Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([NH2:16])[C:6]=2[CH:17]=1.[IH:18].CS[C:21]1[NH:22][CH2:23][CH2:24][N:25]=1.CCOCC>C(O)C>[IH:18].[NH:22]1[CH2:23][CH2:24][NH:25][C:21]1=[N:16][CH:7]1[C:6]2[CH:17]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[CH:11]=[CH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2
Reactant: NC1c2ccccc2C=Cc2ccc(Br)cc21
Reactant: CSC1=NCCN1
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: Brc1ccc2c(c1)C(N=C1NCCN1)c1ccccc1C=C2

Procedure:
6.90 grams (0.024 mole) of 3-bromo-5H-dibenzo[a,d]cycloheptene-5-ylamine, 2.95 grams (0.012 mole) of 2-methylmercapto-4,5-dihydroimidazole hydroiodide, and 65 milliliters of absolute ethanol were stirred together and refluxed for 28 hours. At the end of this period, the solvent was evaporated under reduced pressure and the residue triturated with five 100 milliliter portions of diethyl ether to obtain a purified residue. The purified residue was dissolved in 20 milliliters of absolute ethanol and 300 milliliters of ether added thereto whereupon a solid precipitated. The mixture was stirred thoroughly, the solvent decanted to obtain a residue which was placed on a Still-silica column and eluted with 5 percent methanol in chloroform. The eluted fractions were examined by thin layer chromatography (TLC), the homogeneous TLC fractions combined, and the solvent then vaporized to obtain the desired N-(2-imidazolidinylidene)-3-bromo-5H-dibenzo[a,d]cyclohepten-5-amine hydroiodide product as residue. The product was crystallized from chloroform to obtain purified product, m.p. 240°-241° C. (dec.). Elemental analyses were as follows: Calc'd for C18H17BrIN3 : C, 44.84; H, 3.55; N, 8.72. Found: C, 44.75; H, 3.48; N, 8.46.
Reaction SMILES: [C:1]1([C:7]2([C:12](O)=[O:13])CC[CH2:9][CH2:8]2)C=CC=C[CH:2]=1.[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH2:29])[CH2:27][CH2:28][C@H:23]2[CH2:22]1.C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[CH2:1]([CH:7]([CH2:8][CH3:9])[C:12]([NH:29][C@@H:26]1[C@H:24]2[C@H:23]([CH2:22][N:21]([CH2:20][C:19]3[CH:30]=[CH:31][CH:32]=[C:17]([C:16]([F:33])([F:15])[F:34])[CH:18]=3)[CH2:25]2)[CH2:28][CH2:27]1)=[O:13])[CH3:2]
Reactant: N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: CCC(CC)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21

Procedure:
The title compound was prepared by substituting 2-ethylbutanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.90 (d, J=6.7, 1H), 7.71 (s, 1H), 7.61 (d, J=7.7, 1H), 7.54 (d, J=7.7, 1H), 7.46 (t, J=7.7, 1H), 4.51-4.43 (m, 1H), 3.49 (s, 2H), 2.83 (ddd, J=2.9, 7.8, 16.8, 1H), 2.75 (dd, J=2.9, 9.5, 1H), 2.52-2.43 (m, 1H), 2.37 (dd, J=2.9, 9.1, 1H), 2.35-2.30 (m, 1H), 2.25 (dd, J=7.6, 9.4, 1H), 2.01 (tt, J=4.8, 9.5, 1H), 1.89 (dt, J=7.3, 11.6, 1H), 1.77 (ddt, J=7.5, 9.3, 15.2, 2H), 1.70-1.60 (m, 2H), 1.51-1.37 (m, 2H), 1.34-1.26 (m, 1H), 0.95 (t, J=7.4, 3H), 0.83 (t, J=7.4, 3H); MS (ESI+) m/z 383 (M+H)+.
Reaction SMILES: CO[C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.Cl.CC(C)=[O:21]>>[N:11](=[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]1[CH:4]=[CH:3][C:17]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:21]
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Reactant: CC(C)=O
Agent: Cl
Product: ON=C1C=CC=CC1C=Cc1ccccc1
Temperature: 25 °C
Yield: 97 %

Procedure:
A 2-L, three-necked flask equipped with a mechanical stirrer, thermometer and nitrogen inlet was charged with 10-methoxyiminostilbene I (110.0 g, 0.49 mol) and 330 mL acetone. A 10% solution of hydrochloric acid (28.6 g, 0.08 mol) was then added. The reaction mixture was stirred at ambient temperature for 1–1.5 hours until reaction completion. The product was precipitated by the addition of 660 mL of deionized water, and the resulting suspension was stirred for 3–4 hours. The suspension was filtered and washed with water. After drying, oximinostilbene (99.92 g, 97%) was obtained as a bright yellow solid having a purity of 99% by HPLC.
Reaction SMILES: [NH3:1].O=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]([F:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].O>C1(C)C=CC=CC=1>[NH2:1]/[C:3](/[C:11]([F:14])([F:13])[F:12])=[C:4](/[F:10])\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: N
Reactant: CCOC(=O)C(F)C(=O)C(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(F)=C(\N)C(F)(F)F

Procedure:
Ammonia is introduced with stirring into a solution of 7.5 g of ethyl 3-oxo-2,4,4,4-tetrafluorobutyrate in 20 ml of toluene at 75° C. up to saturation. Then the reaction mixture is heated using a water separator for 5 hours, during which ethyl 3-amino-2,4,4,4-tetrafluorocrotonate is formed as an intermediate.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16]C1C=CC(I)=C(C=1)C(O)=O>>[F:16][C:3]1[CH:2]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[CH:4]=1
Reactant: O=C(O)c1cc(F)ccc1I
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Product: O=C(O)c1ccc(F)cc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 13, substituting 4-fluoro-2-iodo-benzoic acid for 5-fluoro-2-iodo-benzoic acid. 1H NMR (400 MHz, CD3OD): 7.93 (s, 2H), 7.88 (dd, J=8.7, 5.9 Hz, 1H), 7.56 (dd, J=9.2, 2.5 Hz, 1H), 7.38-7.30 (m, 1H).
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:20]([O:24][C:25](=[O:30])[NH:26][CH2:27][CH2:28]Br)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25](=[O:30])[NH:26][CH2:27][CH2:28][N:7]1[CH2:8][CH2:9][N:4]([CH2:10][C:11](=[O:12])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:5][CH2:6]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=C(CN1CCNCC1)Nc1ccccn1
Agent: Cl
Product: CC(C)(C)OC(=O)NCCN1CCN(CC(=O)Nc2ccccn2)CC1

Procedure:
The title compound is synthesized by coupling of 2-piperazin-1-yl-N-pyridin-2-yl-acetamide trihydrochloride dehydrate (commercially available from ABCR GmbH) and (2-Bromo-ethyl)-carbamic acid tert-butyl ester analogously to the preparation of Intermediate 269.2 as a colorless oil; ES-MS: M+H=364.3: CtRet=4.07.
Reaction SMILES: [CH3:1][C:2]1[C:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:21]=2[CH3:30])=[C:5]2[N:6]=[C:7]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:8]=[C:9]([C:10]#[N:11])[N:4]2[N:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][C:2]1[C:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[C:21]=2[CH3:30])=[C:5]2[N:6]=[C:7]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:8]=[C:9]([C:10]3[N:31]=[N:32][NH:33][N:11]=3)[N:4]2[N:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nn2c(C#N)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn2c(-c3nn[nH]n3)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Yield: 42.6 %

Procedure:
To a 5 mL microwave vial was added in 2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)pyrazolo[1,5-a]pyrimidine-7-carbonitrile (68 mg, 0.164 mmol), sodium azide (85 mg, 1.310 mmol) and ammonium chloride (70.0 mg, 1.310 mmol) in N,N-Dimethylformamide (DMF) (1 mL). The reaction was subjected to microwave irradiation at 180° C. for 15 min. The reaction mixture was added to a saturated NH4Cl solution and extracted with DCM (30 mL×2). The combined organic phases were dried and concentrated. The residue was purified on silica column (20˜60% EtOAc/Hexane) and then (5% MeOH/DCM) to give the titled product (32 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H) 2.46 (s, 3H) 3.47-3.79 (m, 8H) 4.01 (s, 2H) 7.15-7.34 (m, 2H) 7.40 (d, J=8.15 Hz, 1H) 7.53 (d, J=7.74 Hz, 1H); LC/MS: MS (ES+) m/e 459.3 [M+H]+.
Reaction SMILES: FC(F)(F)COP([CH2:13][C:14]([O:16][CH3:17])=[O:15])(OCC(F)(F)F)=O.C1OCCOCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:48][C:49]1[CH:50]=[C:51]([C:59]2[N:63]=[C:62]([C:64]3[CH:71]=[CH:70][C:67]([CH:68]=O)=[CH:66][CH:65]=3)[O:61][N:60]=2)[CH:52]=[CH:53][C:54]=1[O:55][CH:56]([CH3:58])[CH3:57]>C1COCC1>[Cl:48][C:49]1[CH:50]=[C:51]([C:59]2[N:63]=[C:62]([C:64]3[CH:65]=[CH:66][C:67](/[CH:68]=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[CH:70][CH:71]=3)[O:61][N:60]=2)[CH:52]=[CH:53][C:54]=1[O:55][CH:56]([CH3:57])[CH3:58]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1Cl
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)/C=C\c1ccc(-c2nc(-c3ccc(OC(C)C)c(Cl)c3)no2)cc1
Temperature: -78 °C
Yield: 73.5 %

Procedure:
A two-neck round bottom flask was charged with methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (0.235 ml, 1.109 mmol), 18-crown-6 (1465 mg, 5.54 mmol) and THF (15 ml). The mixture was then cooled to −78° C. under an atmosphere of nitrogen. Potassium bis(trimethylsilyl)amide (221 mg, 1.109 mmol) was added and the mixture stirred for a few minutes. 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde (380 mg, 1.109 mmol) was added and the mixture stirred at −78° C. for 90 minutes and then left to warm to room temperature overnight. Reaction was quenched by the addition of saturated NH4Cl (aqueous). The mixture was separated and the aqueous layer was extracted with ether (3×10 mL). The combined organics were dried over MgSO4 and concentrated to give an off-white solid. The solid was triturated with MeOH and collected by vacuum filtration and washed with MeOH (3×10 mL). Collected solid was dried overnight in a vacuum oven to give (Z)-methyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)acrylate (325 mg, 73.5%).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].Cl[C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=1.O>CN(C)C=O>[CH3:28][C:27]1[O:26][C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:24][C:23]=1[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:4]2[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:2]([O:1][C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=3)=[N:3]2)=[CH:16][CH:17]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(Oc3ccc(C(F)(F)F)cn3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1.00 g) in N,N-dimethylformamide (80 ml), sodium hydride (60%, oily, 100 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. 2-Chloro-5-trifluoromethylpyridine (0.45 g) was added to the reaction mixture, which was stirred at 90° C. for two hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). A mixture of the obtained oily substance, 1 N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (10 ml) was stirred at room temperature overnight, diluted with 1 N hydrochloric acid (5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(5-trifluoromethyl-2-pyridyloxy)-1H-pyrazol-4-yl]propionic acid was obtained (960 mg, yield: 76%). This was recrystallized from ethyl acetate-hexane. Melting point: 107–108° C.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[C:17]#[CH:18].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH2:16]([NH:19][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)[C:17]#[CH:18]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: C#CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C#CCNCc1ccc(Oc2ccccc2)cc1
Reaction time: 18 h
Yield: 93.6 %

Procedure:
4-Phenoxybenzaldehyde (5.0 g, 25.2 mmol) and propargylamine (1.46 g, 26.5 mmol) were dissolved in 100 mL of 1% acetic acid in methanol under an atmosphere of dry nitrogen. Sodium cyanoborohydride (1.66 g, 26.5 mmol) was added, and stirring was continued for 18 hours at which time the solvent was removed under reduced pressure. The residue was suspended in ether, washed with 5% NaHCO3 and brine, and dried over Na2SO4 to give 5.6 g (93%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:25]1[C:34]([OH:35])=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=1)[C:5](=[O:24])[N:6]2[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:25]3[C:34](=[CH:33][C:28]4[O:29][CH2:30][CH2:31][O:32][C:27]=4[CH:26]=3)[O:35][CH2:36]1)[C:5](=[O:24])[N:6]2[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2c(Br)cccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 4-bromo-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (66%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.47-7.16 (m, 12H), 6.85 (s, 1H), 6.82-6.76 (m, 1H), 6.57 (s, 1H), 5.92 (s, 1H), 5.66 (ABq, 2H), 4.22-4.14 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11][OH:12])[C:7]([O:9][CH3:10])=[O:8].[N:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1>C(O)C>[N:28]1[CH:33]=[CH:32][C:31]([CH:34]=[N:1][C:2]2[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=2[CH2:4][N:5]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:6]([CH2:11][OH:12])[C:7]([O:9][CH3:10])=[O:8])=[CH:30][CH:29]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: O=Cc1ccncc1
Solvent: CCO
Product: COC(=O)C(CO)N(Cc1ccccc1N=Cc1ccncc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 65.2 %

Procedure:
A mixture of 0.50 g (1.268 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 1.268 mmol of 4-pyridinecarboxaldehyde in 7 ml of anhydrous ethanol was refluxed for 1.5 hours and the mixture concentrated under vacuum to dryness. To the residue was added H2O and ethyl acetate. The ethyl acetate layer was separated and concentrated to dryness under vacuum. The solid was purified by thick layer chromatography on silica gel with hexane-ethyl acetate as solvent to give 0.40 g of solid product (plus a small amount of starting material). Anal. for C24H25N3O6S: Calc'd: C,59.6; H,5.2; N,8.7; Found: C,57.6; H,5.7; N,7.4; Mass spectrum (ES) 484 (M+H)-product; 395.1 (M+H)-starting material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:18])[NH:13]2.[OH:19][CH:20]([CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1[CH:31]=O)=[O:24].N1CCCCC1>C(O)C>[OH:19][CH:20]([CH2:33][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1/[CH:31]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH:17]=[CH:16][CH:15]=2)=[O:24]
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2F)N1
Reactant: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(/C=C2\C(=O)Nc3cccc(-c4ccc(F)cc4F)c32)[nH]1
Yield: 60 %

Procedure:
4-(2,4-Difluoro-phenyl)-1,3-dihydro-indol-2-one (73.5 mg, 0.3 mmol) was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide (excess) and piperidine in ethanol to give 75 mg (60%) of the titled compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]([CH2:12][CH3:13])[CH2:10][CH:9]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:8]2[C:30]([CH3:34])=[N:31][N:32]([CH3:33])[C:7]1=2)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].C1COCC1.Cl[C:47]([O:49][CH3:50])=[O:48]>O>[CH2:1]([O:3][C:4]([N:6]1[CH:11]([CH2:12][CH3:13])[CH2:10][CH:9]([N:14]([CH2:15][C:16]2[CH:17]=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=2)[C:47]([O:49][CH3:50])=[O:48])[C:8]2[C:30]([CH3:34])=[N:31][N:32]([CH3:33])[C:7]1=2)=[O:5])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)N1c2c(c(C)nn2C)C(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1c2c(c(C)nn2C)C(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)CC1CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(3,5-Bis-trifluoromethyl-benzylamino)-6-ethyl-1,3-dimethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-b]pyridine-7-carboxylic acid ethyl ester (0.02 g, 0.04 mmol) obtained in step (vi), and K2CO3 (0.016 g, 0.12 mmol) were charged to a flask under a nitrogen atmosphere. Dry THF (5 mL) was added to this mixture, and the resulting mixture was stirred at room temperature for about 30 min, after which time methyl chloroformate (0.011 g, 0.12 mmol) was added dropwise. The reaction was stirred at room temperature overnight. Water was then added to the reaction mixture and the product was extracted with ethyl acetate. The resulting organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum to provide a residue. This residue was purified by column chromatography over 100-200 mesh silica gel using 8% ethyl acetate in petroleum ether as eluent, to afford the title compound. Yield: 0.01 g (50%).
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Cl:15])(=O)C>>[CH3:1][O:2][CH:3]([Cl:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(OC)c1ccccc1
Reactant: CC(=O)Cl
Product: COC(Cl)c1ccccc1
Temperature: 45 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a 300 mL-volume Kjeldahl flask, 50 g of benzaldehyde dimethyl acetal and 27.08 g of acetyl chloride were added, and the mixture was stirred at 45° C. for 3 hours. After the reaction, the low boiling point residue was removed under reduced pressure to obtain 49.8 g of α-chlorobenzyl methyl ether.
Reaction SMILES: [P:1]([O-])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[P:1]([Cl:23])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of dibenzyl phosphate (3.76 g, 13.5 mmol) in CH2Cl2 (10 mL) was treated with oxalyl chloride (1.17, 13.5 mmol) and DMF (0.5 mL). The mixture was stirred at room temperature for 1 h, the solvent was removed by rotary evaporation and the residue was dried in vacuo for 2 h to afford dibenzyl chlorophosphate as a yellowish solid. The residue was suspended in CH2Cl2 (5 mL), cooled to 0° C., treated with a solution of benzylic alcohol M (1.7 g, 6.7 mmol) in CH2Cl2 (5 mL) then DBU (2.02 mL, 13.5 mmol, added dropwise). The mixture was stirred at room temperature for 1 h30, and the solvent was removed by rotary evaporation. The residue was purified by column chromatography over silica gel using a gradient of 0-10% EtOAc/hexane as eluent.
Reaction SMILES: [CH2:1]([CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:20][C:21]1[CH:29]=[C:25]([C:26]([OH:28])=[O:27])[C:24]([OH:30])=[CH:23][CH:22]=1>C(O)(=O)C>[C:26]([C:25]1[CH:29]=[C:21]([N:20]2[C:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:1][C:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH2:12][C:11]2=3)[CH:22]=[CH:23][C:24]=1[OH:30])([OH:28])=[O:27]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1C(=O)Cc2ccccc21)c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2Cc2ccccc2-3)ccc1O

Procedure:
A mixture of 4.0 g. (0.016 mole) of 1-phenacyl-2-indanone, 2.45 g. (0.016 mole) of 5-aminosalicylic acid and 10 ml. of glacial acetic acid was heated under reflux under nitrogen for 2 hours, cooled and filtered. The collected solid was washed with petroleum ether and recrystallized from acetic acid to provide 4.6 g. (78%) of yellow crystals, m.p. 201°-205°.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:41])[C:19]2[O:25][C:24]3[C:26]([Cl:37])=[CH:27][C:28]([N:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32]O)=[CH:29][C:23]=3[CH2:22][S:21](=[O:39])(=[O:38])[C:20]=2[CH:40]=1)=[O:15].C(=O)(O)[O-]>C1(C)C(C)=CC=CC=1.O>[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:41])[C:19]2[O:25][C:24]3[C:26]([Cl:37])=[CH:27][C:28]([N:30]4[CH2:31][CH2:32][O:36][CH2:35][CH2:34]4)=[CH:29][C:23]=3[CH2:22][S:21](=[O:38])(=[O:39])[C:20]=2[CH:40]=1)=[O:15]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCO)CCO)cc(Cl)c1O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCOCC3)cc(Cl)c1O2

Procedure:
Catalytic amount of p-toluene sulphonic acid (PTSA) was added to a stirred solution of compound of Example 13 (1 g, 2.19 mmol) in xylene (50 mL). Reaction mixture was refluxed in Dean-Stark apparatus for 6 h and xylene was removed by distillation. Reaction mixture was diluted with 50 mL water, neutralized using 10% sodim bicarbonate solution and extracted using ethyl acetate (3×50 mL), washed with brine (2×10 mL), dried on sodium sulphate. The crude product obtained was purified by column chromatography (silica gel, ethylacetate/pet. ether) to obtain the title compound. Yield: 0.32 g, (33%); mp: >320° C.; 1H NMR (DMSO-d6, 300 MHz): δ 2.68 (s, 3H, CH3), 3.15 (s, 4H, 2CH2), 3.74 (s, 4H, 2CH2), 3.90 (s, 3H, OCH3), 4.65 (s, 2H, CH2), 6.76 (s, 1H, Ar), 6.88 (s, 1H, Ar), 8.06 (s, 1H, Ar), 8.44 (s, 1H, Ar); MS: m/e (El) 437 (M+).