mmol) (commercially available from TCI America) in THF (75 mL) over 15 minutes, stirred for 16 hours at room temperature, treated with aqueous ammonium chloride (200 mL) and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried (MgSO4), filtered, and concentrated to an oil. The oil was purified on silica gel with a gradient of 2% to 5% ethyl acetate/hexanes to provide 11.8 g (87%) of the desired compound.