Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[Cl:26])=[CH:14][CH:15]=2)[C:10]([NH:27][C:28](=[O:55])[C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:31][C:30]=2[N:42]([CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)C(=O)C(F)(F)F)=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[Cl:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][N:9]=[C:10]2[NH:27][C:28](=[O:55])[C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]2)=[CH:31][C:30]=1[NH:42][CH:49]1[CH2:50][CH2:51][O:52][CH2:53][CH2:54]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4ccc(OCc5cc(F)ccc5Cl)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(OCc5cc(F)ccc5Cl)cc34)c(NC3CCOCC3)c2)CC1
Yield: 53.1 %

Procedure:
5-(2-Chloro-5-fluoro-benzyloxy)-3-{4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoylamino}-indazole-1-carboxylic acid tert-butyl ester (100 mg, 0.1269 mmol) in DCM (1.3 mL) was treated at room temperature with TFA (0.195 mL, 2.538 mmol). After 2 hours the volatiles were evaporated and the residue was treated with MeOH (3 mL) and TEA (0.357 mL, 2.538 mmol) and refluxed for three hours. After evaporation of the volatile components the crude was diluted with DCM (25 mL), washed with water, aqueous NaHCO3, water and finally brine, dried over sodium sulfate, evaporated and purified by flash chromatography over silica gel (eluent: DCM:7N NH3 in MeOH 93:7) to give 40 mg of title compound.
Reaction SMILES: C([O:4][CH:5]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[C:20]([CH2:32][OH:33])[CH:19]=1)[CH2:6][NH:7][C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][N:11]1[CH:15]=[N:14][N:13]=[CH:12]1)(=O)C.[H][H]>[Pd].CO>[CH3:17][C:8]([NH:7][CH2:6][CH:5]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:32][OH:33])[CH:19]=1)[OH:4])([CH3:16])[CH2:9][CH2:10][N:11]1[CH:15]=[N:14][N:13]=[CH:12]1
Reactant: [H][H]
Reactant: CC(=O)OC(CNC(C)(C)CCn1cnnc1)c1ccc(OCc2ccccc2)c(CO)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(CCn1cnnc1)NCC(O)c1ccc(O)c(CO)c1

Procedure:
5 g of 1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-(1,1-dimethyl-3-[1,2,4]triazol-4-yl-propylamino)-ethanol acetate are hydrogenated with 0.5 g of palladium on charcoal (5%) in 100 mL methanol. After the theoretically calculated amount of hydrogen has been taken up the catalyst is filtered off and the filtrate is evaporated down. The residue is dissolved in 10 mL ethanol and seeded. Then the product that crystallises out is suction filtered and washed. Yield: 3.2 g (74%, acetate); m.p.=125-127° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][CH2:11][C:12]([O:14]C)=O)[CH3:9])=[CH:4][CH:3]=1.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17].FC(F)(F)C(O)=O>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([N:10]2[CH2:11][C:12](=[O:14])[N:18]([CH2:16][CH3:17])[C:19]2=[O:20])[CH3:9])=[CH:6][CH:7]=1
Reactant: COC(=O)CN[C@H](C)c1ccc(Br)cc1
Reactant: CCN=C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCN1C(=O)CN([C@H](C)c2ccc(Br)cc2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(R)-Methyl 2-(1-(4-bromophenyl)ethylamino)acetate (6G3) (0.845 mmol, 230 mg) was dissolved in DCM (10 ml) and ethyl isocyanate (6C4) (1.690 mmol, 120 mg) added. The mixture was stirred at room temperature for 3 hours, then concentrated and re-dissolved in DCM (5 ml) and trifluoroacetic acid (0.845 mmol, 96 mg) added. Stirring was continued for 1 h and the reaction diluted with DCM (15 ml) and water (20 ml) and the organic phase separated using a hydrophobic fritted tube. Concentration afforded (R)-1-(1-(4-bromophenyl)ethyl)-3-ethylimidazolidine-2,4-dione (6G4) which was used without further purification; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, 2H) 7.18 (d, 2H) 5.43 (q, 1H) 3.76 (d, 1H) 3.56 (q, 2H) 3.46 (d, 1H) 1.57 (d, 3H) 1.22 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[C:11]4[CH:17]=[CH:18][CH:19]=[CH:20][C:10]4=[CH:9][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([OH:21])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]1[S:30][CH:29]1[CH2:31]Cl>CC(C)=O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[C:11]4[CH:17]=[CH:18][CH:19]=[CH:20][C:10]4=[CH:9][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([O:21][CH2:31][CH:29]2[CH2:28][S:30]2)[CH:3]=1
Reactant: O=c1c2cc3ccccc3cc2oc2cc(O)cc(O)c12
Reactant: ClCC1CS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c2cc3ccccc3cc2oc2cc(OCC3CS3)cc(O)c12
Temperature: 57.5 °C
Yield: 20.8 %

Procedure:
1,3-dihydroxy-12H-benzo[b]xanthen-12-one (0.05 g, 0.18 mmol) synthesized in Step 1 of Example 18, K2CO3 (0.07 g, 0.54 mmol), and anhydrous acetone (18 mL) were charged to a dry round-bottom flask. Under stirring, epithiochlorohydrin (0.07 g, 0.72 mmol) dissolved in anhydrous acetone (2 mL) was added thereto. The reaction liquid was stirred with reflux at a temperature of 55 to 60° C. under a nitrogen atmosphere (overnight). Solid of the reaction mixture was filtered and removed, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:3 (v/v)) to give the title compound (13.1 mg, 20.8%) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[C@H:10]([N:24]([CH3:38])[C:25](=[O:37])[CH:26]=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-])=O)[CH:29]=3)[CH2:9][CH2:8][C@@:7]4([OH:39])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[C@H:10]([N:24]([CH3:38])[C:25](=[O:37])[CH:26]=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=3)[CH2:9][CH2:8][C@@:7]4([OH:39])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:2][CH2:3]1
Reactant: CN(C(=O)C=Cc1cccc([N+](=O)[O-])c1)[C@@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C(=O)C=Cc1cccc(N)c1)[C@@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 70 °C
Reaction time: 2 h

Procedure:
360 mg of the 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(N-methyl-3-nitrocinnamamido)morphinan 78 and 1.07 g of stannous chloride dihydrate were dissolved in 7.5 ml of ethanol followed by heating to 70° C. and stirring for 2 hours. After cooling the reaction mixture to room temperature, 2 N aqueous sodium hydroxide was added while cooling with ice to neutralize followed by extraction with dichloromethane. The organic layers were combined and washed with saturated brine followed by drying and concentration. Inorganic substances were removed by chromatographic filtration [silica gel; chloroform:methanol (9:1)]. The resulting unpurified target compound was converted to a 2 hydrochloride to obtain 310 mg. ##STR66##
Reaction SMILES: CC(C)[N:3]=C=NC(C)C.[CH3:10][C:11]1[C:16]([NH:17][C:18]([C:20]2[S:24][C:23]([NH:25][C:26]3[CH:27]=[C:28]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][OH:41])[CH2:35][CH2:34]4)[N:29]=[C:30]([CH3:32])[N:31]=3)=[N:22][CH:21]=2)=[O:19])=[C:15]([Cl:42])[CH:14]=[CH:13][CH:12]=1.[NH:43](C(OC(C)(C)C)=O)[C@H:44]([C:48]([OH:50])=O)[CH:45]([CH3:47])[CH3:46].C1(C)C=CC(S([O-])(=O)=O)=CC=1.CN(C)C1C=C[NH+]=CC=1>C(Cl)Cl.CN(C=O)C>[CH3:10][C:11]1[C:16]([NH:17][C:18]([C:20]2[S:24][C:23]([NH:25][C:26]3[CH:27]=[C:28]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][OH:41])[CH2:35][CH2:34]4)[N:29]=[C:30]([CH3:32])[N:31]=3)=[N:22][CH:21]=2)=[O:19])=[C:15]([Cl:42])[CH:14]=[CH:13][CH:12]=1.[NH2:43][C@H:44]([C:48]([NH2:3])=[O:50])[CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)N=C=NC(C)C
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1cc[nH+]cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cc1nc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)cc(N2CCN(CCO)CC2)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@H](N)C(N)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
DIC (302 mg, 2.4 mmol) was added with stirring to a DMF (4 mL) solution of dasatinib (196 mg, 0.4 mmol), Boc-Val-OH (104 mg, 0.48 mmol), and DPTS (124 mg, 0.4 mmol). The resulting mixture was stirred at room temperature for five hours. After this period, DCM (100 mL) was added to the reaction mixture which was allowed to stir for an additional 20 minutes. The mixture was transferred into a separatory funnel and washed with 5% NaCl (100 mL×3). The organic phase was dried over Na2SO4 and the solvent removed under reduced pressure. The resulting residue was purified by column chromatography (biotage: DCM/CH3OH, CH3OH, 5-10%, 20 CV). The obtained solid was redissolved in 5.0 mL of TFA/DCM (2:3) and the solution was stirred at room temperature for one hour. TFA and DCM were removed under reduced pressure. The residue was dissolved in 150 mL of DCM and the resulting solution was washed with 5% Na2CO3 and then 5% NaCl. The desired product was obtained (160 mg, yield: 68%) as a white solid; 1H NMR (500 MHz, CD3OD). δ 0.96 (d, 3H), 0.99 (d, 3H), 2.03 (m, 1H), 2.32 (s, 3H), 2.47 (s, 3H), 2.59 (t, 4H), 2.71 (t, 2H), 3.64 (t, 4H), 4.32 (m, 2H), 6.00 (s, 1H), 7.22 (m, 2H), 7.34 (d, 1H), 8.14 (s, 1H); LC-MS (m/z) calcd., 586.2. Found 587.2 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[CH:10]=2)[CH2:4][CH2:3]1.[N:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][C:29](N)=[O:30])=[O:27])=[CH:22][CH:21]=1.N1C=CC=CC=1.C>O.C(Cl)(Cl)Cl>[F:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:29]([NH:28][C:26]([C:23]3[CH:22]=[CH:21][N:20]=[CH:25][CH:24]=3)=[O:27])=[O:30])[CH2:3][CH2:4]1)[CH:18]=[CH:17]2
Reactant: NC(=O)NC(=O)c1ccncc1
Reactant: NC1CCN(Cc2ccc3cc(F)ccc3c2)CC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC(=O)c1ccncc1)NC1CCN(Cc2ccc3cc(F)ccc3c2)CC1

Procedure:
A mixture of 4-amino-1-[(6-fluoro-2-naphthalenyl)methyl]piperidine (1.3 g, 5 mmol), 4-pyridoylurea (0.9 g, 5 mmol) and pyridine (6 ml) was stirred at reflux for 16 hours. The solution was diluted with water (8 ml) and the precipitated dark brown product collected by filtration to give 1.5 g. The crude product was dissolved in chloroform (25 ml), shaken with decolourising charcoal, filtered and evaporated. The residue was suspended in hot ethanol (20 ml) and succinic acid (0.44 g) added to give a clear solution which crystallised on standing. The product crystals were collected by filtration and washed with ethanol to give the succinate salt of the title compound. m.p. 187°-188° C.
Reaction SMILES: [CH2:1]([N:4]([CH3:20])[CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14][CH2:13]2)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([S:37]([C:34]1[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=1)(=[O:39])=[O:38])[CH2:15][CH2:14][CH2:13]2)[CH3:20])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CC=CCOc1ccc2c(c1)CCCN2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN(C)CC=CCOc1ccc2c(c1)CCCN2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To 54 mg (0.2 mmol) Allyl-methyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-but-2-enyl]-amine in 2 ml CH2Cl2 3 drops of Huenig's base and 527 mg (0.25 mmol) 4-chlorobenzene sulfonylchloride were added. The solution was stirred at RT for 2 h, concentrated and purified by column chromatography on silica gel with CH2Cl2/MeOH 19:1 to yield 70 mg (78%) Allyl-{4-[1-(4-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yloxy]-but-2-enyl}-methyl-amine as yellow oil, MS: 447 (MH+, 1Cl).
Reaction SMILES: [C:1]1(=[O:11])[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][CH2:6]3)[CH2:3][O:2]1.CO>C1(C)C=CC=CC=1.[Cl-].[Na+]>[OH:11][CH:1]1[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][CH2:6]3)[CH2:3][O:2]1
Reactant: O=C1OCC2C3CCC(C3)C12
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: OC1OCC2C3CCC(C3)C12
Reaction time: 6 h
Yield: 97.6 %

Procedure:
30.4 g (0.2 mole) of hexahydro-4,7-methano-iso-benzofuran-1(3H)-one are introduced into 800 ml of absolute toluene, under an inert gas, and 84.8 ml (0.3 mole) of sodium bis-(2-methoxy-ethoxy)-dihydridoaluminate (70% strength solution in toluene), diluted with 200 ml of absolute toluene, are allowed to run in at -70° to -78° C. The mixture is stirred at -70° to -78° C. for 6 hours. Thereafter, 580 ml of 50% strength aqueous methanol are added dropwise at -70° C. and the mixture is subsequently stirred at 20° C. for 15 minutes and diluted with 400 ml of saturated aqueous sodium chloride solution. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution and dried over sodium sulphate and the solvent is evaporated off in vacuo. 30.1 g (98% yield) of 1-hydroxyoctahydro-4,7-methano-iso-benzofuran are obtained in this manner.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:23]O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1.C(O)C.O>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]([NH2:23])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccc(Br)cc2[nH]1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: NC1c2ccccc2-c2c(-c3nc4ccc(Br)cc4[nH]3)cccc21
Temperature: 25 °C
Yield: 18.3 %

Procedure:
Stir, at ambient temperature, a mixture of 390 mg of 4-(6-bromo-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z, E) in a mixture of 2 ml of acetic acid, 2 ml of ethanol and 2 ml of water in the presence of 65 mg of powdered zinc. After half an hour, add a further 65 mg of powdered zinc and maintain the stirring for approximately 3 hours. Add Celite, filter over sintered glass and wash the precipitate with 200 ml of a mixture of methanol and dichloromethane (20/80 by volume). Evaporate the filtrate to dryness under vacuum, add twice 50 ml of toluene and, each time, re-evaporate to dryness under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of dichloromethane and a 7N solution of ammonia in methanol (90/10 by volume). In this way, we obtain 69 mg of 4-(6-bromo-1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-amine, in the form of a beige foam with the following characteristics:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[C:28](B(O)O)[CH:29]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:26]4[CH:25]=[C:24]([Cl:23])[CH:29]=[CH:28][C:27]=4[O:33][CH3:34])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: COc1ccc(Cl)cc1B(O)O
Product: COc1ccc(Cl)cc1-c1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Yield: 66 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (5-chloro-2-methoxyphenyl)boronic acid (0.365 g, 1.96 mmol generally according to the procedure described for Intermediate 184 provided 0.382 g (66%) of (±)-[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:4).
Reaction SMILES: Br[C:2]1[C:8]([I:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:10].C1(O)C=CC=CC=1.I.[H][H]>>[Cl:10][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([I:9])[CH:2]=1)[NH2:6]
Reactant: Nc1cc(Cl)c(Br)c(I)c1
Reactant: [H][H]
Agent: I
Solvent: Oc1ccccc1
Product: Nc1cc(Cl)cc(I)c1
Yield: 90 %

Procedure:
55.5 parts of 4-bromo-3-chloro-5-iodoaniline, 250 parts of phenol, 8 parts of hydroiodic acid (57% strength) and 15 parts of ruthenium-on-charcoal catalyst (5% strength) are reacted with hydrogen under a pressure of 23 to 47 bars and at 145° C., during the course of 2 hours, whilst stirring. After the usual working up, 38 parts of 3-chloro-5-iodo-aniline are obtained. Yield: 90% of theory.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:21][C:22]2[C:23]([N+:28]([O-:30])=[O:29])=N[CH:25]=[CH:26][CH:27]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCC1C=CC=[C:35]([C:39]([F:42])([F:41])[F:40])C=1[N+]([O-])=O.BrCC1C([N+]([O-])=O)=NC=CC=1>>[C:8]1([C:7](=[N:14][CH:15]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:35]([C:39]([F:42])([F:41])[F:40])[C:23]=2[N+:28]([O-:30])=[O:29])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1c(CBr)cccc1C(F)(F)F
Reactant: CCOC(=O)C(Cc1cccnc1[N+](=O)[O-])N=C(c1ccccc1)c1ccccc1
Agent: O=[N+]([O-])c1ncccc1CBr
Product: CCOC(=O)C(Cc1cccc(C(F)(F)F)c1[N+](=O)[O-])N=C(c1ccccc1)c1ccccc1

Procedure:
Ethyl 2-(diphenylmethyleneamino)-3-[2-nitro-3-(trifluoromethyl)phenyl]propanoate (18) Ethyl 2-(diphenylmethyleneamino)-3-[2-nitro-3-(trifluoromethyl)phenyl]propanoate (18) was prepared according to the general procedure for the synthesis of ethyl 2-(diphenylmethyleneamino)-3-(2-nitropyridin-3-yl)propanoate (5) in Example 1, except that 1-(bromomethyl)-2-nitro-3-(trifluoromethyl)benzene (17) from the previous step was used in place of 3-(bromomethyl)-2-nitropyridine (3) (Yield: 3.2 g, 28% over 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][C:36]([C:38]1[C:39]2[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=2[S:41][CH:42]=1)=[O:37].C(N(CC)CC)C>CN(C=O)C.O>[S:41]1[CH:42]=[C:38]([C:36](=[O:37])[CH2:35][NH:34][C:12]([C:10]2[S:11][C:7]3[C:6]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:14])[C:39]2[CH:46]=[CH:45][CH:44]=[CH:43][C:40]1=2
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Reactant: NCC(=O)c1csc2ccccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3csc4ccccc34)nc12
Reaction time: 48 h
Yield: 44.1 %

Procedure:
0.30 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 0.19 g 1,1′-carbonyl-diimidazole in 6 ml DMF were stirred at room temperature for 4 hours. 0.26 g 2-amino-1-benzo[b]thiophen-3-yl-ethanone hydrochloride and 0.–16 ml triethylamine were added and stirring was continued for two days at room temperature. 100 ml water was added and the mixture was extracted with ethylacetate. The precipitate was filtered to yield 0.21 g (44%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-benzo[b]thiophen-3-yl-2-oxo-ethyl)-amide as a yellow solid; M.p.: 256–258° C.; MS (ISP): m/e=468 (M+H+).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][C@H:8]([C:13]([O:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[CH:29]=[C:28]([F:30])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[C@H:19]([OH:31])[C@@H:18]1[OH:32])=[O:14])[C@H:9]([CH2:11][CH3:12])[CH3:10])=[O:6])[CH3:4].[CH2:33]([O:40][C:41]([NH:43][C@H:44]([C:52](O)=[O:53])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C.C(N(CC)C=O)C>CN(C)C=O>[CH2:33]([O:40][C:41]([NH:43][C@H:44]([C:52]([NH:2][C@H:3]([C:5]([NH:7][C@H:8]([C:13]([O:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[CH:29]=[C:28]([F:30])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[C@H:19]([OH:31])[C@@H:18]1[OH:32])=[O:14])[C@H:9]([CH2:11][CH3:12])[CH3:10])=[O:6])[CH3:4])=[O:53])[CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:42])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)N)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCN(C=O)CC
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reaction time: 17 h
Yield: 35 %

Procedure:
0.46 Gram of 5'-O-(N-alanylisoleucyl)-5-fluorouridine hydrochloride obtained in Example 4 was dissolved in dimethylformamide (20 ml), and 1.51 g (5.30 mmol) of N-benzyloxycarbonylphenylalanine and 1.10 g (6.74 mmol) of diethylphosphoryl cyanide were then added. To this solution was added dropwise under ice-cooling a solution of 2.40 g (23.8 mmol) of triethylamine in diethylformamide (3 mmol), and the reaction liquid was kept for 17 hours at -20° C. and then concentrated under reduced pressure. The residue was dissolved in chloroform (200 ml) and the solution was washed with a 3% aqueous solution of potassium hydrogen carbonate (100 ml). The aqueous layer was further extracted with chloroform (100 ml). These organic layers were dried (over Na2SO4) and then concentrated under reduced pressure, and the residue was subjected to separation/purification by way of silica gel column chromatography (first time: a linear gradient of chloroform containing 3%→6% methanol; second time: a linear gradient of chloroform containing 3%→6% methanol) whereby 1.25 g (35%) of 5'-O-[N-{(N-benzyloxycarbonylphenylalanyl)alanyl}isoleucyl]-5-fluorouridine was obtained as a colorless powdery solid.
Reaction SMILES: O.CO[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([CH:12]=[O:13])=[O:11].[CH3:14][CH:15]([NH2:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1.[CH3:28]S(C)=O>>[CH3:14][CH:15]([N:27]=[C:12]([O:13][CH3:28])[C:10]([C:5]1[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:11])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1
Reactant: COc1ccccc1C(=O)C=O
Reactant: CS(C)=O
Reactant: COc1ccc(CC(C)N)cc1OC
Solvent: O
Product: COC(=NC(C)Cc1ccc(OC)c(OC)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.9 g of 2-methoxyphenylglyoxal hydrate (crude oil) are dissolved in 15 ml of dimethylsulfoxide, and 5.25 g of α-methyl-3,4-dimethoxyphenethylamine are added thereto. The mixture is stirred at room temperature for 30 minutes, whereby a solution of α-(α-methyl-3,4-dimethoxyphenethylimino)-2-methoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([OH:11])[C:5]=1[N+:12]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.O.C(OCC)(=O)C.Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([OH:11])[C:5]=1[NH2:12]
Reactant: COC(=O)c1ccc(Br)c(O)c1[N+](=O)[O-]
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)c(O)c1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of 4-bromo-3-hydroxy-2-nitro-benzoic acid methyl ester (Example 6.2) (3.13 g) in tetrahydrofuran (40 ml) was added a solution of sodium dithionite (10.23 g) in water (40 ml). The reaction mixture was stirred at 60° C. for 2 hours. Then the reaction was diluted with ethyl acetate (80 ml) and aqueous hydrochloric acid (1M) (30 ml) and the mixture vigorously shaken. The phases were separated and the aqueous phase was extracted with ethyl acetate (60 ml). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to give 2-amino-4-bromo-3-hydroxy-benzoic acid methyl ester (2.46 g). 1H-NMR (400 MHz, CDCl3): 7.35 (d, 1H), 6.72 (d, 1H), 6.05 (s, 1H), 5.47 (s, 1H), 3.87 (s, 3H) ppm.