Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[NH:21][O:22][CH3:23])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[N:21]([O:22][CH3:23])[C:8](=[O:9])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]2)=[CH:16][CH:15]=1
Reactant: CONC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(C(=O)C=C1OC(C)(C)OC1=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 88 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-[bis-(4-fluoro-phenyl)-methyl]-O-methyl-hydroxylamine as described in the preparation of compound 1-C gave the title amide as white crystals (88% yield): mp 137° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.74 (6H, s, CH3), 3.26 (3H, s, OCH3), 6.42 (1H, s, CH), 6.81 (1H, s, CH), 7.03 (4H, m, aromatics), 7.28 (4H, m, aromatics). Anal. calcd for C21H19F2NO5: C, 62.53; H, 4.75; N, 3.47. Found: C, 62.49; H, 4.66; N, 3.35.
Reaction SMILES: C1(COC2N=C(C(O)=O)C=CC=2C2CCOC2)CC1.[CH:20]1([CH2:23][O:24][C:25]2[N:30]=[C:29]([C:31]([OH:33])=O)[CH:28]=[CH:27][C:26]=2[CH:34]2[CH2:38][CH2:37][CH2:36][O:35]2)[CH2:22][CH2:21]1.[NH2:39][C@@H:40]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:41]([NH2:43])=[O:42]>>[C:41]([C@@H:40]([NH:39][C:31]([C:29]1[CH:28]=[CH:27][C:26]([CH:34]2[CH2:38][CH2:37][CH2:36][O:35]2)=[C:25]([O:24][CH2:23][CH:20]2[CH2:21][CH2:22]2)[N:30]=1)=[O:33])[CH2:44][CH:45]([CH3:47])[CH3:46])(=[O:42])[NH2:43]
Reactant: O=C(O)c1ccc(C2CCCO2)c(OCC2CC2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Agent: O=C(O)c1ccc(C2CCOC2)c(OCC2CC2)n1
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CCCO2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using the mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (mixture from Example 114 d), and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=376.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[C:29]=3[CH2:34][C:35]#[N:36])[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-:40].[K+].[K+]>CS(C)=O.OO>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[C:29]=3[CH2:34][C:35]([NH2:36])=[O:40])[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](O[C@H]1CN(C2=C(CC#N)C(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](O[C@H]1CN(C2=C(CC(N)=O)C(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5.8 mg (0.0107 mmol) {2-[(3R,4S)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]-5-oxocyclopent-1-en-1-yl}acetonitrile (step C) in 5 drops DMSO was added 10 mg (0.072 mmol) potassium carbonate and 5 drops 30% aq. hydrogen peroxide. The reaction mixture was stirred at RT for 4 h, then the volatiles removed overnight using a nitrogen gas stream. The residue was purified by prep TLC on silica gel eluting with methylene chloride/methanol (9/1). The UV active band (˜Rf=0.7) was isolated to afford the title compound as a glassy clear solid. 1H-NMR (CD3OD): δ: 1.44 (d, 3H, 6.5 Hz), 2.43 (br. s, 2H), 2.76 (br. s, 2H), 3.3-4.45 (m, 8H), 4.77 (q, 1H, 6.5 Hz), 6.98 (t, 2H, 8.5 Hz), 7.18 (m, 2H), 7.72 (s, 2H), 7.83 (s, 1H)ppm. MS: 559.1 (M+H) observed.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[N:11]=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[O:9][N:8]=1.[CH:16](O)([CH2:18][CH3:19])[CH3:17]>>[CH3:6][C:7]1[N:11]=[C:10]([CH2:12][C:13]([O:15][CH:16]([CH2:18][CH3:19])[CH3:17])=[O:14])[O:9][N:8]=1
Reactant: Cc1noc(CC(=O)O)n1
Reactant: CCC(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(C)OC(=O)Cc1nc(C)no1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 36.4 %

Procedure:
Using the procedure of Example 17, 12 g of phosphorous oxychloride were slowly added to a mixture of 12 g of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 8.9 g of dry sec.-butanol and the rate of addition was adjusted to a reaction temperature of 65°±5° C. The resulting reaction mixture was stirred for 90 minutes at 65° C., and then treated as in Example 17. The product was distilled at 68° C. and 1.5 mm Hg to obtain 6.1 g (35% yield) of sec.-butyl 3-methyl-1,2,4-oxadiazol-5-yl-acetate. The purity of the final product was about 95% (according to TLC and PMR spectrum) and it had a refractive index nD25 =1.438.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH3:16][N:17]([CH3:25])[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([C:19](=[CH:18][N:17]([CH3:25])[CH3:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:7]
Reactant: CCOC(=O)C=CN(C)C
Reactant: O=C(O)c1cc(Br)ncc1F
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)ncc1F
Temperature: 110 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
To a solution of 2-bromo-5-fluoroisonicotinic acid (25 g, 113.64 mmol, 1 equiv.) in toluene (251 mL) was added thionyl chloride (41.5 mL, 568.19 mmol, 5 equiv.). The reaction was stirred at 110° C. for 4 h. The reaction was cooled to room temperature and concentrated. The residue was re-suspended in THF (100 mL) and added drop-wise to a solution of ethyl 3-(dimethylamino)acrylate (16.3 mL, 113.64 mmol, 1 equiv.) and triethylamine (23.8 mL, 170.46 mmol, 1.5 equiv.) in THF (151 mL). The reaction was stirred at 70° C. for 5 h. The reaction was cooled to room temperature and diluted with water. The reaction was partitioned between water (300 mL) and ethyl acetate (300 mL). The aqueous layer was extracted with ethyl acetate (2×300 mL), and the organics were washed with 1 N HCl (300 mL) and saturated brine (300 mL), dried over sodium sulfate, and concentrated. The compound was purified (silica gel chromatography) and concentrated to provide ethyl 2-(2-bromo-5-fluoroisonicotinoyl)-3-(dimethylamino)acrylate as a solid (28.6 g, 73%). Calcd for C13H14BrFN2O3 [M+H]+: 346.90.
Reaction SMILES: ClCCCl.S(Cl)(Cl)=O.[Cl:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2/[C:24](=[N:28]\[O:29][CH3:30])/[C:25]([OH:27])=O)=[CH:14][CH:13]=[CH:12][N:11]=1.[CH3:31][NH2:32].CO>O.CN(C)C=O>[Cl:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2/[C:24](=[N:28]\[O:29][CH3:30])/[C:25]([NH:32][CH3:31])=[O:27])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN
Reactant: CO/N=C(/C(=O)O)c1ccccc1COc1cccnc1Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cccnc1Cl
Yield: 42.8 %

Procedure:
1,2-Dichloroethane (1 ml), thionyl chloride (0.03 g, 0.28 mmol) and dimethylformamide (DMF)(0.01 ml) were added to (E)-2-(2-chloro-3-pyridyloxymethyl)-α-methoxyiminophenylacetic acid (0.05 g, 0.14 mmol). The mixture was stirred under reflux for 1 hour. To the reaction mixture was added 40% methylamine/methanol solution (1 ml) under ice-cooling. The mixture was stirred at 0° C. for 1 hour. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with methylene chloride (50 ml) twice. The methylene chloride layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-[2-(2-chloro-3-pyridyloxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (0.02 g, 42.8 %) as colorless crystals.
Reaction SMILES: [C:1](OC1C2C(=CC=C(C)C=2)N(CC)C1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([N:27]1[C:35]2[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=2)[C:29](=[O:37])[C:28]1=[O:38])[CH2:24][CH2:25][CH3:26]>>[C:1]([O:37][CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)[N:27]([CH2:23][CH2:24][CH2:25][CH3:26])[C:28]1=[O:38])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: CCCCN1C(=O)C(=O)c2cc(Cl)ccc21
Product: CCCCN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21

Procedure:
Was made in an analogous fashion to 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate using 1-butyl-5-chloroindoline-2,3-dione. 1H NMR δ 8.11 (t, 2H), 7.60 (t, 1H), 7.44 (m, 3H), 7.33 (d, 1H), 6.82 (d, 1H), 6.10 (s, 1H), 3.73 (m, 2H), 1.72 (m, 2H), 1.44 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][C:36]([C:38]1[CH:47]=[CH:46][C:41]2[O:42][CH2:43][CH2:44][O:45][C:40]=2[CH:39]=1)=[O:37].C(N(CC)CC)C>CN(C=O)C.O>[O:42]1[C:41]2[CH:46]=[CH:47][C:38]([C:36](=[O:37])[CH2:35][NH:34][C:12]([C:10]3[S:11][C:7]4[C:6]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[N:9]=3)=[O:14])=[CH:39][C:40]=2[O:45][CH2:44][CH2:43]1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Reactant: NCC(=O)c1ccc2c(c1)OCCO2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3ccc4c(c3)OCCO4)nc12
Yield: 50.2 %

Procedure:
0.35 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 0.22 g 1,1′-carbonyl-diimidazole in 6 ml DMF were stirred at room temperature for 4 hours. 0.30 g 2-amino-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethanone hydrochloride and 0.18 g triethylamine were added and stirring was continued over night at room temperature. 100 ml water was added and the mixture was extracted with ethylacetate. Chromatography on silicagel with ethylacetate/hexane 1:1 yielded 0.28 g (50%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid [2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-oxo-ethyl]-amide as a yellow solid; M.p.: 206–208° C.; MS (ISP): m/e=470 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9](=[N:11][OH:12])[CH3:10])[CH:6]=[CH:7][CH:8]=1.ClC1C=C(C(=NO)C)C=C(Cl)C=1.[Cl:27][C:28]1[N:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:41]Cl)[C:30](=[O:34])[N:31]([CH3:33])[N:32]=1>>[Cl:27][C:28]1[N:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:41][O:12][N:11]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[CH3:10])[C:30](=[O:34])[N:31]([CH3:33])[N:32]=1
Reactant: Cn1nc(Cl)n(-c2ccccc2CCl)c1=O
Reactant: CC(=NO)c1cccc(C(F)(F)F)c1
Agent: CC(=NO)c1cc(Cl)cc(Cl)c1
Product: CC(=NOCc1ccccc1-n1c(Cl)nn(C)c1=O)c1cccc(C(F)(F)F)c1

Procedure:
Preferred oximes of Formula IV for use in this process include 1-[3-(trifluoromethyl)phenyl]ethanone oxime, 1-[3,5-(bistrifluoromethyl)phenyl]ethanone oxime, and 1-[3,5-dichlorophenyl]ethanone oxime. Examples of the process of Step 2 include the reaction of 5-chloro-4-[2-(chloromethyl)phenyl]-2,4-dihydro-2-methyl-3H-1,2,4-triazol-3-one one with -1-[3,5-(bistrifluoromethyl)phenyl]ethanone oxime to form 5-chloro-2,4-dihydro-2-methyl-4-[2-[[[[1-[3(trifluoromethyl)phenyl]-ethylidene]amino]oxy]methyl]phenyl]-3H-1,2,4-triazol-3-one; the reaction of 5-chloro-4-[2-(chloromethyl)phenyl]-2,4-dihydro-2-methyl-3H-1,2,4-triazol-3-one with 1-[3,5-(bistrifluoromethyl)phenyl]ethanone oxime to form 5-chloro-2,4-dihydro-2-methyl-4-[2-[[[[1-[3(bistrifluoromethyl)phenyl]-ethylidene]amino]oxy]methyl]phenyl]-3H- 1,2,4-triazol-3-one.
Reaction SMILES: C(OC([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:35][C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=2)[C:23]2[N:24]=[N:25][N:26]([CH2:28][CH2:29][O:30]C(C)(C)C)[N:27]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl.O1CCOCC1.C(OCC)(=O)C>[F:49][C:46]([F:47])([F:48])[C:38]1[CH:37]=[C:36]([CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:39]=1)[CH2:35][N:22]([C@@H:12]1[C:13]2=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=[C:21]2[NH:8][CH2:9][CH2:10][CH2:11]1)[C:23]1[N:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[N:27]=1
Reactant: CC(C)(C)OCCn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(C(=O)OC(C)(C)C)c3cc4c(cc32)COC4)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: OCCn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)COC4)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve (S)-9-{(3,5-bis-trifluoromethyl-benzyl)-[2-(2-tert-butoxy-ethyl)-2H-tetrazol-5-yl]-amino}-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (0.140 mmol) in 4 M hydrochloric acid/dioxane (10 mL). After stirring overnight at room temperature, neutralize the reaction with aqueous sodium carbonate and dilute with ethyl acetate (20 mL). Dry the organic portion over sodium sulfate, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel eluting with ethyl acetate/hexane (10-40%) to provide the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=3)[C:14]([C:25]([OH:27])=O)=[CH:13][N:12]=2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH2:54]>O.CN(C=O)C>[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH:54][C:25]([C:14]1[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)=[N:16][C:11]([NH:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:12][CH:13]=1)=[O:27]
Reactant: CN(C)CCN
Reactant: Cc1cccc(Nc2nc(NCCc3ccc(O)cc3)ncc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2nc(NCCc3ccc(O)cc3)ncc2C(=O)NCCN(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A 4 ml portion of DMF solution containing 352 mg of 2-{[2-(4-hydroxyphenyl)ethyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxylic acid was mixed with 223 mg of WSC hydrochloride, 157 mg of HOBt and 103 mg of 2-dimethylaminoethylamine, followed by stirring overnight at room temperature. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with saturated brine and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (chloroform:methanol:aqueous ammonia) and then recrystallized (hexane-ethyl acetate) to obtain 291 mg of N-(2-dimethylaminoethyl)-2-{[2-(4-hydroxyphenyl)ethyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH2:5][CH2:6][N:7]=1)[CH3:2].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[N:8]1([CH2:5][CH2:6][NH:7][C:3](=[O:4])[CH2:1][CH3:2])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: C1COCCN1
Reactant: CCC1=NCCO1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Product: CCC(=O)NCCN1CCOCC1
Yield: 83 %

Procedure:
Under the same conditions as Example 13, 2.5 gm (25 mmoles) of 2-ethyl-2-oxazoline, 2.2 gm (25 mmoles) of morpholine and 0.59 mg of zinc acetate are reacted to yield 83 percent N-(2-morpholinylethyl)propionamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.[H-].[Na+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2cccc(Cl)c2)cc1

Procedure:
3-Chlorophenol (1.9 g) was stirred with 4-fluoro-benzaldehyde (1.8 g) and sodium hydride (0.46 g of an 80% suspension in oil) in dimethylformamide (50 ml) at 110° C. under an atmosphere of nitrogen for 16 hours. The solution was diluted with water and extracted with diethyl ether. The ethereal extract was dried (Na2SO4), concentrated and purified by chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:9) to give the title compound as a colourless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[O:5])C.[O:11]1[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[O:11]1[CH2:16][CH2:15][CH:14]([N:8]2[CH:9]=[CH:10][C:6]([C:4]([OH:3])=[O:5])=[N:7]2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)c1cc[nH]n1
Reactant: CS(=O)(=O)OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccn(C2CCOCC2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
A vial was charged with ethyl-1H-pyrazole-3-carboxylate (3.74 g, 26.7 mmol), the crude methanesulfonic acid tetrahydro-pyran-4-yl ester (29.4 mmol), Cs2CO3 (17.4 g, 53.4 mmol), and DMF (100 mL). The reaction mixture was heated to 80° C. and stirred overnight. The reaction was then partitioned between CH2Cl2 (250 mL) and water (250 mL), and the organic layer was washed with water (5×250 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product containing 2 regioisomers was purified via flash chromatography on silica gel (95:5-50:50 hexanes:EtOAc) and the later eluting isomer was isolated. This was purified on silica gel a second time (85:15-60:40 hexanes:EtOAc) to give the pure desired product (1.14 g, 19%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[NH:3]1.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[NH:3]1
Reactant: COC(=O)C(C)c1ccc2c(c1)C=CC(C)(C)N2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(C)c1ccc2c(c1)CCC(C)(C)N2
Yield: 102.5 %

Procedure:
3 g of methyl 2-(1,2-dihydro-2,2-dimethylquinolin-6-yl)propionate (Compound 7) were added to absolute ethanol. Palladium-on-carbon was further added to the solution, and the mixture was reacted with bubbling hydrogen gas at room temperature for 4 hours with stirring. After the reaction, the catalyst was filtered off and ethanol was distilled off to give 3.1 g of methyl 2-(1,2,3,4-tetrahydro-2,2-dimethylquinolin-6-yl)propionate (Compound 11).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][C:30]3[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=3)[C:23]=1[F:39])=[O:19])=[CH:12]2.[N:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46](O)=[O:47])[CH:41]=1.CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:46]([C:42]2[CH:41]=[N:40][CH:45]=[CH:44][CH:43]=2)=[O:47])=[CH:17][CH:16]=3)=[O:19])=[C:23]([F:39])[C:24]=1[O:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=1
Reactant: O=C(O)c1cccnc1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(NC(=O)c5cccnc5)ccc4[nH]3)c2F)c1
Yield: 22.3 %

Procedure:
The title compound (0.011 g, 19%) was prepared from 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.050 g, 0.086 mmol), 3-pyridinecarboxylic acid (0.011 g, 0.086 mmol), DIPEA (0.075 mL, 0.43 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.065 g, 0.257 mmol) in a similar manner as described in the general procedure. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.66 (s, 1H), 10.38 (s, 1H), 9.16 (s, 2H), 8.80 (s, 1H), 8.38 (s, 1H), 8.12 (s, 1H), 7.72-7.97 (m, 1H), 7.32-7.97 (m, 7H), 7.19 (s, 1H), 4.58 (d, 2H). MS: m/z 574 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[S:12][CH:13]=[CH:14][C:10]=2[CH:9]=1.[CH3:17][NH:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[S:12]1[CH:13]=[CH:14][C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][N:18]([CH3:17])[CH2:19][CH2:20][OH:21])[CH:16]=[CH:15][C:11]1=2
Reactant: CNCCO
Reactant: ClCCCOCCc1ccc2sccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(CCO)CCCOCCc1ccc2sccc2c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
In 6 mL of N,N-dimethylformamide is dissolved 0.80 g of 5-[2-(3-chloropropyloxy)ethyl]benzo[b]-thiophene, to which are added 0.51 mL of 2-(methylamino)ethanol and 0.87 g of potassium carbonate. The mixture is stirred at 80° C. for 3 hours. The reaction mixture is introduced into a mixture of water and ethyl acetate. The organic layer is separated, washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=10:1). Thus, 0.59 g of 2-{[3-(2-benzo[b]thiophen-5-ylethoxy)propyl]-(methyl)amino]-1-ethanol is obtained as an oily product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15](Br)=[C:14]2[C:10]=1[C:11]([C:20](=O)[C:21](OC)=[O:22])=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH2:20][CH2:21][OH:22])=[CH:12][NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1c[nH]c2c(Br)cc(F)c(OCc3ccccc3)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: OCCc1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Reaction time: 0.33 h
Yield: 56 %

Procedure:
A solution of 17-2 (1.98 g, 4.874 mmol) in dry 1,4-dioxane (80 mL) was added dropwise to a slurry of LiAlH4 (1.85 g, 48.74 mmol) in dry 1,4-dioxane (40 mL) at reflux. The mixture was held at reflux for 1 h. The mixture was then cooled, quenched with 2 mL H2O, 2 mL NaOH (15%) solution, and 6 mL H2O. After stirring for 20 min, the mixture was filtered and the filtrate was concentrated. The resulting residue was purified by column chromatography on silica gel with hexanes/ethyl acetate (1:0 to 1:1) as eluent to afford 17-3 as a colorless oil in 56% yield (1.0 g). 1H NMR (300 MHz, CDCl3) δ (ppm) 7.97 (br, 1H), 7.47-7.50 (m, 2H), 7.34-7.43 (m, 3H), 6.96-6.98 (m, 3H), 5.27 (d, J=1.1 Hz, 2H), 3.74 (dt, J=6.3, 6.0 Hz, 2H), 2.96 (t, J=6.3 Hz, 2H), 1.47 (t, J=6.3 Hz, 1H). APCI [M+1]: 286.1
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:34][CH:35]1[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([OH:43])[C:37]([CH3:45])([CH3:44])[CH2:36]1)(=[O:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[N:25]([OH:30])[C:24]([CH3:32])([CH3:31])[CH2:23]1)=[O:20]>ClCCl.CO>[C:10]([O:34][CH:35]1[CH2:36][C:37]([CH3:45])([CH3:44])[N:38]([O:43][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:39]([CH3:42])([CH3:41])[CH2:40]1)(=[O:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH:22]1[CH2:23][C:24]([CH3:31])([CH3:32])[N:25]([O:30][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:26]([CH3:28])([CH3:29])[CH2:27]1)=[O:20]
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OC(=O)Nc3ccccc3)C(C)(C)C2)CC(C)(C)N1OC(=O)Nc1ccccc1
Yield: 75.8 %

Procedure:
Phenyl isocyanate (9.5 g, 80 mmol) is added over 5 minutes to a suspension of 20.0 g (39 mmol) of di-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl) sebacate in 125 ml of dichloromethane. The resulting solution is refluxed for 30 minutes and then evaporated to obtain a solid. The crude solid is briefly refluxed in methanol, filtered off, and recrystallized from 2-propanol: dichloromethane to give 22.2g (76% yield) of white solid, m.p. 159-61° C.(dec).