Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:18]([O:22][C:23]([C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:26](O)=[O:27])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:18]([O:22][C:23]([C@@H:25]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:26]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:27])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)c1cc(N)cc(-c2ccncc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)[C@H](Cc2ccccc2)C(=O)OC(C)(C)C)cc(-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To a solution of methyl 3-amino-5-(pyridin-4-yl)benzoate 45.1.C (4.70 g, 20.6 mmol) in DMF (50 mL) was added (S)-2-(tert-butoxycarbonyl)-3-phenylpropanoic acid (6.56 g, 24.7 mmol, available from Aldrich), diisopropylethylamine (5.40 mL, 30.9 mmol) and 2-(1H-Benzotriazole-1-yl)-1,1,3,3-Tetramethyluronium hexafluorophosphate (9.36 g, 24.7 mmol). The resulting mixture is stirred overnight at room temperature. The mixture was then partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with additional EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (0-100% EtOAc/hexane) to afford (S)-methyl 3-(2-(tert-butoxycarbonyl)-3-phenylpropanamido)-5-(pyridin-4-yl)benzoate 45.1.D (3.00 g, 31% yield).
Reaction SMILES: [CH:1](=[N:8]/[CH2:9][CH2:10][CH:11]=[CH2:12])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)Cl>CCO>[CH2:1]([NH:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC/N=C/c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: C=CCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of (E)-N-benzylidenebut-3-en-1-amine (1.298 gm, 8.15 mmol) in EtOH (25 mL) cooled to 0° C. was added NaBH4 (0.324 g, 8.56 mmol) portionwise over 40 min. After addition, the reaction mixture was stirred at rt for 3 hr. The reaction mixture was filtered and the filtrate was concentrated to give a white semi-solid residue. To the residue 50 mL of DCM was added. The resulting milky solution was stirred for 15 min and then was filtered. The obtained clear filtrate was concentrated to give N-benzylbut-3-en-1-amine (1.30 g, 6.85 mmol, 84% yield) as a pale yellow oil. Anal. Calcd. for C11H15N m/z 161.2. found: 162.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.42-7.21 (m, 5H), 5.79 (ddt, J=17.1, 10.2, 6.9 Hz, 1H), 5.13-4.99 (m, 2H), 3.80 (d, J=6.8 Hz, 2H), 3.29 (q, J=6.8 Hz, 1H), 2.71 (q, J=6.9 Hz, 1H), 2.29 (q, J=6.8 Hz, 1H), 1.25 (dt, J=9.1, 7.1 Hz, 1H), 1.12-1.03 (m, 1H).
Reaction SMILES: O.[N+:2]([C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7])([O-:4])=[O:3].[Br:15]Br.N>C(O)(=O)C>[Br:15][C:8]1[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=1[NH2:7]
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: BrBr
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of H2O (3.75 L) and acetic acid (375 mL) at RT was added 2,4-dinitroaniline (500 g, 2.73 mol) followed by drop wise addition of bromine (210 mL, 4.09 mol) over 30 min. The reaction mixture was stirred at RT for 15 min and then heated to 100° C. for 2 h. The reaction was cooled to RT and poured onto ice-cold H2O (5-6 L) and basified (pH 8-10) with aqueous ammonia. The solid was filtered, washed with cold H2O and dried under vacuum. This solid was washed with n-pentane to obtain i (600 g, 84%).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([O:8][CH:9]2[C:14]3[C:15]([OH:42])=[C:16]4[C:27](=[O:28])[C:26]5[C:21](=[C:22]6[O:35][CH:34]7[O:36][C:30]([CH3:41])([CH:31]([OH:40])[CH:32]([NH:38][CH3:39])[CH:33]7[OH:37])[C:23]6=[CH:24][C:25]=5[OH:29])[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[CH:12]([C:43]([O:45][CH3:46])=[O:44])[C:11]([OH:48])([CH3:47])[CH2:10]2)[CH:5]([O:49][CH3:50])[C:4]([O:52][CH3:53])([CH3:51])[CH:3]1[O:54][CH3:55].[C:56](OC(=O)C)(=[O:58])[CH3:57]>CO>[CH3:1][CH:2]1[O:7][CH:6]([O:8][CH:9]2[C:14]3[C:15]([OH:42])=[C:16]4[C:27](=[O:28])[C:26]5[C:21](=[C:22]6[O:35][CH:34]7[O:36][C:30]([CH3:41])([CH:31]([OH:40])[CH:32]([N:38]([C:56]([CH3:57])=[O:58])[CH3:39])[CH:33]7[OH:37])[C:23]6=[CH:24][C:25]=5[OH:29])[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[CH:12]([C:43]([O:45][CH3:46])=[O:44])[C:11]([OH:48])([CH3:47])[CH2:10]2)[CH:5]([O:49][CH3:50])[C:4]([O:52][CH3:53])([CH3:51])[CH:3]1[O:54][CH3:55]
Reactant: CC(=O)OC(C)=O
Reactant: CNC1C(O)C2Oc3c(cc(O)c4c3C(=O)c3cc5c(c(O)c3C4=O)C(OC3OC(C)C(OC)C(C)(OC)C3OC)CC(C)(O)C5C(=O)OC)C(C)(O2)C1O
Solvent: CO
Product: COC(=O)C1c2cc3c(c(O)c2C(OC2OC(C)C(OC)C(C)(OC)C2OC)CC1(C)O)C(=O)c1c(O)cc2c(c1C3=O)OC1OC2(C)C(O)C(N(C)C(C)=O)C1O
Reaction time: 4 h

Procedure:
Eight hundred mg of N-demethylnogalamycin is dissolved in a mixture of 10 ml of methanol and 2 ml of acetic anhydride. After the solution has stood at room temperature for 4 hours, it is evaporated to dryness under reduced pressure. The residue is chromatographed on 90 g of silica gel using chloroform-methanol (19:1) and collecting 201 five-ml fractions. Fractions 100-201 are combined and evaporated to dryness in vacuo to give 470 mg of N-acetyl-N-demethylnogalamycin; homogenous by TLC, Rf 0.38 in CHCl3 --CH3OH (9:1); [α]D +485°; (c 0.286, CHCl3); UV (EtOH) 236 nm (ε38,400), 258 nm (ε19,200), 290sh nm (ε12,800); IR (Nujol) 3380, 1715, 1705, 1650, 1615, 1585, 1285, 1215, 1135, 1100, 1045, 1025, 1000, 915, 875, 820, 750 cm-1 ; 1H NMR (CDCl3) δ1.1-1.7 (m, 12H), 2.10 (s, 3H), 3.20 (s, 3H), 3.25, 3.53, 3.62, 3.68 (4s, 12H), 2.8-4.62 (m), 5.22, 5.55, 5.88 (3 broad s, 3H), 7.26 (s, 1H), 7.52 (s, 1H), 13C NMR (CDCl3) δ191.1, 179.8, 174.7, 171.6, 161.6, 155.8, 146.9, 143.8, 136.5, 133.5, 130.4, 125.2, 116.1, 114.2, 113.9, 100.7, 95.62, 84.3, 81.0, 77.8, 75.7, 74.0, 71.5, 69.4, 67.3, 61.1, 59.2, 58.7, 56.8, 52.2, 48.5, 40.0, 32.2, 29.4, 23.6, 22.4, 18.0, 14.6; mass spectrum m/e 815.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:40]#[N:41])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C:32]3([CH3:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:39])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:40]#[N:41])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C:32]3([CH3:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:39])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CC2(C)CCOCC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Product: COc1cn(C(CC2(C)CCOCC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
69.0 mg (119 μmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-methyltetrahydro-2H-pyran-4-yl)propanoyl}amino)benzoate (racemate) in 4.3 ml of ethanol/water (3/1) were reacted with 198 mg (609 μmol) of caesium carbonate according to General Method 4, giving the title compound after preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 38 mg (57% of theory)
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9][C:8]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:7]1=2)[CH3:2].O.NN>CO.[Ni]>[CH2:19]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9][C:8]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:7]1=2)[CH3:20]
Reactant: CCN(CC)CCN1CCSc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CCN(CC)CCN1CCSc2cc(N)ccc21
Temperature: 25 °C
Yield: 107.2 %

Procedure:
To a stirred solution of N,N-diethyl-2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanamine (1.109 g, 3.76 mmol) in MeOH (30 mL) was added Raney-Nickel (slurry in water; ˜0.1 g, 3.76 mmol) followed by hydrazine hydrate (1.828 mL, 37.6 mmol). The mixture was immersed in a preheated oil bath and refluxed for 30 minutes. The solution was cooled to room temperature, filtered through Celite, and washed with MeOH. The crude material was filtered through a silica plug (3.5% (2M NH3 in MeOH):CH2Cl2). The solvent was evaporated to give the product as dark brown oil (1.07 g, quantitative). 1H NMR (CDCl3) δ 6.58 (d, J=8.7 Hz, 1H), 6.45 (d, J=2.7 Hz, 1H), 6.40 (dd, J=2.7, 8.7 Hz, 1H), 3.53-3.50 (m, 2H), 3.30 (m, 4H), 3.03-2.99 (m, 2H), 1.03 (t, J=7.2 Hz, 6H); ESI-MS (m/z, %): 268, 266 (MH+, 100), 100 (52).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH3:9][S:10][S:11](C)(=O)=O>O.C(O)C>[CH3:9][S:10][S:11][N:2]([CH3:1])[C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5]
Reactant: CN[C@@H](CS)C(=O)O
Reactant: CSS(C)(=O)=O
Solvent: O
Solvent: CCO
Product: CSSN(C)[C@@H](CS)C(=O)O
Reaction time: 2 h
Yield: 60 %

Procedure:
A solution of N-methylcysteine (Undhein, K., & Eidem, A., 23 Acta Chem. Scandinavica 3129-3133 (1970) (1.5 g, 11.1 mmol) in H2O (20 ml) was stirred at room temperature, under an atmosphere of argon, and treated with a solution of methyl methanethiol sulfonate (3.0 ml, 29.2 mmol) in ethanol (10 ml). The reaction mixture was stirred at this temperature for two hours and then diluted with H2O (100 ml) and washed with ether (4×40 ml). The aqueous layer was acidified to pH 2 and passed through an Amberlite IRA 93 (--OH form) column. The column was washed with water and the effluent was collected and evaporated to dryness under reduced pressure to give a white solid (1.2g, 60%), mp 194°-5° C. NMR (D2O, TMS ext. standard): δ2.2(3H, s), 2.5(3H, s), 3.2(2H,d), 3.7(1H,q).
Reaction SMILES: [CH:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>>[CH:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-isopropyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20]C(=O)C)=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:18])[CH2:19][OH:20])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4]([NH:26][CH2:27][CH:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:3]=1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of acetic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (0.2 g, 0.35 mmol) in MeOH (10 ml) is added potassium carbonate (0.098 g, 0.7 mmol) and the reaction mixture is stirred at room temperature for 1 hour. The solvent is removed in vacuo and the solvent is partitioned between DCM and water. The organic portion is separated, dried (MgSO4) and concentrated in vacuo to afford the title product.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:32]=[CH:31][C:23]3[N:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:26][C:22]=3[CH:21]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:11]=[C:9]1[NH:8][C:7]2[C:2]([C:20]3[CH:32]=[CH:31][C:23]4[N:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:26][C:22]=4[CH:21]=3)=[CH:3][CH:4]=[CH:5][C:6]=2[S:10]1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: O=c1[nH]c2c(Br)cccc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(=O)Nc1nc2ccc(-c3cccc4sc(=O)[nH]c34)cc2s1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
4-Bromobenzo[d]thiazol-2(3H)-one (69.9 mg, 0.304 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (124.9 mg, 3.925 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (39.7 mg, 56.6 μmol), and sodium carbonate (0.30 mL, 2.0 M in water, 0.60 mmol) were suspended in 1,2-dimethoxyethane (1.4 mL) and ethanol (0.39 mL). The reaction flask was fit with a reflux condensor and the solution was heated in a preheated oil bath (85° C.) and stirred under nitrogen for 7 hours, at which time the reaction was slowly allowed to cool to RT. After sitting at RT for 4 days, more PdCl2(PPh3)2 (37.3 mg) was added, and stirring was resumed at 85° C. for 4 hours. Then, the reaction was cooled to RT and filtered through a silica gel plug with 10:1 DCM/MeOH. The filtrate was concentrated and purified on HPLC (10-95% MeCN/water with 0.1% TFA over 40 minutes) to provide N-(6-(2-oxo-2,3-dihydrobenzo[d]thiazol-4-yl)benzo[d]thiazol-2-yl)acetamide. MS (ESI pos. ion) m/z: 342 (MH+). Calculated exact mass for C16H11N3O2S2: 341.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38]>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:4]3[CH:3]=[C:2]([NH:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[C:31]([F:30])([F:39])[F:40])[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:28])([CH3:29])[CH3:27]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccccc4C(F)(F)F)cc3n2C(=O)OC(C)(C)C)cn1
Yield: 88 %

Procedure:
The title compound was prepared in 88% yield from compound (10) and 2-trifluoromethyl phenylamine using the method described for Preparation 35. 1H-NMR (CDCl3, 500 MHz): δ 1.49 (s, 9H), 1.69 (s, 9H), 6.61 (d, J=0.95 Hz, 1H), 6.82 (br s, 1H, NH), 7.12 (t, J=7.57 Hz, 1H), 7.51 (t, J=8.20 Hz, 1H), 7.61 (m, 1H), 7.65 (d, J=7.57 Hz, 1H), 7.83 (d, J=0.63 Hz, 1H), 7.89 (d, J=8.20 Hz, 1H), 8.22 (d, J=0.95 Hz, 1H), 8.50 (d, 0.95 Hz, 1H). 19F-NMR (CDCl3): δ −61.43.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1[CH:14]=[O:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[C:19]([CH3:25])[CH:18]=1.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1[CH:14]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=1[CH3:25])[OH:15]
Reactant: Cc1cc(Cl)ccc1[Mg]Br
Reactant: Cn1nc(-c2ccccn2)c(C=O)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1C(O)c1c(-c2ccccn2)nn(C)c1Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazole-4-carbaldehyde (16.38 g, 73.9 mmol) in THF (350 mL) was cooled to about −40 to −50° C. then 0.5 M (4-chloro-2-methylphenyl)magnesium bromide in THF (163 mL, 81 mmol) was added dropwise over about 15 min. The mixture was allowed to warm to rt then cooled in an ice bath. Saturated aqueous NH4Cl (400 mL) was added then the mixture was extracted with EtOAc (2×300 mL). The organic layer was washed by brine (400 mL), dried over Na2SO4, filtered and concentrated in vacuo to give (5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)(4-chloro-2-methylphenyl)methanol (25.7 g, 100%): LC-MS (Table 1, Method g) Rt=2.49 min, m/z 348/350 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 8.56 (d, J=5.0 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.96-7.90 (m, 1H), 7.40-7.36 (m, 1H), 7.22-7.16 (m, 3H), 7.09-7.05 (m, 1H), 6.23 (d, J=7.8 Hz, 1H), 3.87 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH3:35])[CH:9]([CH3:23])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=O)[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[Cl:46])[C:40](Cl)=[O:41].P([O-])([O-])([O-])=O>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH3:35])[CH:9]([CH3:23])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]#[N:22])[CH:19]=1)[N:16]([C:40](=[O:41])[C:39]1[CH:43]=[CH:44][C:45]([Cl:46])=[C:37]([Cl:36])[CH:38]=1)[CH2:15][CH2:14]2)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)NCC2
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: O=P([O-])([O-])[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc(C#N)c2c(c1)CCN2C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.5 %

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide (97 mg) in methylene chloride (1 ml) and pyridine (1 ml) was added 3,4-dichlorobenzoyl chloride (84 mg), and the mixture was stirred at room temperature for 20 hours. The pH of the reaction mixture was adjusted to pH 7 with phosphate buffer solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and ethyl acetate (4/1) as eluent to give 98 mg of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]-1-(3,4-dichlorobenzoyl)indoline-7-carbonitrile as an oil.
Reaction SMILES: S(=O)(=O)(O)[OH:2].CN(C=N[C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22]C)=[O:21])=[N:15][CH:16]=1)C>O>[OH:2][C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([OH:22])=[O:21])=[N:15][CH:16]=1
Reactant: COC(=O)c1cccc(-c2ncc(N=CN(C)C)cn2)c1
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cccc(-c2ncc(O)cn2)c1
Temperature: 25 °C

Procedure:
160 ml (2.88 mol) of concentrated sulfuric acid are added to a suspension of 103.5 g (364 mmol) of methyl 3-[5-(dimethylaminomethyleneamino)-pyrimidin-2-yl]benzoate in 1.3 l of water, and the mixture is heated at the boil for 4 hours. The reaction mixture is cooled to room temperature, diluted with water and filtered with suction. The residue is washed with water and dried in vacuo: 3-(5-hydroxypyrimidin-2-yl)benzoic acid as brownish crystals; m.p. 293-295° C.; ESI 217 (M+H); HPLC: Rt=3.25 min (method C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=[C:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1.[C:28](Cl)(=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O.[OH-].[NH4+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=[C:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1
Reactant: CCCCCCCC(=O)Cl
Reactant: COc1ccc2c(c1)C(N1CCN(CCCO)CC1)=Cc1ccccc1S2
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCC(=O)OCCCN1CCN(C2=Cc3ccccc3Sc3ccc(OC)cc32)CC1
Reaction time: 48 h

Procedure:
To a solution of 10.0 grams of 8-methoxy-10-[4-(3-hydroxypropyl)piperazino]dibenzo[b,f]thiepin in 50 milliliters of benzene was added 9.1 grams of caprylyl chloride (octanoyl chloride) and the mixture was allowed to stand for 48 hours. Thereafter 150 milliliters of water and 20 milliliters of concentrated aqueous ammonium hydroxide solution was added thereto and the resulting mixture was shaken with benzene. The benzene extract was separated form the aqueous solution, filtered, and the filtrate was washed with water, dried over anhydrous potassium carbonate, and the benzene was evaporated therefrom. The residue was dissolved in 30 milliliters of acetone and to this solution was added a solution of 2.9 grams of maleic acid in 10 milliliters of acetone.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[N:3]=1.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[NH2:1][C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:27]3[CH:28]=[CH:29][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:25][CH:26]=3)[CH:8]=2)[N:3]=1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: Nc1nc(NC2CCCCC2)c2cc(Br)ccc2n1
Product: CC(=O)Nc1ccc(-c2ccc3nc(N)nc(NC4CCCCC4)c3c2)cc1
Yield: 95 %

Procedure:
This compound was synthesized from the product of example 20 and 4-acetamidophenyl-boronic acid, in 95% yield, using the procedure described for example 7, and was characterized by its mass spectrum as follows: MS (m/z): 376 ([M+H]+, 100).
Reaction SMILES: [CH3:1][Mg]I.[C:4]1([C:10]23[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:18][CH:12]([C:13]4=[O:20])[CH2:11]2)[CH2:17]3)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCOCC.C1COCC1>[CH3:1][C:13]1([OH:20])[CH:12]2[CH2:18][CH:16]3[CH2:17][C:10]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)([CH2:19][CH:14]1[CH2:15]3)[CH2:11]2
Reactant: C[Mg]I
Reactant: O=C1C2CC3CC1CC(c1ccccc1)(C3)C2
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)C2CC3CC1CC(c1ccccc1)(C3)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Freshly prepared methylmagnesium iodide in ether (1 M, 85 mL), was added through a canola to 5-phenyladamantan-2-one (9.6 g, 42.5 mmol) obtained in step II, in THF (85 mL) at 0° C. After stirring at 0° C. for 0.5 h, the reaction mixture was quenched by adding sat. aq. NH4Cl solution. The organic layer was separated and the aqueous layer was extracted with diisopropylether. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to obtain 2-methyl-5-phenyl-adamantan-2-ol (9.9 g) as an off-white solid in 97% yield. M.R: 98-100.4° C. m/z (M+23) 265; 1H NMR (CDCl3) 300 MHz δ 7.42-7.28 (m, 4H), 7.24-7.18 (m, 1H), 2.47-2.26 (m, 2H), 2.14-2.09 (m, 3H), 1.96-1.70 (m, 6H), 1.61-1.57 (m, 2H), 1.42 (s, 3H). 13C NMR (CDCl3) 75 MHz δ 150.0, 128.1 (2C), 125.7, 124.8 (2C), 73.3, 44.0 (2C), 40.5 (2C), 39.6 (2C), 35.9, 32.0, 27.6.