Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[O:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)[N:9]=2)=[CH:4][CH2:3]1.[C:26]([C:28]1[N:29]=[C:30]([C:41](O)=[O:42])[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=1)#[N:27].[K]>>[CH3:1][C:2]1([CH3:25])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:41]([C:30]3[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[C:28]([C:26]#[N:27])[N:29]=3)=[O:42])=[CH:12][CH:11]=[C:10]([CH:15]3[CH2:16][C:17]([CH3:24])([CH3:23])[O:18][C:19]([CH3:22])([CH3:21])[CH2:20]3)[N:9]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2nc(C3CC(C)(C)OC(C)(C)C3)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Agent: [K]
Product: CC1(C)CC=C(c2nc(C3CC(C)(C)OC(C)(C)C3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 92 %

Procedure:
2-(4,4-Dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-ylamine (as prepared in the previous step, 10.0 g, 0.029 mol) was coupled to 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt as described in Example 1, step (b) to obtain the title compound (15.8 g, 92%) after purification on silica gel (30-70% EtOAc-hexane) as a white solid: Mass spectrum (ESI, m/z): Calcd. for C33H49N5O3Si, 592.3 (M+H), found 592.4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH2:32][CH3:33])[CH2:27][CH2:26]2)=[C:21]([C:35]([F:38])([F:37])[F:36])[CH:20]=1.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH2:32][CH3:33])[CH2:27][CH2:26]2)=[C:21]([C:35]([F:38])([F:37])[F:36])[CH:20]=1
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1Cl
Reactant: CCC(=O)N1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1Nc1ccc(N2CCN(C(=O)CC)CC2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a solution of 5.0 ethyl 4,6-dichloroquinoline-3-carboxylate (1.08 g, 4 mmol, 1 equiv.) in 1,4-dioxane (10 mL) at room temperature was added compound 5.1 1-(4-(4-amino-2-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one (1.2 g, 4 mmol, 1 equiv.). The resulting solution was heated to 80° C. and stirred 4 h before cooling to room temperature. NaOH ON aqueous solution, 3 mL) was added. The solution was diluted with EtOAc (30 mL) and washed with water (30 mL×2) and brine (30 mL). The organic phase was dried over Na2SO4. After removal of solvents, the residue was purified via flash chromatography (CH2Cl2: MeOH=20:1) to afford the desired product 5.2 ethyl 6-chloro-4-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenylamino)quinoline-3-carboxylate (2 g; 93%). LC-MS: (M+H): 622.20
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>CCOCC.CO.[Cu]I>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:29]#[C:28][C:26]([OH:30])([CH3:27])[CH3:25])=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Solvent: CCOCC
Solvent: CO
Product: CC(C)(O)C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide, which can be prepared according to the procedure in PCT Publication No. WO 00/41505, and 2-methyl-3-butyn-2-ol were reacted in the presence of CuI and (PhP3)2Cl2 by the general procedure of Example 1, Step A, and the mixture stirred at RT for 4 h. The reaction mixture was diluted with 50% Et2O/MeOH and filtered through Celite®. The filtrate was concentrated under reduced pressure and further purified by flash chromatography on silica (CH2Cl2–10% MeOH/CH2Cl2 gradient elution) to give 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methyl-1-butynyl)anilino]-N-(2-hydroxyethoxy)benzamide (97%) as a cream solid; m.p. (CH2Cl2/Hexane) 139–142° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.78 (br s, 1 H), 7.46–7.40 (m, 1 H), 7.28–7.19 (m, 2 H), 7.07 (dd, J=8.4, 1.5 Hz, 1 H), 6.79 (ddd, J=8.7, 8.7, 4.7 Hz, 1 H), 5.43 (br s, 1 H), 4.70 (br s, 1 H), 3.86 (t, J=4.7 Hz, 2 H), 3.57 (t, J=4.7 Hz, 2 H), 1.45 (s, 6 H). Anal. Calcd for C20H19F3N2O4: C, 58.8; H, 4.7; N, 6.9. Found C, 58.5; H, 4.8; N, 6.7.
Reaction SMILES: [C:1](=[S:16])(OC1C=CC=CN=1)OC1C=CC=CN=1.[NH:17]1[C:21]2=[N:22][CH:23]=[CH:24][C:25]([CH2:26][NH2:27])=[C:20]2[CH:19]=[CH:18]1>O1CCCC1>[N:27]([CH2:26][C:25]1[CH:24]=[CH:23][N:22]=[C:21]2[NH:17][CH:18]=[CH:19][C:20]=12)=[C:1]=[S:16]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: NCc1ccnc2[nH]ccc12
Solvent: C1CCOC1
Product: S=C=NCc1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
O,O-di-2-pyridinyl thiocarbonate (1136 mg, 4.89 mmol) was added to a solution of (1H-pyrrolo[2,3-b]pyridin-4-yl)methanamine (720 mg, 4.89 mmol) in tetrahydrofuran (THF) (60 mL). Let stir at RT for 30 minutes and concentrated. The residue was purified via Biotage (0% to 50% gradient EtOAc:Hex; 25 g-HP-silica gel column) to obtain 690 mg of 4-(isothiocyanatomethyl)-1H-pyrrolo[2,3-b]pyridine. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.26 (s, 2H) 6.57 (dd, J=3.54, 1.77 Hz, 1H) 7.07 (d, J=4.80 Hz, 1H) 7.50-7.63 (m, 1H) 8.26 (d, J=4.80 Hz, 1H) 11.86 (br. s., 1H); MS[MH]+=190.0
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2c(c1)CCO2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc2occc2c1
Temperature: 25 °C
Yield: 21 %

Procedure:
To a solution of 2,3-dihydro-benzofuran-5-carbaldehyde described in Preparation Example 174 (6.00 g, 40.5 mmol) in toluene (120 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (18.3 g, 81 mmol), and the solution was refluxed for 4 hours 30 minutes. The reaction solution was cooled to room temperature, water was added, the solution was extracted with ethyl acetate and tetrahydrofuran, and the organic layer was washed with brine. Anhydrous magnesium sulfate was added to the organic layer for drying, which was then filtered, the filtrate was concentrated in vacuo, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), and the title compound (1.24 g, 21%) was obtained as a pale yellow oil.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OCC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Reaction time: 2 h
Yield: 87.5 %

Procedure:
(Bromomethyl)cyclopentane was obtained by the following procedure. A solution of commercially available cyclopentanemethanol (20 g) in dry pyridine (220 ml) was stirred at 0° while 4-toluenesulfonyl chloride (42 g) was added. The mixture was stirred at 0° for two hours, and was then held without stirring at 4° overnight. It was then poured into water and the product was extracted into dichloromethane. The dichloromethane extract was washed with 10% (w/v) HCl solution, water, and brine in succession, and was then dried (MgSO4) and evaporated. There was thus obtained the desired intermediate compound, cyclopentylmethyl (4-methylphenyl)sulfonate (44.42 g, 87% yield) as a clear oil. Without further purification, this material was dissolved in dry DMF (175 ml). Lithium bromide (45.5 g) was then added with stirring. The mixture was heated to 45° for three hours, and then cooled to room temperature. The mixture was then diluted with pentane (800 ml), and washed with water (800 ml). The water layer was extracted with an additional portion of pentane (200 ml) and was discarded. The combined pentane layers were washed with water (1000 ml), and brine (200 ml) in succession, and then dried (MgSO4). The solvent was distilled away at atmospheric pressure, and the residue was then vacuum distilled. The desired (bromomethyl)cyclopentane (23.64 g, 83% yield) was obtained as a colorless mobile oil, distilling at 54°-55° at a pressure of 2000 Pascals (15 Torr).
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH:13]([CH3:18])[CH2:12]1)([O:8][CH2:9][CH3:10])=[O:7].C([BH3-])#[N:20].[Na+]>CO>[NH2:20][CH:14]1[CH2:15][CH2:16][N:11]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:12][CH:13]1[CH3:18]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)N1CCC(=O)C(C)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(N)C(C)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (5 g, 64.93 mmol) was added to the stirred solution of 1-carbethoxy-3-methyl-4-piperidone (1.4 g, 7.56 mmol) in methanol (25 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.5 g, 7.93 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-carbethoxy-3-methylpiperidine. Yield 1.0 g (72%), C9H18N2O2, m/z 187 (M+1), PMR (CDCl3): 0.94 (dd, 3H), 1.22 (m, 1H), 1.26 (t, 3H), 1.6 (m, 1H), 1.82 (m,1H), 2.4 (m,1H), 2.82 (m, 1H), 3.34 (m, 2H), 3.64 (m, 1H) 4.14 (q, 2H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:43])[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:18]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([NH:34]C(OC(C)(C)C)=O)[CH2:29]3)=[N:17][C:16]=2[N:15]([CH3:42])[C:13]1=[O:14])=[O:2].FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:43])[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:18]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]3)=[N:17][C:16]=2[N:15]([CH3:42])[C:13]1=[O:14])=[O:2]
Reactant: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1NC=O)c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=CCn1c(N2CCCC(N)C2)nc2c1c(=O)n(CC(=O)c1ccccc1NC=O)c(=O)n2C
Temperature: 25 °C

Procedure:
A solution of 180 mg of 1-[2-(2-formylaminophenyl)-2-oxoethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert-butyloxycarbonylamino)piperidin-1-yl]xanthine in 4 mL of methylene chloride is combined with 1 mL of trifluoroacetic acid and stirred for half an hour at ambient temperature. For working up, the reaction mixture is made slightly alkaline with 1 N sodium hydroxide solution and the aqueous phase is extracted with methylene chloride. The combined organic phases are evaporated down and purified through a silica gel column. Yield: 130 mg (87% of theory); Rf value: 0.38 (Ready-made reversed phase TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid (100:100:0.1)); mass spectrum (ESI+): m/z=494 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:17][N:18]=[N+]=[N-])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:17][NH2:18])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CCCCC[C@@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC[C@@H](C)C[C@H](CN)CC(=O)OC(C)(C)C
Yield: 71.3 %

Procedure:
A solution of compound 160 (1.86 g, 6.25 mmol) in THF (50 mL) was shaken over 5% Pd/C under hydrogen and pressure for 8 hours with three purges of hydrogen. The catalyst was filtered off and the filtrate evaporated. The crude material was chromatographed on silica eluting with methanol to give 161 as an oil (1.21 g, 71%). 1H NMR (400 MHz, CDCl3) δ 2.70 (dd, J=12.9, 4.40 Hz, 1H), 2.54 (dd, J=12.7, 6.59 Hz, 1H), 2.26 (dd, J=14.5, 6.96, 1H), 2.12 (dd, J=14.5, 6.47 Hz, 1H), 1.91 (m, 1H), 1.91 (m, 1H), 1.43 (s, 12H), 1.39–1.25 (m, 4H), 1.14–1.07 (m, 1H), 1.03–0.97 (m, 1H), 0.86–0.82 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](=O)[CH2:18][CH:19]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[CH2:33][CH2:32][C:31]3=NOC)[C:20](=[O:27])[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:42]1CCOCC1>CC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[O:27][C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:19]([C:28]3[CH:29]=[C:33]4[C:34](=[CH:35][CH:36]=3)[C:30](=[O:42])[CH2:31][CH2:32]4)[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCO1
Reactant: CON=C1CCc2ccc(C(CC(=O)C3CCCN(C(=O)OCc4ccccc4)C3)C(=O)c3ccncc3)cc21
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCc2cc(-c3cc(C4CCCN(C(=O)OCc5ccccc5)C4)oc3-c3ccncc3)ccc21
Temperature: 90 °C
Yield: 69 %

Procedure:
A solution of the product of Step 4 (4.0 g, 7.42 mmol) in 1,4-dioxane (100 ml) and acetone (250 ml) was treated with 5M hydrochloric acid (50 ml) and the mixture heated at 90° C. for 5 hours. After cooling to room temperature, the reaction was concentrated and re-dissolved in chloroform and saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried, concentrated in vacuo and purified by silica gel chromatography eluting with ethyl acetate/dichloromethane (4:6) to yield the title compound (2.50 g, 69%); MS(ES+) m/e 493 [M+H]+.
Reaction SMILES: [CH:1]1([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Na]>CO.Cl>[C:1]1([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC(=O)C1C=CCCCCCCCCC1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)C1=CCCCCCCCCCC1
Reaction time: 8 h
Yield: 90.3 %

Procedure:
Methyl 2-cyclododecene-1-carboxylate (7.75 g; 34.6 m. moles, 85% purity as shown by G.L.C.), was added to a solution of sodium (0.9 g; 39 m. moles) in methanol (50 ml) and the mixture was allowed to stand at 50° C. for 8 hours and then at room temperature for a further 16 hours. The reaction mixture was diluted with dilute hydrochloric acid, extracted four times with ether and the combined extracts washed with dilute sodium carbonate solution. The dried (MgSO4) extract was evaporated to give methyl 1-cyclododecene-1-carboxylate (7.0 g; 85% purity as shown by G.L.C.). This corresponds to a yield of 90%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][N:11]1[C:15]([CH3:16])=[C:14]([C:17](O)=[O:18])[C:13](=[O:20])[N:12]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.O>[F:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:17]([C:14]1[C:13](=[O:20])[N:12]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:11]([CH3:10])[C:15]=1[CH3:16])=[O:18]
Reactant: Nc1ccc(O)cc1F
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(O)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a suspension of 4-amino-3-fluorophenol (1.0 g, 7.87 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (2.19 g, 9.44 mmol) in CH2Cl2 (20 mL) were added EDCI (3.02 g, 15.7 mmol) and HOAT (0.21 g, 1.57 mmol). The reaction mixture was refluxed for 20 hours, and then cooled to rt. Water (10 mL) was added and the mixture stirred at rt overnight, then filtered and the filter cake was washed with water (5 mL), followed by purifying by a silica gel column chromatography (CH2Cl2/MeOH (v/v)=70/1) to give the title compound as a beige white solid (1.25 g, 46.6%).
Reaction SMILES: Br[CH:2]1[CH2:15][CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[C:3]1=O.Cl.[NH:18]1[CH:22]=[C:21]([CH2:23][C:24]([NH2:26])=[S:25])[N:20]=[CH:19]1>>[NH:18]1[CH:22]=[C:21]([CH2:23][C:24]2[S:25][C:2]3[CH2:15][CH2:14][C:13]4[C:12]5[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=5[CH:6]=[CH:5][C:4]=4[C:3]=3[N:26]=2)[N:20]=[CH:19]1
Reactant: O=C1c2ccc3ccccc3c2CCC1Br
Reactant: NC(=S)Cc1c[nH]cn1
Agent: Cl
Product: c1ccc2c3c(ccc2c1)-c1nc(Cc2c[nH]cn2)sc1CC3

Procedure:
Starting compounds: 2-bromo-1,2,3,4-tetrahydrophenanthren-1-one, 4-imidazolylthioacetamide hydrochloride
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:17]=1.[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[N:8][C:7]=2[C:17]=1[N+:20]([O-:22])=[O:21]
Reactant: COc1cc2nc(-c3ccncc3)sc2cc1OC
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc2sc(-c3ccncc3)nc2c([N+](=O)[O-])c1OC
Temperature: 0 °C

Procedure:
To a solution of 5,6-dimethoxy-2-pyridin-4-yl-benzothiazole (1.1 g) in sulfuric acid (10 ml) was added potassium nitrate (0.5 g). After 60 minutes in room temperature the mixture was poured into ice water and filtered. Recrystallization from acetone yielded the pure product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]([NH:17][C:13]1[CH:12]=[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[CH:16]=[CH:15][CH:14]=1)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1cccc(-c2cccc(N)c2)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2cccc(NC(=O)CNC(=O)OC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a mixture of 3′-amino-[1,1′-biphenyl]-3-carboxylic methyl ester (1.14 g) and N-(tert-butoxycarbonyl)glycine (0.879 g) in methylene chloride (20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.20 g). The mixture was stirred for 3 h at room temperature, then washed twice with 1 N aqueous HCl, twice with saturated aqueous sodium bicarbonate and once with brine. The mixture was dried over sodium sulfate, filtered and concentrated to give a foam. Purification by silica gel chromatography eluting with 7:3 hexane/ethyl acetate gave 1.6 g of the title compound as a colorless oil. Electrospray MS (positive ion): (M+Na) 407.0.
Reaction SMILES: [N:1]1([CH:10]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:11](OS(C)(=O)=O)[CH2:12]OC(=O)C2C=CC([N+]([O-])=O)=CC=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-:36].[Na+]>O1CCOCC1.O>[O:36]1[CH2:12][CH:11]1[CH:10]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CS(=O)(=O)OC(COC(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)n1ccc2ccccc21
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(C(C2CO2)n2ccc3ccccc32)cc1

Procedure:
A solution of (2RS,3RS)-4-nitro-benzoic acid-3-indol-1-yl-2-methanesulfonyloxy-3-phenyl-propyl ester in dioxane (30 mL) and a 2N aqueous solution of sodium hydroxide (15 mL) were stirred at room temperature for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with 5% aqueous sodium carbonate and water, dried over anhydrous sodium sulfate, filtered, and concentrated to give (1RS,2SR)-1-(oxiranyl-phenyl-methyl)-1H-indole as an oil. MS (ESI) m/z 250 ([M+H]+).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[CH2:22]([C:24]1[CH:25]=[CH:26][C:27]([OH:38])=[C:28]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])[CH:29]=1)[CH3:23]>>[C:30]([C:28]1[CH:29]=[C:24]([CH2:22][CH3:23])[CH:25]=[CH:26][C:27]=1[O:38][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=1)(=[O:31])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Reactant: CCc1ccc(O)c(C(=O)c2ccccc2)c1
Product: CCc1ccc(Oc2cccc(Oc3ccc(CCC(=O)O)c(C)c3)c2)c(C(=O)c2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with (5-ethyl-2-hydroxy-phenyl)-phenyl-methanone as in Example 18 to afford 0.220 g (50%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C31H28O5 481.2015, found 481.2032 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCCC1
Reactant: O=C1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCN1
Product: O=C(/C=C/c1cccc(Cl)c1)N1CCC(=O)N(CCN2CCCC2)CC1

Procedure:
In analogy to the procedure described in intermediate 4A, 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 3A]) and 1-(2-chloro-ethyl)-pyrrolidine gave the title compound as off-white powder. MS: 376.5 (MH+, Cl).
Reaction SMILES: [CH:1]([NH:3][NH2:4])=O.[N:5]([CH2:8][C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[C:6]=[S:7].C(O)C>N1C=CC=CC=1>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH2:8][N:5]1[CH:1]=[N:3][N:4]=[C:6]1[SH:7]
Reactant: NNC=O
Reactant: S=C=NCc1ccco1
Solvent: CCO
Solvent: c1ccncc1
Product: Sc1nncn1Cc1ccco1
Yield: 83.7 %

Procedure:
A solution of formic acid hydrazide (439 mg, 7.809 mmol) in pyridine (20 ml) was added to a solution of 2-isothiocyanatomethyl-furan (1 g, 7.185 mmol) in pyridine (20 ml). Reaction took place at room temperature overnight, and ethanol (20 ml) was added directly to the reaction and placed in 80 C bath overnight. Solvent was evaporated and the title compound (1.09 g, 83%) was obtained from purification by SPE chromatography on silica gel with 500 ml 20%, 250 ml 25%, 250 ml 30%, 250 ml 35%, 250 ml 40%, and 250 ml 50% ethyl acetate in hexanes. 1H NMR (CD3OD), δ (ppm): 14.0 (bs, 1H), 8.19 (s, 1H), 7.52 (q, 1H), 6.52 (m, 1H), 6.42 (m, 1H), 4.90 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.Cl.[CH3:16][C:17]1[C:18]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:19][C:20]([CH3:24])=[C:21]([CH3:23])[CH:22]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([C:18]3[C:17]([CH3:16])=[CH:22][C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=3)[CH2:26][CH2:27]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Agent: Cl
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)nc1C
Yield: 51.8 %

Procedure:
Using 4-bromo-2-methanesulfonylbenzoic acid (3.5 g) and 1-(3,5,6-trimethylpyridin-2-yl)piperazine hydrochloride (3 g) described in Preparation Example 91 and by the reaction and treatment in the same manner as in Preparation Example 119, the title compound (3 g) was obtained.