Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:17])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:17][C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:10][C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1sc(-c2ccccc2)nc1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2)sc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
A solution of 5.9 g (23.85 mmol) of 4-methyl-2-phenyl-thiazole-5-carboxylic acid ethyl ester in 30 ml of absolute THF was added to a suspension of 1.1 g (29 mmol) of lithium aluminium hydride in 20 ml of THF, under an argon atmosphere at 0-5° C. Afterwards, the mixture was stirred at ambient temperature for 1 hour. Then, a small amount of water was added cautiously, followed by 50 ml of ethyl acetate and 20 g of anhydrous sodium sulfate and stirring was continued for 0.5 hours. Then, the reaction mixture was filtered, the filtrate was evaporated, leaving 3.85 g (78.6% of theory) of (4-methyl-2-phenyl-thiazol-5-yl)-methanol as yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH:10]=[CH:14][N:15]([CH3:17])[CH3:16])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(C)c(C)c1
Product: Cc1ccc(C(=O)C=CN(C)C)cc1C

Procedure:
A mixture of 50 g. of 3',4'-dimethylacetophenone and 50 ml. of dimethylformamide dimethylacetal is refluxed for 16 hours. On cooling the desired compound crystallizes from the reaction mixture. After hexane is added, the desired compound is recovered by filtration, m.p. 108°-110° C.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[C:7]([CH3:18])([CH3:17])[CH2:6][C:5]1=[O:19])([CH3:3])[CH3:2]>CO>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([CH3:17])([CH3:18])[CH2:6][C:5]1=[O:19])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)CC(C)(C)c2cc([N+](=O)[O-])ccc21
Solvent: CO
Product: CC(C)N1C(=O)CC(C)(C)c2cc(N)ccc21
Reaction time: 5 h

Procedure:
N-Isopropyl 4,4,-dimethyl-2-oxo-6-nitroquinoline (Compound 40, 220 mg, 0.84 mmol) was dissolved in CH3OH (3 ml). The solution was cleansed by flushing with N2 gas, and thereafter a catalytic amount of 10% Pd/C was added. The resulting mixture was hydrogenated at room temperature for 5 hours. After evaporation of the solvent the title compound was obtained in quantitative yield as a light purple oil. (184.2 mg 94%) 1H NMR d 1.23 (s, 6H), 1.49 (d, J=7.0 Hz, 6H), 2.36 (s, 2H), 4.68 (q, J=7.0 Hz, 1H), 6.55 (dd, J1=2.8 Hz, J2 =8.6 Hz, 1H), 6.64 (d, J=2.6 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])[CH2:4][CH:5]([OH:16])[CH2:6][NH:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH3:2].C1(C)C=CC(S(O)(=O)=[O:31])=CC=1.ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Ca+2].[OH-]>C(O)C>[CH2:1]([N:3]([CH2:17][CH2:18][CH2:19][S:20]([CH2:21][CH2:22][CH3:23])=[O:31])[CH2:4][CH:5]([OH:16])[CH2:6][NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCSCCCN(CC)CC(O)CNc1ccc(C#N)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCO
Product: CCCS(=O)CCCN(CC)CC(O)CNc1ccc(C#N)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
A solution of 4-[[3-[ethyl[3-(propylthio)propyl]amino]-2-hydroxy-propyl]amino]-benzonitrile (2.0 g, 5.9 mmol) and toluene-4-sulfonic acid (2.3 g, 11.9 mmol) in ethanol (50 ml) was stirred 1/2 h at room temperature. The mixture was cooled to -10 ° C. and solid 3-chloroperbenzoic acid was added during 1/2 h. The solution was stirred for 1 h at room temperature. Solid calcium hydroxide (1.2 g, 16.4 mmol) was added, followed by stirring for 15 minutes. Filtration and evaporation gave an oily residue. Purification by column chromatography on silica gel yielded 1.0 g of the title compound.
Reaction SMILES: C(S[C:9]1[CH2:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:11]=2[N:10]=1)C1C=CC=CC=1.O.O.[NH2:29][NH2:30]>CO.O1CCCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:11]2[N:10]=[C:9]([NH:29][NH2:30])[CH2:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]=2[CH:22]=1
Reactant: NN
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCC(SCc1ccccc1)=N2
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 8 h

Procedure:
Thus obtained 2-benzylmercapto-7-chloro-5-phenyl-3H-1,4-benzodiazepine (4 parts) is dissolved in 100 parts by volume of a mixture of methanol and tetrahydrofuran (1:1) and 10 parts by volume of hydrazine hydrate is added thereto. After being left standing overnight at room temperature, the reaction mixture is poured into water and extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. Evaporation of the solvent affords 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine. Recrystallization from a mixture of chloroform and benzene gives colorless crystals. M.P. 203°-205° C (decomposition). Thus obtained product is identical with the product prepared in Examples 1 and 9.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[C:13]1(B(O)O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:21]3[C:22]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:18]=[CH:19][CH:20]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: OB(O)c1cccc2ccccc12
Reactant: CC1Cc2cccc(Cl)c2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1Cc2cccc(-c3cccc4ccccc34)c2C1=O
Temperature: 125 °C
Reaction time: 9 h
Yield: 89.9 %

Procedure:
2.5 g (13.8 mmol) of 7-chloro-2-methyl-1-indanone (1), 2.86 g (16.6 mmol) of naphthylboronic acid, 0.22 g (0.68 mmol) of tetrabutylammonium bromide and 3.66 g (34.6 mmol) of sodium carbonate were placed in 40 ml of o-xylene in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 1.55 mg (0.0069 mmol) of palladium acetate and 7.3 mg (0.027 mmol) of triphenylphosphine, the reaction mixture was stirred for 9 hours at 125° C. After addition of 40 ml of water, the phases were separated, the aqueous phase was extracted 3 times with 40 ml each time of ether, the combined organic phases were washed with 40 ml of water and 40 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 3.38 g of (16) as solid.
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11]O.P(Br)(Br)[Br:18].P([O-])([O-])[O-]>C1(C)C=CC=CC=1>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][Br:18]
Reactant: BrP(Br)Br
Reactant: OCc1ccc(F)c(Br)c1
Agent: [O-]P([O-])[O-]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Fc1ccc(CBr)cc1Br
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Pyridine (0.7 cm3) and a solution of 3-bromo-4-fluorobenzyl alcohol (5 g) in dry toluene (50 cm3) were added to a stirred solution of phosphorus tribromide (2.64 g) in dry toluene (50 cm3) under an atmosphere of nitrogen, the temperature of the reaction mixture being maintained at -10° C. during the addition. The mixture was allowed to warm to the ambient temperature (ca. 20° C.) and was stirred for one hour. The mixture was poured into ice and the products extracted into diethyl ether. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulphate to give an orange-red oil, shown by thin layer chromatography to contain two components. NMR spectroscopy of the mixture suggested the presence of a phosphite intermediate and the required product. The oil was redissolved in dry toluene (50 cm3) and further phosphorus tribromide (0.2 g) and pyridine (0.7 cm3) added. The mixture was stirred at 50° C. for 4 hours and then stood at the ambient temperature for 17 hours. The mixture was poured into ice and sodium bicarbonate solution added to neutralise the resulting acid mixture. The products were extracted into diethyl ether, and the combined organic extracts washed with brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent gave a white solid which was purified by flash column chromatography on a silica gel support, eluting with petroleum ether containing 5% by volume diethyl ether, to give the title compound (4.6 g) as a colourless crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:26])[N:13]([C:16](=[O:25])[C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=4)[C:14]=2[CH:15]=1)=[CH:10][C:9]([F:27])=[CH:8][CH:7]=3.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:26])[N:13]([C:16]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)=[O:25])[C:14]=2[CH:15]=1)=[CH:10][C:9]([F:27])=[CH:8][CH:7]=3
Reactant: COc1ccc(C(=O)N2c3cc(F)ccc3-c3ccc(F)cc3C2C)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2cc(F)ccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
4-[(3,8-Difluoro-6-methylphenanthridin-5(6H)-yl)carbonyl]phenol—A stirred suspension of 3,8-difluoro-5-(4-methoxybenzoyl)-6-methyl-5,6-dihydrophenanthridine (0.20 g, 0.55 mmol) and cyclohexene (1.64 g, 20.0 mmol) was treated at room temperature under nitrogen with a solution of 1.0 M boron tribromide in dichloromethane (4.0 mL, 4.0 mmol). After stirring for approximately two hours at room temperature, the reaction was cooled to −20° C. and quenched with methanol (5 mL). The solvent was evaporated in vacuo to a dark oil. The dark oil was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of between 5% and 30% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min to afford, after evaporation of the solvent in vacuo and trituration with diethyl ether-hexane, the title compound (0.19 g, 0.54 mmol, 99%) as a homogeneous, colorless, racemic solid, m.p. 193-195° C.; MS [(+ESI), m/z]: 352 [M+H]+; MS [(−ESI), m/z]: 350 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ: 1.21 (d, J=7.0 Hz, 3H), 5.71 (q, J=6.8 Hz, 1H), 6.55 (dd, J=10.5, 2.5 Hz, 1H), 6.70 (d, J=8.6 Hz, 2H), 7.06 (td, J=8.6, 2.6 Hz, 1H), 7.16 (d, J=8.6 Hz, 2H), 7.27 (td, J=8.8, 2.7 Hz, 1 H), 7.38 (dd, J=9.2, 2.7 Hz, 1H), 7.97 (dd, J=9.0, 6.4 Hz, 1H), 8.01 (dd, J=9.1, 6.0 Hz, 1H), 10.04 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CCOC(C)=O>[CH2:1]([NH:9][C:17](=[O:18])[O:19][CH2:20][CH3:21])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cl
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of phenethylamine (60.5 g, 0.5 mol) and Na2CO3 (63.6 g, 0.6 mol) in EtOAc/H 0 (800 mL, 4:1) was added ethyl chloroformate, dropwise, (65.1 g, 0.6 mol) at 0° C. during a period of 1 h. The mixture was warmed to RT and stirred for an additional 1 h. The organic phase was separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with H2O and brine, dried (Na2SO4), concentrated in vacuo and purified by flash chromatography to afford ethyl phenethylcarbamate (90.2 g). 1H NMR (400 MHz, CDCl3) δ 7.32-7.18 (m, 5H), 4.73 (brs, 1H), 4.14-4.08 (q, J=6.8 Hz, 2H), 3.44-3.43 (m, 2H), 2.83-2.79 (t, J=6.8 Hz, 2H), 1.26-1.21 (t, J=6.8 Hz, 3H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C-:22]#[N:23].[K+]>O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)#[N:23]
Reactant: [C-]#N
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(C#N)cc1
Temperature: 0 °C
Yield: 45.8 %

Procedure:
In the same manner as Example 18-(1), there was produced a solution containing the diazonium salt derived from 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (3.06 g). The solution was neutralized carefully with saturated aqueous sodium carbonate followed by addition of an ice-cooled solution of potassium cyanide (1.88 g) and cuprous cyanide (1.17 g) in water (12 ml). The mixture was stirred for an hour and the crystals which formed were recovered by filtration, washed with water, 1N aqueous sodium hydroxide, 1N hydrochloric acid and water in that order and dissolved in aqueous ethanol. The solution was treated with activated carbon and concentrated to dryness under reduced pressure. The residue was purified by silica gel (190 g) column chromatography [eluent: chloroform-methanol (20:1)] to give 6-(4-cyanophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.469 g).
Reaction SMILES: [NH2-].[Na+].Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:25])[CH:16]=1>O1CCCC1>[F:25][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[C:21]([F:22])([F:23])[F:24])[CH2:14][N:11]([C:8]1[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=1)[NH2:12]
Reactant: Fc1cc(CBr)ccc1C(F)(F)F
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NN(Cc1ccc(C(F)(F)F)c(F)c1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
A flask containing tetrahydrofuran (2.0 mL) was charged with sodium amide (152 mg, 3.69 mmol; Aldrich) and chilled to 0° C. (4-Fluorophenyl)hydrazine hydrochloride (400 mg, 3.17 mmol; Aldrich) was added in portions. After 5 minutes, the solid had completely dissolved and the ice bath was removed. Stirring was continued for 1 hour, then the solution was chilled again in an ice bath and 4-(bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene (598 mg, 2.33 mmol; Alfa Aesar) was added dropwise. After 30 minutes, the ice bath was removed and the reaction was heated to 50° C. overnight. The mixture was diluted with water (5 mL) and extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: LC/MS (DCI/NH3) m/z 250 (M+H−NH3)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])/[C:5](/[O:30][CH2:31][CH3:32])=[CH:6]/[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:9][C:8]=1[CH3:29])C.II.[Mg]>CO>[CH3:1][O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:9][C:8]=1[CH3:29]
Reactant: CCOC(=O)/C(=C/c1c(C)cc(OCCc2nc(-c3ccccc3)oc2C)cc1C)OCC
Agent: II
Agent: [Mg]
Solvent: CO
Product: CCOC(Cc1c(C)cc(OCCc2nc(-c3ccccc3)oc2C)cc1C)C(=O)OC
Reaction time: 3 h
Yield: 6.8 %

Procedure:
To a solution of 30 mg of 3-{2,6-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2Z-ethoxy-acrylic acid ethyl ester in 1.5 ml of methanol was subsequently added 1 mg of iodine and 17 mg of magnesium and stirring was continued for 3 h. A further portion of 67 mg of magnesium was added and stirring was continued for 1.5 h. The suspension was filtered, the filtrate evaporated and the residue separated on prep. HPLC (RP-18, CH3CN/H2O, gradient) to give 2 mg (7%) of the title compound as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([CH3:48])([CH3:47])[CH2:10][NH:11][C:12](=[O:46])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][Br:38])=[C:30]([Cl:39])[CH:29]=3)[N:23]=[C:22]([O:40][CH2:41][C:42]([F:45])([F:44])[F:43])[N:21]=2)=[CH:15][CH:14]=1)(C)(C)C.C(Cl)Cl.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>CCOC(C)=O>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[NH2:7][CH2:8][C:9]([CH3:48])([CH3:47])[CH2:10][NH:11][C:12](=[O:46])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][Br:38])=[C:30]([Cl:39])[CH:29]=3)[N:23]=[C:22]([O:40][CH2:41][C:42]([F:43])([F:44])[F:45])[N:21]=2)=[CH:15][CH:14]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CN)CNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a 100 mL round-bottom flask equipped with a stir bar and charged with tert-butyl(3-(4-((4-((4-(3-bromopropoxy)-3-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-2,2-dimethylpropyl)carbamate (1.655 g, 2.136 mmol) was added CH2Cl2 (5 mL), and then trifluoroacetic acid (2.50 mL, 32.4 mmol). The solution was stirred at room temperature for 2 h. The solution was transferred to a 250 mL separatory funnel and was diluted with EtOAc (75 mL). The solution was washed with sat. aq. NaHCO3 (75 mL). The aq. phase was extracted with EtOAc (2×75 mL). The combined organics were washed with sat. aq. NaCl (50 mL); dried over MgSO4; filtered; then concentrated in vacuo to afford N-(3-amino-2,2-dimethylpropyl)-4-((4-((4-(3-bromopropoxy)-3-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamide trifluoroacetic acid as a colorless solid (1.52 g, 100%). MS m/z=674.25 (M+1)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:6][CH2:5]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[NH:8][CH:7]([CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:6][CH2:5]4)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc2c(c1)CCC(CN1CCCC1)N2
Product: Clc1ccc(-c2ccc(C#Cc3ccc4c(c3)CCC(CN3CCCC3)N4)nc2)cc1

Procedure:
Prepared according to general working method I from 6-iodo-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline (260 mg, 0.76 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (162 mg, 0.76 mmol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: OCCc1ccccc1CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccccc1CCO
Temperature: 0 °C
Yield: 23 %

Procedure:
2-[2-(2-Hydroxy-ethyl)-phenyl]-ethanol (6.77 g/40 mmol) was dissolved in methylene chloride (100 mL) and cooled to 0° C. Triethylamine (11.0 mL/80 mmol) and methanesulfonyl chloride (5.25 mL/65 mmol) were added sequentially via addition funnel (dropwise). After an hour the reaction was poured into a separatory funnel and sequentially washed with 1 N hydrochloric acid (100 mL), water (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The resulting organic solution was dried over magnesium sulfate, filtered and concentrated. Column chromatography on silica gel (eluting with 0→10% methanol/methylene chloride afforded methanesulfonic acid 2-[2-(2-hydroxy-ethyl)-phenyl]-ethyl ester (2.25 g/23%). 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 4H), 4.42 (t, J=7.1 Hz, 2H), 3.88 (m, 2H), 3.15 (t, J=7.1 Hz, 2H), 2.93 (t, J=7.1 Hz, 2H), 2.85 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Cl)[CH3:2].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(CCl)OCC
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(CNCc1ccccc1)OCC
Reaction time: 8 h

Procedure:
A stirred mixture of chloroacetaldehyde diethyl acetal (50 g, 0.328 mol), and benzylamine (150.0 g, 1.4 mol) was heated at 130° for 3 h. The mixture was then left at ambient temperature overnight. Next day, water (150 ml) was added, and the resulting solution was basified with sodium hydroxide solution (25 ml, 10 M). The mixture was then extracted with ether (2×100 ml), and the extracts were combined and dried over magnesium sulphate. Evaporation of the ether under reduced pressure afforded a brown oil which was distilled to afford N-benzylaminoacetaldehyde diethyl acetal, b.p. 148°-150°/20 mmHg.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:29])=[C:4]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:8].[C:30]([O:33][CH:34]([CH3:38])[C:35](Cl)=[O:36])(=[O:32])[CH3:31]>CC(N(C)C)=O>[C:30]([O:33][CH:34]([CH3:38])[C:35]([NH:1][C:2]1[C:3]([I:29])=[C:4]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:8])=[O:36])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)C(=O)Cl
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Solvent: CC(=O)N(C)C
Product: CC(=O)OCc1c(I)c(NC(=O)C(C)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Yield: 99.2 %

Procedure:
5-Amino-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (3.20 g, 4.3 mmol) was dissolved in dry dimethylacetamide (4 ml). 2-Acetoxypropionyl chloride (2.17 ml, 17.2 mmol) was then added dropwise with efficient stirring. Stirring was continued over night. After work up according to the procedure in Example 24i, 3.66 g (100%) of product was isolated.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[H-].[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19].O>C1COCC1>[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:1][C:2]2[CH:15]=[CH:14][C:13]3[S:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]=3[CH:3]=2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Oc1ccc2c(c1)Nc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(COc2ccc3c(c2)Nc2ccccc2S3)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
1.08 g (5 mmol) of 2-hydroxy-10H-phenothiazine (J. Med. Chem. (1992) 35, 716) is dissolved, under argon atmosphere, in 20 ml anhydrous THF in a flask. The solution is then cooled down to 0° C. and 0.22 g (5.5 mmol) of NaH (60%) is added by portions. After agitation for 15 minutes, 1.2 g (5.5 mmol) of 4-nitrobenzyl bromide is added by portions and the reaction mixture is agitated for 15 hours at 20° C. before being poured into 50 ml of ice-cooled water. The product is extracted twice with 25 ml CH2Cl2 and the organic solution is washed successively with 25 ml of water and 25 ml of salt water. After drying over MgSO4, filtration and concentration under vacuum, the evaporation residue is purified on a silica column (eluent: CH2Cl2/EtOH: 99/1 to 98/2). After concentration of the purest fractions, a maroon solid is obtained, which is recrystallized using isopropyl acetate. A maroon solid is finally obtained with a yield of 37%.