Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH2:21])=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.[OH2:28].O=O>CN(C=O)C.CCOC(C)=O.[Cu]Cl.[Pd](Cl)Cl>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C@@H:12]([N:8]2[CH2:7][CH2:6][C@:5]([CH2:4][CH2:3][CH2:2][OH:1])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:10][C:9]2=[O:11])[CH3:13])=[CH:19][CH:18]=1)(=[O:28])[CH3:21]
Reactant: C=Cc1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Reactant: O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: O=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Yield: 52 %

Procedure:
A round-bottom flask was charged with copper(I) chloride (49 mg, 0.5 mmol), and a solution of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (80 mg, 0.2 mmol) in DMF (3 mL) was added, followed by H2O (0.5 mL) and palladium(II) chloride (18 mg, 0.1 mmol). The reaction mixture was vigorously stirred under a balloon of oxygen at rt overnight. The reaction was diluted with EtOAc (5 mL), and filtered. The filtrate was separated, and the aqueous layer was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC to afford (R)-3-((S)-1-(4-acetylphenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (40 mg, 52%). 1H NMR (CDCl3): 1.34 (m, 1H), 1.49 (m, 3H), 1.68 (m, 1H), 1.92 (m, 2H), 2.11-2.27 (m, 3H), 2.46 (s, 3H), 2.84 (m, 2H), 3.51 (m, 2H), 5.64 (m, 1H), 6.86 (m, 2H), 7.26 (m, 6H), 7.51 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10](OS(C)(=O)=O)[CH2:11][CH2:12]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[S-2:24].[Na+].[Na+]>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][S:24]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [S-2]
Reactant: CC(C)(C)OC(=O)NCC(CCOS(C)(=O)=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCS1
Temperature: 40 °C
Reaction time: 3 h
Yield: 21.5 %

Procedure:
To a solution of crude methanesulfonic acid 1-(tert-butoxycarbonylamino-methyl)-3-methanesulfonyloxy-propyl ester (1.24 g) in methanol (25 ml) was added sodium sulfide monohydrate (0.84 g). The reaction mixture was stirred at 40° C. for 3 hours. The methanol was partially removed by distillation. Water was added and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified over silica gel (ethyl acetate/heptanes, from 1:4 to 1:1) to give thietan-2-ylmethyl-carbamic acid tert-butyl ester (0.15 g).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]#[N:11].ClC1C(Cl)=CC2N[C:27](=O)[C:26]3=CC=[CH:32][N:25]3[CH2:24][C:23]=2C=1>>[Cl:17][C:13]1[C:14]([Cl:16])=[CH:15][C:2]2[N:1]=[C:10]([N:11]3[CH2:27][CH2:26][N:25]([CH3:32])[CH2:24][CH2:23]3)[C:6]3=[CH:7][CH:8]=[CH:9][N:5]3[CH2:4][C:3]=2[CH:12]=1
Reactant: O=C1Nc2cc(Cl)c(Cl)cc2Cn2cccc21
Reactant: N#Cc1cccn1Cc1cc(Cl)c(Cl)cc1N
Product: CN1CCN(C2=Nc3cc(Cl)c(Cl)cc3Cn3cccc32)CC1

Procedure:
Following the general procedure of Example 1, 1-(2-amino-4,5-dichlorobenzyl)-2-pyrrolecarbonitrile is converted to 7,8-dichloro-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one and thence to the title compound.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:28]=[C:29]([C:33]([CH3:37])([CH3:36])[C:34]#[N:35])[CH:30]=[CH:31][CH:32]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:34]([C:33]([C:29]1[CH:28]=[C:27]([NH:26][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([O:15][C:12]3[CH:13]=[CH:14][C:9]4[N:10]([CH:25]=[C:7]([NH:6][C:4]([CH:1]5[CH2:2][CH2:3]5)=[O:5])[N:8]=4)[N:11]=3)[CH:17]=2)[CH:32]=[CH:31][CH:30]=1)([CH3:37])[CH3:36])#[N:35]
Reactant: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(C)(C#N)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(NC(=O)c2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 44.4 %

Procedure:
Using 3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoic acid (100 mg, 0.30 mmol), 2-(3-aminophenyl)-2-methylpropanenitrile (57 mg, 0.36 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (68 mg, 0.36 mmol), 4-(dimethylamino)pyridine (43 mg, 0.36 mmol) and pyridine (5.0 mL) as starting materials and in the same manner as in Example 318, the title compound (64 mg, 45%) was obtained as a white powder.
Reaction SMILES: [N+:1]([C:4]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[H][H].CCCCCC.C(OCC)(=O)C>[Pd].C(O)C>[NH2:1][C:4]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: [H][H]
Reactant: N#Cc1cccc(O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: N#Cc1cccc(O)c1N
Reaction time: 1 h

Procedure:
A parr bottle was charged with palladium on activated carbon (5%, 0.196g). A solution of 2-nitro-3-hydroxybenzonitrile (1.31 g, 0.008 mol) in 40 ml of ethanol was added. The reaction mixture was placed under 25 psi of hydrogen gas and shaken for 1 hour. TLC (1:1 hexane:ethyl acetate) shows that no starting material remained. The mixture was filtered through Celite® and evaporated to yield 2-amino-3-hydroxybenzonitrile, 1.01 g (0.0075 mol, 94%).
Reaction SMILES: [Br-].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33])[CH2:13][CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[N+]1CCCC1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.C(Cl)(Cl)Cl.CC(O)=[O:42]>C(Cl)Cl>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33])[CH2:13][CH:14]1[C:19]2[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][C:15]1=[O:42])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(CC2C(=[N+]3CCCC3)CCc3ccccc32)cc1OCc1ccccc1
Reactant: CC(=O)O
Agent: [Br-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1CCc2ccccc2C1Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1

Procedure:
A solution of 1-[1-(3-benzyloxy-4-nitrobenzyl)-3,4-dihydro-1H-naphthalen-2-ylidene]-pyrrolidinium bromide (700 mg, 1.59 mmol) in a mixed solvent of 10 mL H2O, 1 mL CHCl3 and 2 mL CH3COOH is stirred at RT for 3 h. The solution is diluted with CH2Cl2 and the organic layer is washed well with water, brine and dried over MgSO4. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 33-50% EtOAc/hexane as eluent to give the title compound as a yellow liquid. NMR (CDCl3): 7.70-7.68 (d, J=8.34 Hz, 1H), 7.40-7.29 (m, 5H), 7.23-7.15 (m, 3H), 6.96-6.94 (dd, J=6.31 Hz, 1 H), 6.57-6.55 (m, 2H), 4.96 (s, 2H), 3.75-3.72 (t, J=6.07 Hz, 1H), 3.34-3.29 (q, J=6.82 Hz, 1H), 3.19-3.14 (q, J=5.30 Hz, 1H), 2.88-2.82 (m, 1H), 2.57-2.46 (m, 3H). (M−1)−=386.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9](O)=[CH:8][C:7]1=[O:13].[F:17][C:18]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>>[F:17][C:18]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=1[CH2:20][NH:21][C:9]1[CH:10]=[CH:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)[C:7](=[O:13])[CH:8]=1
Reactant: O=c1cc(O)ccn1Cc1cccc(F)c1
Reactant: NCc1ccc(F)cc1F
Product: O=c1cc(NCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1

Procedure:
The product from Step 2 (0.5 g, 2.28 mmol) and 2,4-difluoro benzylamine (4 mL, 33.6 mmol) were combined in a nitrogen flushed culture tube. The tube was capped and heated at 180 C for 24 h. The excess amine was distilled in vacuo and the residue was chromatographed on silica (95:5 ethyl acetate:methanol). The final compound was isolated as a light yellow solid (0.16 g, 36%). 1H NMR (400 MHz, CD3OD) δ 7.33 (m, 3H), 7.03 (d, J=8 Hz, 1H), 6.96 (m, 3H), 6.95 (m, 1H), 5.97 (dd, J=3.2 and 8.0 Hz, 1H), 5.48 (d, J=2.56 Hz, 1H), 5.02 (s, 2H), 4.33 (s, 2H) ppm. 19F NMR (400 MHz, CD3OD) δ −113.88 (1F), −115.33 (1F), −116.78 (1F) ppm. ES-HRMS m/z 345.1221 (M+H calcd for C19H17F3N2O requires 345.1209).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5](C(=O)C(C(=O)C(F)(F)F)SC3)=[CH:4][C:3]=2[O:2]1.C1C(NN)=CC=C(S(N)(=O)=[O:30])C=1.Cl.[CH2:34]([OH:36])C>>[CH2:1]1[O:2][C:3]2[C:12](=[C:11]([CH:10]=[CH:5][CH:4]=2)[C:34]([OH:36])=[O:30])[O:13]1
Reactant: CCO
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1c2cc3c(cc2CSC1C(=O)C(F)(F)F)OCO3
Agent: Cl
Product: O=C(O)c1cccc2c1OCO2

Procedure:
6,7-Methylenedioxy-3-(trifluoroacetyl)isothiochroman-4-one from Step 6 (0.64 g, 2.1 mmol) was dissolved in ethanol (100 mL) and 4-sulfonamidophenylhydrazine hydrochloride (0.56 g, 2.5 mmol) was added. The mixture was heated to reflux for 16 hours, and concentrated. The resultant oily solid was dissolved in ethyl acetate and washed with brine and water, dried over MgSO4 and concentrated. Purification was achieved by flash column chromatography eluting with (1:1) ethyl acetate:hexanes. The appropriate fractions were concentrated and recrystallized from ethyl acetate/hexanes. The product was a light brown solid (0.2 g, 21%): mp 272°14 274° C. 1H NMR (DMSO-d6 300 MHz ) 7.98 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 7.44 (bs, 2H), 6.79 (d, J=8.4 Hz, 1H), 6.28 (d, J=8.1 Hz, 1H), 6.14 (s, 2H), 4.09 (s, 2H). Anal.s calc'd for C18H12N3S2O4F3 : C, 47.47; H, 2.66; N, 9.23. Found: C, 47.56; H, 2.73; N, 9.16.
Reaction SMILES: C(N1C2C=CC=CC=2N([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:19][CH2:18]2)=[O:14])C1=O)(C)C.N1CCC(CNC(=O)[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])CC1.[CH3:48]CN(C(C)C)C(C)C>CN1CCCC1=O.C([O-])(O)=O.[Na+]>[C:43]([O:42][C:13]([NH:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]2([C:29]([O:31][CH3:48])=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:21][CH2:22]1)=[O:14])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)n1c(=O)n(C(=O)NCC2CCN(CC3(C(=O)O)CCCC3)CC2)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCCC1
Temperature: 120 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
A mixture of Methyl 1-(iodomethyl)cyclopentanecarboxylate (5.52 g, 0.0206 mol, Step 1), tert-butyl (piperidin-4-ylmethyl)carbamate (8.83 g, 0.0412 mol) and iPr2NEt (10.76 mL, 0.0618 mol) in N-methylpyrrolidone (70 mL) was stirred at 120° C. for 24 h. After cooling, the reaction mixture was diluted with sat. NaHCO3 aq. (200 mL), extracted with AcOEt (200 mL) for three times, and the combined organic layer was washed with water (200 mL) and brine (200 mL). The organic layer was dried over Na2SO4, filtered and concentrated. Removal of the solvent gave a residue, which was chromatographed on a column of silica gel eluting with EtOAc/hexane (1:1) to give 4.91 g (67%) of title compound as a yellow syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=O.[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC(S(O)(=O)=[O:26])=CC=1>O>[Cl:11][C:9]1[CH:10]=[C:2]2[C:3](=[CH:7][CH:8]=1)[C:4](=[O:6])[C:17]1[C:12]([OH:18])=[CH:13][C:14]([OH:26])=[CH:15][C:16]=1[NH:1]2
Reactant: Nc1cc(Cl)ccc1C(=O)[O-]
Reactant: CCCCCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=c1c2ccc(Cl)cc2[nH]c2cc(O)cc(O)c12
Yield: 83.4 %

Procedure:
(Method E-5) 2-Amino-4-chlorobenzoate (50 g, 0.27 mol), dry phlorglucinol (40 g, 0.32 mol), hexanol (120 ml), and p-toluene sulphonic acid (1.6 g, 9 mmol) were mixed and heated to reflux with Dean-Stark removal of water for 2 hrs. On cooling petroleum ether (2 L) was slowly added and the solid was filtered off, washed with petroleum ether and dichloromethane to give the title compound (58.8 g, 0.22 mmol, 83.4%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([OH:21])([CH3:20])[CH3:19])[C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([OH:21])([CH3:19])[CH3:20])[C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2cnc3c(C(C)(C)O)cccn23)n1
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2cnc3c(C(C)(C)O)cccn23)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A solution of 2-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyridin-8-yl]-propan-2-ol (0.5 g) in DCM (100 mL) was cooled to 0° C., and MCPBA (0.376 g) was added. The reaction mixture was stirred at 0° C. for 2 h, then quenched with 10% Na2S2O3 (aq). The organic layer was washed with NaHCO3 (sat'd aq), separated, and dried over Na2SO4, filtered, concentrated, and titurated with EtOAc and filtered to provide 2-[3-(2-methylsulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyridin-8-yl]-propan-2-ol (0.4 g).
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][CH2:12][C:13]([C:15]2[CH:26]=[CH:25][C:18]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=2)=[O:14])=[O:10])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].Cl>O>[ClH:1].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][CH2:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)=[O:14])=[O:10])=[CH:27][CH:28]=1)(=[NH:3])[NH2:4]
Reactant: COC(=O)CCc1ccc(C(=O)CNC(=O)c2ccc(C(=N)N)cc2)cc1
Agent: Cl
Solvent: O
Product: N=C(N)c1ccc(C(=O)NCC(=O)c2ccc(CCC(=O)O)cc2)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
100 mg of methyl p-(p-amidinobenzamidoacetyl)hydrocinnamate hydrochloride were heated with 4 ml of 2 N hydrochloric acid at 100° C. for 60 minutes. The reaction mixture was cooled, 4 ml of water were added, and the mixture was stirred at 5° C. for 2 hours. The crystals which precipitated was filtered off with suction and dried over KOH in vacuo. 70 mg of pure p-(p-amidinobenzamidoacetyl)hydrocinnamic acid hydrochloride, melting point 273°-274° C. (decomposition), were obtained.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.[CH3:27][N:28]([CH2:30][CH:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36](O)[CH:37]=2)[CH2:32]1)[CH3:29].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.N1C=CC=CC=1>[C:1]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][C:4]([C:7]([O:9][C:36]2[CH:37]=[C:38]3[C:33](=[CH:34][CH:35]=2)[CH2:32][CH:31]([CH2:30][N:28]([CH3:29])[CH3:27])[CH2:40][CH2:39]3)=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)CC1CCc2cc(OC(=O)c3ccc(-c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 36 h
Yield: 53.3 %

Procedure:
4-Biphenylylcarboxylic acid (580 mg) and WSC (560 mg) were added to pyridine solution (6 ml) of 2-[(N,N-dimethylamino)methyl]-6-hydroxytetralin (300 mg), which was stirred at room temperature for 36 hours. Saturated sodium bicarbonate solution and water were added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent; hexane˜hexane:ethyl acetate=10:1), and recrystallized (hexane) to give the titled compound (300 mg).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[C:13]([NH:15][C:16]1([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)[CH2:18][CH2:17]1)=[O:14].O[Li:35].O>>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[C:13]([NH:15][C:16]1([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O-:25])=[O:24])=[CH:21][CH:20]=2)[CH2:18][CH2:17]1)=[O:14].[Li+:35]
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3cccc(C(F)(F)F)c3)CC2)cc1
Reactant: [Li]O
Solvent: O
Product: O=C([O-])c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3cccc(C(F)(F)F)c3)CC2)cc1
Product: [Li+]

Procedure:
The title compound (E9) (51 mg) was prepared according to the general procedure for esters hydrolysis starting from (R)-methyl 4-(1-(1-(3-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (D26) (76 mg). (LiOH H2O: 3 eq; reaction time: 3 hrs)
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][N:11]([C:13](F)(F)[CH:14]([F:16])F)C.[F:19][CH:20](F)[C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[N:30]1C=CC=CC=1.CNN>ClCCl.C(#N)C>[CH2:26]([O:25][C:23]([C:22]1[C:21]([CH2:20][F:19])=[N:30][N:11]([CH3:10])[C:13]=1[CH2:14][F:16])=[O:24])[CH3:27]
Reactant: CN(C)C(F)(F)C(F)F
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: c1ccncc1
Agent: CNN
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1c(CF)nn(C)c1CF
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
BF3.OEt2 (1.24 ml, 10.0 mmol) was added to a solution of TFEDMA (1.20 ml, 10.0 mmol) in dry dichloromethane (10 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The residue was then taken up in dry acetonitrile (10 ml). In a second Teflon flask, ethyl 4,4-difluoroacetoacetate (1.03 ml, 10.0 mmol) was added to a solution of pyridine (1.6 ml, 20.0 mmol) in dry acetonitrile (20 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. Methyl hydrazine (0.79 ml, 15.0 mmol) was then added dropwise at room temperature and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (10:0-8:2). (10:0 to 8:2). N-Methyl-3,5-difluoromethyl-4-pyrazolecarboxylic acid ethyl ester (1.75 g, 6.89 mmol, 69%) was obtained as a colourless oil, which crystallized when left to stand.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([NH2:38])[CH2:32][C:33]1([CH2:36][OH:37])[CH2:35][CH2:34]1>>[OH:37][CH2:36][C:33]1([CH2:32][C:31]2[N:38]=[C:26]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:30]=2)[CH2:35][CH2:34]1
Reactant: NC(CC1(CO)CC1)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(CC3(CO)CC3)no2)C1

Procedure:
100 mg (0.25 mmol) of the compound from Example 99A and 62 mg (0.38 mmol) of the compound from Example 67A were reacted according to the General Method 2. Yield: 66 mg (52% of theory)
Reaction SMILES: [CH2:1]([N:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[CH:6]=C(C#N)[C:4]1=[O:13])[CH3:2].[OH-:14].[K+].[CH2:16]([OH:18])[CH3:17]>>[CH2:1]([N:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[CH:6]=[C:17]([C:16]([OH:14])=[O:18])[C:4]1=[O:13])[CH3:2]
Reactant: CCO
Reactant: [OH-]
Reactant: CCn1c(C)c(C)cc(C#N)c1=O
Agent: [K+]
Product: CCn1c(C)c(C)cc(C(=O)O)c1=O
Temperature: 102 °C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
1-Ethyl-3-cyano-5,6-dimethyl-2-pyridone (3-003-03) (3.37 g) was dissolved in 80% ethanol (65 mL), and to the reaction mixture was added potassium hydroxide (7.96 g), and the reaction mixture was refluxed with stirring in oil bath at 102° C. for 24 h. The reaction mixture was evaporated under reduced pressure, and to the residue were added water (50 mL) and ethyl acetate (50 mL). After the reaction mixture was stirred under ice-cooling, and was separated by shaking, and to the aqueous layer was conc. hydrochloric acid (13 mL). The resulting crystal was filtered, and washed with cooled water to give 1-ethyl-3-carboxy-5,6-dimethyl-2-pyridone (3-003-04) (2.734 g, 73.3%, m.p. 164-165° C.) as a yellow ocher crystal.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1C=C[CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH2:17][OH:18])=[CH:13][CH:12]=1.O1C=CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)Cl>[O:9]1[CH2:1][CH2:2][CH2:3][CH2:4][CH:5]1[O:18][CH2:17][CH2:16][O:15][C:14]1[CH:19]=[CH:20][C:11]([Br:10])=[CH:12][CH:13]=1
Reactant: OCCOc1ccc(Br)cc1
Reactant: O=C(O)c1ccccc1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Brc1ccc(OCCOC2CCCCO2)cc1

Procedure:
The starting benzoic acid (I) is made by the reaction of 2-(4-bromophenoxy)ethanol (V) with dihydropyran, in the presence of methylene chloride and p-toluenesulfonic acid.H2O, to give 4-(2-tetrahydropyranyloxyethoxy)bromobenzene (VI). The bromobenzene (VI) is converted to 4-(2-tetrahydropyranyloxyethoxy)benzoic acid (VII) by reacting with magnesium, in tetrahydrofuran and dibromoethane, and then with carbon dioxide. Reaction of (VII) with methanol yields the starting benzoic acid (I). ##STR2##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=CC(C)=C[C:3]=1[NH:9][C:10](=O)C(F)(F)F.[I-].[K+].Cl[CH2:19][C:20]([CH3:22])=[CH2:21].[OH-].[K+].[CH3:25][C:26]([CH3:28])=O>O>[CH3:25][C:26]1[CH:28]=[CH:21][C:20]([CH3:22])=[CH:19][C:10]=1[NH:9][CH2:3][C:2]([CH3:7])=[CH2:1]
Reactant: CC(C)=O
Reactant: Cc1ccc(C)c(NC(=O)C(F)(F)F)c1
Reactant: C=C(C)CCl
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=C(C)CNc1cc(C)ccc1C
Yield: 87 %

Procedure:
To a solution of N-(2,5-dimethylphenyl)-2,2,2-trifluoroacetoamide (5.87 g, 27.0 mmol) in acetone (50 ml) were added potassium iodide (4.49 g 27.0 mmol), 3-chloro-2-methyl-1-propene (8.0 ml, 81 mmol) and pulverized 85% potassium hydroxide (5.3 g, 80 mmol), and the mixture was heated under reflux for 1 hour. Water was added to the reaction mixture and the mixture was extracted twice with hexane. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=100:1, followed by 50:1) to obtain 4.11 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].Br[CH2:12][CH:13]1[O:17][CH2:16][CH2:15][O:14]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][CH2:12][CH:13]1[O:17][CH2:16][CH2:15][O:14]1)[CH3:2]
Reactant: CCOC(CCN)OCC
Reactant: BrCC1OCCO1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(CCNCC1OCCO1)OCC
Temperature: 25 °C

Procedure:
3,3-Diethoxypropylamine (0.11 mole), 2-bromomethyl-1,3-dioxolane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(3,3-diethoxypropyl)-N-(1,3-dioxolan-2-ylmethyl)amine.