Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:24]=1[C:25](O)=[O:26]>>[CH3:33][O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:23]([O:22][CH3:21])[C:24]=1[C:25]([N:17]1[CH2:16][CH:15]2[CH:19]([CH2:20][N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:18]1)=[O:26]
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Product: COc1cccc(OC)c1C(=O)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2,6-dimethoxybenzoic acid. MS (ESI) mass calcd. for C25H26N4O3, 430.51; m/z found, 431.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH3:13])=[C:7]2O.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([CH3:12])[C:8]=1[CH3:13]
Reactant: Cc1nc2c(Cl)cccc2c(O)c1C
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc2c(Cl)cccc2c(Cl)c1C

Procedure:
A mixture of 8-chloro-2,3-dimethylquinolin-4-ol (1.83 g, 8.81 mmol) in phosphorous oxychloride (10.00 mL) was heated to reflux for 2 h, after which time LC-MS indicated only product present. The reaction solution was poured into ice and adjusted to pH>10. The aq. mixture was extracted with 2×75 mL DCM. The combined organic extracts were stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a pale yellow solid, which was not further purified. Mass Spectrum (ESI) m/e=226.0 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH:7]=1.CO>>[C:14]1([NH:13][S:12]([C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:26])=[O:2])[CH:11]=[CH:10][CH:9]=2)(=[O:25])=[O:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1
Solvent: CO
Product: O=C(O)C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-[3-(naphthalen-1-ylsulfamoyl)phenyl]-acrylic acid methyl ester (14d) (0.29 g, 0.79 mmol) in methanol (3 ml) 1N NaOH solution (2.4 ml, 2.4 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5. The title compound was obtained as a white solid (0.22 g, 79%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:11][CH2:10][C@@H:9]([NH2:12])[CH2:8]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CCOCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCN(C2CCOCC2)C1
Reaction time: 2 h

Procedure:
A solution of EXAMPLE 130A (550 mg) in dichloromethane (25 ml) was cooled in an ice bath under nitrogen. 2,2,2-Trifluoroacetic acid (8.333 ml) was added and the reaction was stirred for 2 hours. The product was obtained by concentration and high vacuum drying.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C@:9]1([CH3:30])[C@H:14]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:12]2([CH3:13])[C:11](=[O:29])[CH2:10]1)[C:23]1[CH:22]=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)[CH3:8].C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:7]([C@:9]1([CH3:30])[C@H:14]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:12]2([CH3:13])[C@@H:11]([OH:29])[CH2:10]1)[C:23]1[CH:22]=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)[CH3:8]
Reactant: CC[C@@]1(C)CC(=O)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC[C@@]1(C)C[C@H](O)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Yield: 91.3 %

Procedure:
Lithium aluminum hydride (48 mg; 1.26 mmol) was added to a solution of the 15α-ethyl-15β-methyl ketone (8) (80 mg; 0.25 mmol) in dry tetrahydrofuran at 0° C. Low temperature stirring was maintained for 5 min. Saturated aqueous sodium hydrogen carbonate was added and the mixture was filtered. Standard work-up of the filtrate (ethyl acetate) gave 15α-ethyl-3-methoxy-15β-methylestra-1,3,5 (10)-trien-17β-ol (14) (75 mg; 89%), m.p. 133°-136° C. (from chloroform-methanol); [α]D +67° (c 0.9); νmax 3604 cm-1 (OH); δH 0.88 (3H, t, J 7.2 Hz, 15β-CH2CH3), 0.93 (3H, s, 15β-Me), 1.06 (3H, s, 13β-Me), 1.10 (1H, d, J 11.1 Hz, 14α-H), 1.32 obsc (2H, m, 15β-CH2CH3), 1.39 and 2.04 (each 1H, dd, J 13.2 and 10.0, and 13.2 and 7.9 Hz, 16α- and 16β-H), 2.84 (2H, m, 6-H2), 3.60 (1H, dd, J 10.0 and 7.9 Hz, 17α-H), 3.77 (3H, s, 3-OMe), 6.61 (1H, d, J 2.9 Hz, 4-H), 6.70 (1H, dd, J 8.6 and 2.9 Hz, 2-H), and 7.20 (1H, d, J 8.6 Hz, 1-H); δc 9.4 (C-152), 13.9 (C-18), 23.7 (C-151), 26.1 (C-11), 28.6 (C-7), 29.9 (C-6), 37.1 (C-12), 37.7 (C-8), 38.9 (15β-Me), 39.7 (C-15), 45.0 (C-9), 45.6 (C-14), 55.2 (3-OMe), 55.6 (C-13), 79.3 (C-16), 80.2 (C-17), 111.4 (C-2), 113.6 (C-4), 126.3 (C-1), 133.0 (C-10), 137.7 (C-5), and 157.5 (C-3) (Found: C, 80.0; H, 9.7%; M+, 328. C22H32O2 requires C, 80.4; H, 9.8%; M, 328).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([C:14]#[C:15][C:16](O)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:2]1([NH:1][C:16](=[O:17])[C:15]#[C:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C#Cc1ccccc1
Product: O=C(C#Cc1ccccc1)Nc1ccccc1
Yield: 79.8 %

Procedure:
According to preparation 15, aniline (0.700 g, 7.5 mmol) was coupled to phenylpropiolic acid (1.0 g, 6.8 mmol) to provide 1.2 g (73%) of product. NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].Cl.[N:13]([O-])=O.[Na+]>O>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9]([CH3:10])=[N:13][NH:1]2)=[CH:4][CH:5]=1
Reactant: O=N[O-]
Reactant: CC(=O)c1ccc(F)cc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1n[nH]c2cc(F)ccc12
Temperature: -10 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
1-(2-Amino-4-fluorophenyl)ethanone (9.618 g, 62.9 mmol) was treated with concentrated hydrochloric acid (16 mL) and water (16 mL), and the resulting white suspension was cooled to -10° C. and treated with a solution of sodium nitrite (4.338 g, 62.9 mmol) in 10 mL H2O, maintaining the temperature below 0° C. The resulting solution was filtered directly into a rapidly stirred solution of SnCl2.2H2O (34 g in 200 mL H2O) and the resulting mixture was stirred for 1 h at 20° C., basified (32 g NaOH in 200 mL H2O) and extracted with EtOAc. The combined organic extracts were dried (MgSO4), concentrated and the residue purified by flash chromatography (25% EtOAc in hexane) to give the title compound (3.10 g, 33%) as a white solid; mp 116°-117° C. (from hexane); 1H NMR (360 MHz, CDCl3) δ12.89 (bs, 1H, NH), 7.62 (dd, J=8.8, 5.1 Hz, 1H, indazole), 7.09 (dd, J=9.1, 2.0 Hz, 1H, indazole), 6.93 (dt, J=9.1, 2.0 Hz, 1H, indazole), 2.60 (s, 3H, Me); MS (CI+) m/e 151 (M+H+); Anal. calcd for C8H7FN2 : C, 63.99; H, 4.70; N, 18.66. Found: C, 63.94: H, 4.72; N, 19.10.
Reaction SMILES: [NH2:1][CH:2]([C:7](=[O:36])[NH:8][CH2:9][C:10]([CH3:35])([CH3:34])[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:17]=1)[CH2:3][C:4]([OH:6])=[O:5].CN(C)C=O.C(N(CC)CC)C.[C:49](ON1C(=O)CCC1=O)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[N:52][CH:51]=1>C(#N)C.O>[C:22]1([C:20]2[CH:19]=[C:18]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:17]=[C:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([CH3:34])([CH3:35])[CH2:9][NH:8][C:7]([CH:2]([NH:1][C:49]([C:50]3[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=3)=[O:56])[CH2:3][C:4]([OH:6])=[O:5])=[O:36])[CH:21]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1)CNC(=O)C(N)CC(=O)O
Reactant: O=C(ON1C(=O)CCC1=O)c1cccnc1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1)CNC(=O)C(CC(=O)O)NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 3-amino-3-(N-(6-(4,6-diphenyl(2-pyridyloxy))-2,2-dimethylhexyl)carbamoyl)propanoic acid (100 mg, 0.204 mmol), N,N-dimethylformamide (2 mL), and triethylamine (0.1 mL) was stirred at room temperature for 5 min. Succinimidyl nicotinate (69 mg, 0.315 mmol) was added, and the mixture was stirred for 18 h. The mixture was concentrated under high vacuum, and the residue was purified using reverse-phase HPLC (water-acetonitrile gradient containing 0.1% TFA) to afford 23 mg (19%) of a white powdered solid. ESMS: Calculated for C35H38N4O5, 594.2842 Found 595.2 [M+H]+1; Rt=15.597 min (100% pure, Vydac C18 column; gradient 20 to 100% acetonitrile/water+0.1% TFA over 30 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.CO.[O:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1.[BH3-]C#N.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH:35]4[CH2:36][CH2:37][O:32][CH2:33][CH2:34]4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C5CCOCC5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 60 °C

Procedure:
To a suspension of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (2.50 g, 6.0 mmol) in a mixed solvent of MeOH (42 mL) and DCM (10 mL) was added dihydro-2H-pyran-4(3H)-one (3.33 mL, 36.0 mmol) and TEA (8.36 mL, 60.0 mmol). The reaction mixture was heated at 60° C. for 1 h before NaCNBH3 (1.66 g, 26.4 mmol) was added. The mixture was heated at 60° C. for another 2 h, cooled down to room temperature, diluted with DCM (60 mL), dry loaded onto silica gel (12.5 g), and purified by silica gel chromatography (DCM with 1% NH3 to 10% MeOH in DCM with 1% NH3 gradient) to provide 5-chloro-N2-(2-fluoro-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid; 1H NMR (DMSO-d6, 400 MHz) δ 12.08 (br, 1H), 9.58 (br, 1H), 8.65 (d, J=28.4 Hz, 1H), 8.02 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.03 (d, J=12.4 Hz, 1H), 6.08 (br, 1H), 3.89 (dd, J=10.8, 3.6 Hz, 2H), 3.28 (t, J=10.4 Hz, 2H), 2.99 (d, J=10.8 Hz, 2H), 2.64-2.43 (m, 2H), 2.24-2.15 (m, 8H), 1.71-1.40 (m, 8H); ESMS m/z 500.2 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:3]=1.[C:19]([O:23][C:24](=[O:33])[N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C=O)C.ClCCl>[C:19]([O:23][C:24](=[O:33])[N:25]([CH:26]1[CH2:27][CH2:28][N:29]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:4][N:3]=2)[CH2:30][CH2:31]1)[CH3:32])([CH3:22])([CH3:20])[CH3:21]
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CC1
Temperature: 130 °C
Yield: 87.9 %

Procedure:
Add 1-chloro-4-(4-fluorophenyl)-phthalazine (3.00 g, 11.6 mmol) to a solution of methyl-piperidin-4-yl-carbamic acid tert-butyl ester (2.98 g, 13.9 mmol) and triethylamine (3.52 g., 34.8 mmol) in DMF (30 mL). Heat at 130° C. for 3 days. Dissolve the reaction mixture in dichloromethane and wash with brine. Dry the organic phase with sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography (20:5:1, hexane:ethyl acetate: 2 M ammonia in methanol) to yield the title compound as a solid (4.45 g, 88%). ES/MS m/z 437.2 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:24][O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18](/[C:21](=[N:24]/[O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])/[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CON
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: COC(=O)CO/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 31 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and methyl 2-(aminooxy)acetate (intermediate K) in 31% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, CD3OD), δ ppm 9.32 (s, 1H), 8.86 (m, 1H), 8.38 (d, 1H), 8.06 (m, 2H), 7.90 (dd, 1H), 7.56 (dd, 1H), 6.24 (s, 2H), 4.87 (s, 2H), 3.79 (s, 3H), 2.45 (s, 3H). LCMS (method B): [MH]+=392, tR=2.16 min.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]=[C:11]=[O:12])[CH:5]=1.[Cl:14][C:15]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=1[NH2:17]>C(OCC)(=O)C>[Cl:14][C:15]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:11](=[O:12])[NH:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:2])=[O:13]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cccc(N=C=O)c1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(C(=O)O)c1)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 200 mg 3-Isocyanato-benzoic acid methyl ester in 2 ml ethyl acetate is added dropwise a solution of 162 mg 2,4-dichloroaniline in 1 ml ethyl acetate. After 5 h at RT the solvent was removed under reduced pressure and the residue dissolved in 5 ml MeOH/THF/H2O 2:2:1. 100 mg lithium hydroxide monohydrate was added and the mixture stirred over night at RT. After removal of the solvent the residue was acidified by addition of 5 ml half concentrated HCl. The precipitating acid was filtered off and dried.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:10]([C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCN(Cc2ccccc2)CC1
Yield: 90.1 %

Procedure:
A solution of N-Boc-L-proline 0.645 g (3 mmol), 1-benzylpiperazine 0.528 g (3 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) 1.152 g (6 mmol) and catalytic amount of 4-(dimethylamino) pyridine in methylene chloride (50 ml) was stirred at room temperature overnight. The reaction mixture was concentrated and applied to flash column chromatography using methylene chloride and methanol (100:5) as eluents to give 1.01 g of desired product in 90% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:34])[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][N:29]([CH2:32]C)[CH2:30]C.Cl.ClCl>ClCCl.CO>[ClH:1].[Cl:19][C:20]1[CH:21]=[C:22]([NH:34][C:16](=[O:18])[C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:32]
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Agent: Cl
Agent: ClCl
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCOc1ccc(NC(=O)C#Cc2ccc(-c3ccc(Cl)cc3)cc2)cc1Cl

Procedure:
Prepared analogously to Example 3.7.c. from (4′-chlorobiphenyl-4-yl)propynoic acid and 3-chloro-4-(2-diethylaminoethoxy)phenylamine. Yield: 0.28 g (58% of theory); melting point: 226° C.-233° C.; C27H26Cl2N2O2 (M=481.41)*HCl; calc.: molecular ion peak (M+H)+: 481/3/5 (Cl2); found: molecular ion peak (M+H)+: 481/3/5 (Cl2); Rf value: 0.45 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>C(O)C>[NH2:6][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(CN)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Hydrazine monohydrate (1 mL, 20.58 mmol) was added to an ethanol (20 mL) solution of the compound (1.45 g, 4.21 mmol) synthesized in (1), and the mixture was stirred at room temperature for 24 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was re-suspended in ethanol, and allowed to stand under ice-cooled conditions. After filtration, the filtrate was concentrated under reduced pressure to obtain the target (823 mg, 91%).
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])=[CH:3][Cl:4].[NH2:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([O:27][CH3:28])[N:20]=1>O1CCOCC1>[Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([O:27][CH3:28])[N:20]=1)=[O:17])(=[O:13])=[O:14])=[CH:3][Cl:4]
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Reactant: COc1nc(N)nc(OC)n1
Solvent: C1COCCO1
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(Cl)=CCl)nc(OC)n1

Procedure:
7.4 g of 2-(1,2-dichlorovinyloxy)phenylsulfonyl-isocyanate and 3.9 g of 2-amino-4,6-dimethoxy-1,3,5-triazine are heated to 70°-80° C. in 60 ml of absolute dioxane for 3 hours. After cooling the mixture is treated with activated carbon, filtered and evaporated to 1/5 of the original volume. From the residue crystallise 9.4 g of N-[2-(1,2-Dichlorovinyloxy)phenylsulfonyl]-N'-(4,6-dimethoxy-1,3,5-triazin-2-yl)urea, m.p. 199°-200° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([C:20]1[NH:21][C:22]([CH2:27][OH:28])=[C:23](CO)[N:24]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(O)C>[CH2:9]([C:20]1[NH:21][C:22]([CH2:27][OH:28])=[C:23]([Cl:1])[N:24]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCc1nc(CO)c(CO)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCO
Product: CCCCCCCCCCCc1nc(Cl)c(CO)[nH]1
Reaction time: 2 h

Procedure:
1.10 Grams (8.3 mmol) of the N-chlorosuccinimide was added little by little to a solution consisting of 2.15 g (7.6 mmol) of a 2-undecyl-4,5-bis(hydroxymethyl) imidazole and 200 ml of ethanol at a temperature of 40° to 45° C. over a period of about 23 minutes. The mixture was stirred at the same temperature for two hours to effect the reaction and, then, ethanol was distilled off under reduced pressure. The resulting reaction product was washed with water and was then recrystallized from acetone to obtain a creamy-white fine crystalline 2-undecyl-4-chloro-5-(hydroxymethyl) imidazole in an amount of 1.16 g (yield, 53.1%). By using acetonitrile, furthermore, the recrystallization was effected twice to obtain a colorless crystalline product in pure form. The TLC and spectra of this compound were the same as the properties exhibited the above-mentioned 2-undecyl-4-chloro-5-(hydroxymethyl) imidazole.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:11])=[O:7].[BH3-]C#N.[Na+].[CH3:29][N:30]([CH3:39])[C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.C1(N=C=O)C=CC=CC=1>CO.CC(O)=O.CO.CC#N>[CH3:29][N:30]([CH3:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35][N:17]2[CH2:18][CH2:19][CH:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:20]=[CH:21][CH:22]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=3)[CH2:15][CH2:16]2)=[CH:33][CH:32]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCNCC1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C=Nc1ccccc1
Solvent: CC#N
Solvent: CO
Product: CN(C)c1ccc(CN2CCC(CNC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)CC2)cc1
Temperature: 60 °C
Reaction time: 19 h

Procedure:
A solution of 4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (20.0 mg, 0.058 mmol) in CH3OH (1.0 ml) and NaBH3CN (16.5 mg) were added to a solution of 4-(dimethylamino)benzaldehyde (30.4 mg, 0.204 mmol) in 5 % CH3COOH/CH3OH (1.0 mL). The reaction mixture was stirred at 60° C. for 19 h. The solvent was evaporated to afford a solid. CH3CN (2.0 mL) and phenyl isocyanate (6.9 mg, 0.048 mmol) were added to the solid and the mixture was stirred at 25° C. for 1 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH3OH (20 mL). Product was eluted using 2 N NH3—CH3OH (6 mL) and the eluant was concentrated to afford 1-(4-(dimethylamino)benzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (compound No. 937) as a pale yellow oil (13.5 mg, 49%): The purity was determined by RPLC/MS (87%); ESI/MS m/e 477.3 (M++H, C25H31F3N4O2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25](O)=[O:26])[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][N:39]([C:25]([C:21]2[N:22]([CH3:24])[CH:23]=[C:19]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH:17]([CH3:18])[N:8]([C:6]5[CH:5]=[C:4]([N:28]6[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]6)[N:3]=[C:2]([NH2:1])[N:7]=5)[CH2:9]4)=[CH:14][CH:13]=3)[CH:20]=2)=[O:26])[CH2:38]1
Reactant: CC1Cc2ccc(-c3cc(C(=O)O)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CN(C)C1CCNC1
Product: CC1Cc2ccc(-c3cc(C(=O)N4CCC(N(C)C)C4)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 87A, Step 9 starting from 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1-methyl-1H-pyrrole-2-carboxylic acid (Example 87A, Step 8) and N,N-dimethylpyrrolidin-3-amine. LCMS (M+H)+: m/z=558.3.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][OH:14])[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][N:2]([CH2:12][CH2:13][O:14][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN(CCO)c1nc2ccccc2o1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCOc1ccc(C=O)cc1)c1nc2ccccc2o1
Temperature: 25 °C

Procedure:
To a solution of 2-[N-methyl-N-(2-benzoxazolyl) amino]ethanol (9.6 g), triphenylphosphine (13.1 g) and 4-hydroxybenzaldehyde (6.1 g) in dry tetrahydrofuran (150 ml) was added dropwise a solution of diethyl azodicarboxylate (9.0 g) in dry tetrahydrofuran (30 ml), under a blanket of nitrogen with stirring at room temperature. The solution was stirred overnight at room temperature following which the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether (300 ml), filtered and the ether solution was washed with dilute sodium hydroxide solution (200 ml), saturated brine (200 ml), dried (MgSO4), filtered and the solvent evaporated. The title compound (mp 97°-98° C.) was obtained after chromatography on silica-gel, eluting with dichloromethane.