Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])#[N:2].ClCCCl.S(=O)(=O)(O)O.[N+:32]([O-])([O-:34])=[O:33].[K+]>O>[C:1]([C:3]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][C:12]([N+:32]([O-:34])=[O:33])=[C:8]([CH:7]=1)[C:9]([OH:11])=[O:10])#[N:2]
Reactant: O=[N+]([O-])[O-]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Oc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCCl
Solvent: O
Product: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)O)c1
Temperature: 0 °C

Procedure:
The product from (a) (9.22 g) was added in portions to a mixture of 1,2-dichloroethane (25 ml) and concentrated sulphuric acid (40 ml) stirred at 0° C. Potassium nitrate (3.13 g) was then added in portions with stirring at 0° C., over a period of 15 minutes. The mixture was then stirred at 0° C. for 30 minutes, allowed to warm to room temperature, and poured into 200 ml of ice and water. The mixture was stirred until the ice had melted, and filtered with suction. The solid which separated on evaporation of the dichloroethane was washed with water and taken up in ether. The ether solution was treated with charcoal, dried and petroleum (b.p. 40°-60° C.) added. The solid which separated was identified as the required benzoic acid derivative (7.8 g) having a melting point of 190°-192° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH:5]=[CH2:6].[OH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1.[OH-].[K+].O.S([O-])(O)(=O)=O.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1CCCC1=O.O>[CH:5]([O:4][CH2:3][CH2:2][O:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)=[CH2:6]
Reactant: C=COCCCl
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Br-]
Solvent: O
Solvent: CN1CCCC1=O
Product: C=COCCOc1ccc(C(=O)O)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
76.97 g (722 mmol) of a chloroethylvinylether, 9.70 g (30.1 mmol) of a tetrabutylammoniumbromide, and 100.00 g (602 mmol) of ethyl 4-hydroxybenzoate, all manufactured by Tokyo Kasei Kogyo Co., Ltd. were mixed with an N-methylpyrrolidone solvent and stirred at a temperature of 120° C. for 3 hours so as to be reacted. The resulting solution was diluted with water and extracted with ethyl acetate so as to remove the solvent thereby obtaining a crude ethyl 4-(2-vinyloxyethoxy)benzoate. A solution of 43.69 g (662 mmol) of potassium hydroxide with 85% purity was added to the ester and reacted at a temperature of 100° C. for 6 hours to be hydrolyzed, followed by dilution and precipitation with a solution of 91.40 g (662 mmol) of sodium hydrogensulfate monohydrate thereby obtaining a crude crystal of 4-(vinyloxyethoxy)benzoic acid. The resulting crude crystal was dissolved in acetonitrile so as to be recrystallized thereby obtaining a needle-like crystal of 4-(vinyloxyethoxy)benzoic acid with an HPLC purity of 99.5 percent or higher. The yield was 104.0 g (83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13]([O-])=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.[K+].N1C=CC=CC=1.C(Cl)(=O)C([Cl:28])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13]([Cl:28])=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(Cn2nnnc2C(=O)[O-])cc1
Agent: [K+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nnnc2C(=O)Cl)cc1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
Potassium 1-(4-methoxybenzyl)-1H-tetrazole-5-carboxylate (10.0 g) and pyridine (1.8 ml) were stirred together in dry toluene (140 ml) at 10° C. Oxalyl chloride (30.7 ml) was added, and the mixture was stirred at 15° C. for 1 hour. The mixture was filtered and the residual solid was washed with dry toluene (100 ml). The filtrate and washings were combined and evaporated in vacuo to give crude 1-(4-methoxybenzyl)-1H-tetrazole-5-carbonyl chloride, which was used immediately in the next stage.
Reaction SMILES: O=[C:2]1[C:10]2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]([O:16]C)=[O:15].O.NN.[F:21][C:22]1[C:31]([CH:32]([C:34]2[N:38]3[N:39]=[C:40](C(=O)C)[CH:41]=[CH:42][C:37]3=[N:36][N:35]=2)[CH3:33])=[C:30]([F:46])[CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[N:27]2.Cl>CO>[F:21][C:22]1[C:31]([CH:32]([C:34]2[N:38]3[N:39]=[C:40](/[C:2](=[N:3]/[O:12][CH2:13][C:14]([OH:16])=[O:15])/[CH3:10])[CH:41]=[CH:42][C:37]3=[N:36][N:35]=2)[CH3:33])=[C:30]([F:46])[CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[N:27]2
Reactant: COC(=O)CON1C(=O)c2ccccc2C1=O
Reactant: CC(=O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: C/C(=N\OCC(=O)O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
Methyl 2-(1,3-dioxoisoindolin-2-yloxy)acetate (237 mg, 1.01 mmol) and hydrazine monohydrate (50 mg, 1.0 mmol) were dissolved in methanol (3 mL) and heated at 70° C. for 2 h. After filtration, the solid was washed with EtOAc. The combined solution was concentrated and the residue was diluted with methanol. A solution of NaOH (6 N, 3 mL) was added and the mixture was stirred at 70° C. for 2 h. The solution was concentrated, acidified with 3 N HCl to pH 1 and filtered. The solid was washed with water, and the combined solution was concentrated. The residue was diluted with DCM, then ketone 53.5 (40 mg, 0.113 mmol) and HCl (4 N HCl in dioxane, 0.7 mL) were added. It was stirred at rt for 24 h. After concentration, the residue was purified by prep-HPLC to give 21 mg (34%) of the title compound as white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.90 (s, 1H), 8.97 (d, 1H), 8.45 (d, 1H), 8.26 (d, 1H), 7.70 (d, 1H), 7.60 (d, 1H), 5.27 (q, 1H), 4.76 (s, 2H), 2.03 (d, 3H), 1.94 (s, 3H). LCMS (method B): [MH]+=427, tR=2.259 min. Chiral separation (method L) provided enantiomeric pure compounds example 68-R (tR=7.71 min) and example 68-S (tR=9.99 min).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:18][CH:19]=1)[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=3[CH3:11])=[O:8])[CH2:24][CH2:25]2)=[N:18][CH:19]=1)[CH3:13]
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C)c1
Yield: 59.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 6-fluoro-4-methylnicotinic acid (500 mg) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (649 mg) described in Preparation Example 53, the title compound (640 mg) was obtained.
Reaction SMILES: C1([O:7][C:8](=[O:18])[C:9]2[CH:17]=[CH:16][C:12]([C:13]([O-])=[O:14])=[CH:11][CH:10]=2)C=CC=CC=1.[NH3:19]>>[C:13]([NH2:19])(=[O:14])[C:12]1[CH:16]=[CH:17][C:9]([C:8]([OH:7])=[O:18])=[CH:10][CH:11]=1
Reactant: O=C([O-])c1ccc(C(=O)Oc2ccccc2)cc1
Reactant: N
Product: NC(=O)c1ccc(C(=O)O)cc1
Yield: 99 %

Procedure:
6.0 grams (0.025 mols) of monophenylterephthalate were brought together with 26.2 grams of liquid ammonia for reaction under the same conditions specified in Example 10. After working up the product as in all of the preceding examples, there were obtained 4.1 grams (99% of theory) of terephthalic acid monoamide.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:25]=[C:24]4[C:20]([N:21]=[CH:22][NH:23]4)=[C:19]([N:26]4[CH2:31][CH2:30][CH2:29][CH:28]([C:32](O)=[O:33])[CH2:27]4)[N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1C=CC2N(O)N=[N:41]C=2C=1.C(Cl)CCl.N>CN(C=O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:25]=[C:24]4[C:20]([N:21]=[CH:22][NH:23]4)=[C:19]([N:26]4[CH2:31][CH2:30][CH2:29][CH:28]([C:32]([NH2:41])=[O:33])[CH2:27]4)[N:18]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCCC(C(=O)O)C4)c4nc[nH]c4n3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCCC(C(N)=O)C4)c4nc[nH]c4n3)cc2)CC1
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
To a solution of 1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-9H-purin-6-yl)piperidine-3-carboxylic acid (40 mg, 0.086 mmol) and HOBt (30 mg, 0.196 mmol) in DMF (2 mL), EDC (35 mg, 0.183 mmol) was added. After being stirred for 90 min, NH3 (0.5 M in dioxane, 1.00 mL, 0.500 mmol) was added. The mixture was stirred for 2 h. More EDC (52 mg, 0.271 mmol) was added. It was stirred for another 20 h. The mixture was then purified by HPLC to give the titled compound (30 mg). MS 464.3 (M+H); UV 204.8, 273.8 nm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[F:12][C:13]([F:22])([F:21])[C:14]([OH:20])([CH3:19])[CH2:15][C:16]([NH2:18])=O>>[NH2:18][CH2:16][CH2:15][C:14]([CH3:19])([OH:20])[C:13]([F:22])([F:21])[F:12]
Reactant: CC(O)(CC(N)=O)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)(CCN)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.8 %

Procedure:
A 1.0M solution of lithium aluminium hydride in tetrahydrofuran (30 ml, 30.0 mmol) was added dropwise to a solution of 4,4,4,-trifluoro-3-hydroxy-3-methyl butyramide (1.77 g, 10 mmol). The reaction was stirred at room temperature for 20 h, then quenched with water (1.2 ml), then 4M aqueous sodium hydroxide (1.2 ml), then water (3.6 ml). The inorganic salts were filtered off and the filtrate evaporated to dryness to yield 4-amino-1,1,1-trifluoro-2-methylbutan-2-ol (1.27 g, 81%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Br.[NH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1.O>[OH-].[Na+].ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:11][C:12]1[C:17]([O:18][CH2:4][C:3]2[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:10])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: Nc1ncccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Nc1ncccc1OCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
A mixture of 2,6-dichlorobenzyl bromide (50 g, 0.209 mol) and 2-amino-3hydroxypyridine (20.9 g, 0.19 mol) in 40% aqueous sodium hydroxide solution (200 ml) and dichloromethane (200 ml) was treated with Adogen 464 (5 ml) and stirred vigorously at room temperature for 16 hours. A further 200 ml of water was added and the product extracted into dichloromethane, dried, and the solvent evaporated to yield a solid (43.1 g, 76%), m.p. 141°-142° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)[CH2:3][NH:4][C:5]1[S:6][C:7]([C:10]2[CH:15]=[C:14](F)[C:13]([N+:17]([O-])=O)=[CH:12][C:11]=2[F:20])=[N:8][N:9]=1.FC1C=C([N+]([O-])=O)C(F)=C[C:34]=1[C:43](O)=[O:44]>>[NH2:1][C@@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=1)[CH2:3][NH:4][C:5]1[S:6][C:7]([C:10]2[CH:15]=[C:14]3[C:13](=[CH:12][C:11]=2[F:20])[NH:17][C:43](=[O:44])[CH2:34]3)=[N:8][N:9]=1
Reactant: O=C(O)c1cc(F)c([N+](=O)[O-])cc1F
Reactant: N[C@H](CNc1nnc(-c2cc(F)c([N+](=O)[O-])cc2F)s1)Cc1ccc(C(F)(F)F)cc1
Product: N[C@H](CNc1nnc(-c2cc3c(cc2F)NC(=O)C3)s1)Cc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared according to the procedure described for Example 2 starting with N—((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(2,5-difluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-amine, which was prepared in a similar manner as shown in Scheme 1 with 2,5-difluoro-4-nitrobenzenecarboxylic acid as the starting material. 2,5-Difluoro-4-nitrobenzenecarboxylic acid was purchased from Ryan Scientific Inc. LCMS (API-ES) m/z (%): 452.5 (100%, M++H); 1H NMR (400 MHz, CD3OD): δ ppm 3.13-3.26 (m, 2H), 3.62-3.71 (m, 3H), 3.78-3.84 (m, 1H), 3.85-4.10 (m, 1H), 3.99 (d, J=2.35 Hz, 4H), 6.83-6.89 (m, 1H), 7.61 (d, J=8.02 Hz, 2H), 7.75 (d, J=8.02 Hz, 2H), 7.99 (d, J=6.85 Hz, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([NH:9][C:10](=[O:21])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19]O)[CH2:14][CH2:13]2)=[C:7]([S:22][CH3:23])[CH:6]=[C:5]([CH3:24])[N:4]=1.[CH2:25]([O:32][C:33]1[CH:42]=[CH:41][C:36]2[N:37]=[C:38]([SH:40])[NH:39][C:35]=2[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:25]([O:32][C:33]1[CH:42]=[CH:41][C:36]2[N:37]=[C:38]([S:40][CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][N:12]([CH2:11][C:10]([NH:9][C:8]4[C:3]([S:2][CH3:1])=[N:4][C:5]([CH3:24])=[CH:6][C:7]=4[S:22][CH3:23])=[O:21])[CH2:13][CH2:14]3)[NH:39][C:35]=2[CH:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Reactant: Sc1nc2ccc(OCc3ccccc3)cc2[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccc(OCc4ccccc4)cc3[nH]2)CC1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
Under argon, N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide (1.00 g, 2.70 mmol), 5-benzyloxy-2-mercaptobenzimidazole (2.57 g, 10.0 mmol), and triphenylphosphine (2.50 g, 9.53 mmol) were dissolved in N,N-dimethylformamide (30 mL). To the solution, under cooling with ice, diethyl azodicarboxylate (1.27 mL, 8.07 mmol) was added dropwise, followed by stirring for one hour at the same temperature. Ethyl acetate and 1 mol/L hydrochloric acid were added to the reaction mixture. The aqueous layer was separated from the mixture, and the organic layer was further extracted with 1 mol/L hydrochloric acid. The obtained aqueous layers were combined and adjusted to basic conditions with a 1 mol/L aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was removed under reduced pressure. The thus-obtained residue was purified through silica gel column chromatography (chloroform : saturated ammonia-methanol=20:1), to thereby yield 1.56 g of 2-[4-[2-(5-benzyloxybenzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide as a colorless amorphous product (yield 94.9%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9]O)[CH:2]=1.[BrH:11]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][Br:11])[CH:2]=1
Reactant: OCCCc1cccnc1
Reactant: Br
Product: BrCCCc1cccnc1

Procedure:
To 17.0 g (124 mmoles) of 3-(3-pyridyl)-1-propanol was added 240 mL of 48% hydrobromic acid. The mixture was heated under reflux for 4 hours, and then evaporated to dryness to afford the hydrobromide salt of 3-(3-pyridyl)-1-bromopropane as an oil in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])C=O)=[CH:4][C:3]=1[F:12].C1(C)C=CC=CC=1.[CH:20]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])OCC.C(=O)(O)[O-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH:20]([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])=[CH:4][C:3]=1[F:12]
Reactant: CCOC(OCC)OCC
Reactant: O=CC(=O)c1ccc(Br)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(OCC)C(=O)c1ccc(Br)c(F)c1
Temperature: 110 °C
Reaction time: 6 h
Yield: 92.1 %

Procedure:
A 22 L flask was charged with the hydrate of (4-bromo-3-fluorophenyl)-2-oxoacetaldehyde (5, 1020 g, 4.41 mol), toluene (7.5 L), triethyl orthoformate (1633 g, 1.8 L, 11.04 mol, 2.5 equiv), para-toluene sulfonic acid (33.5 g, 0.176 mol, 0.4 equiv) at room temperature, and the resulting reaction mixture was heated to 110° C. and stirred at 110° C. for 6 h. When HPLC showed that the reaction was complete, the reaction mixture was cooled down to room temperature before being poured into a 50 L separation funnel along with ethyl acetate (7.5 L) and the saturated aqueous sodium bicarbonate solution (NaHCO3, 3 L). The mixture was stirred and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 L). The combined organic layers were washed with brine (4 L), dried with sodium sulfate (Na2SO4), and concentrated under the reduced pressure to afford crude 1-(4-bromo-3-fluorophenyl)-2,2-diethoxyethanone (6, 1240 g, 1345.7 g theoretical, 92.1% yield) which was used in the subsequent reaction without further purification. For 6: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94-7.94 (m, 2H), 7.78 (dd, 1H, J=8.51, 2.08 Hz), 5.40 (s, 1H), 3.77-3.60 (m, 4H), 1.16-1.14 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25]([CH3:28])[C:24]=2[CH:29]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[CH:22][C:23]3[O:27][CH:26]=[C:25]([CH3:28])[C:24]=3[CH:29]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Cc1coc2ccc(N)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2occ(C)c2c1
Reaction time: 0.08 h
Yield: 87.7 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (128 mg, 0.571 mmol) in dichloromethane (3 mL) was added pyridine (110 μL, 1.36 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-3-methyl-benzofuran (80 mg, 0.54 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (8 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a yellow solid (159 mg, 87%), single spot at Rf 0.65 (2:1 hexane:ethyl acetate). mp 119.5-120.1° C., HPLC purity 99% (tR 2.22 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.82 (1H, d, J=7.9 Hz), 7.54 (1H, d, J=7.9 Hz), 7.38 (1H s), 7.28-7.22 (2H, m), 7.15 (1H, t, J=8.0 Hz), 6.83 (1H, dd, J=8.7, 2.2 Hz), 6.56 (1H, s, N—H, 2.72 (3H, s), 2.15 (3H, s). LCMS: 334.07 (M−). FAB-MS (MH+, C16H14ClNO3S): calcd 335.0383, found 335.0383.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[C:4]([N+:32]([O-])=O)[CH:3]=1.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:32])[C:5]([NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)=[CH:6][C:7]=1[Cl:8]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [Ni]
Solvent: CO
Product: Nc1cc(Cl)c(Cl)cc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 8 parts of N-(4,5-dichloro-2-nitrophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine and 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst if filtered off and the filtrate is evaporated, yielding 4,5-dichloro-N1 -{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,2-benzenediamine as an oily residue.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[CH3:15])C.C(OC(=O)COC1C=CC=CC=1CCCOC)C.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)=[N:41][CH:42]=1>>[Cl:49][C:46]1[CH:45]=[CH:44][C:43]([C:40]2[N:41]=[CH:42][C:37]([CH2:36][N:13]([CH3:14])[C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:16])=[C:8]([CH3:15])[CH:9]=3)=[CH:38][CH:39]=2)=[CH:48][CH:47]=1
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)nc1
Reactant: CCOC(=O)COc1ccc(NC)cc1C
Agent: CCOC(=O)COc1ccccc1CCCOC
Product: Cc1cc(N(C)Cc2ccc(-c3ccc(Cl)cc3)nc2)ccc1OCC(=O)O

Procedure:
A] The title compound was prepared in analogy to example 4, but using in step C] (2-methyl-4-methylamino-phenoxy)-acetic acid ethyl ester (prepared in analogy to example 5F])instead of [2-(3-methoxy-propyl)-phenoxy]-acetic acid ethyl ester and 5-chloromethyl-2-(4-chloro-phenyl)-pyridine instead of [rac]-3-(1-chloro-butyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine, as off-white crystals of mp. 174–76° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:36])[C@@H:10]([NH:23][C:24](=[O:35])[CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.[C:44]1([C:50](Cl)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[C:31]([O:30][C:28]([NH:27][CH2:26][CH2:25][C:24]([NH:23][C@H:10]([C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:50]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:36])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:35])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the crude product of tert-butyl (5S)-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-5-{[3-(tert-butoxycarbonylamino)propionyl]amino}-6-oxohexylcarbamate and triethylamine (0.50 g) in chloroform (30 ml) was added triphenylmethyl chloride (1.37 g), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give tert-butyl (5S)-5-{[3-(tert-butoxycarbonylamino)propionyl]amino}-6-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-6-oxohexylcarbamate (1.62 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][NH2:16]>O1CCCC1>[CH3:15][NH:16][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CN
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC)nc1NC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.5 mmol) and 29% methylamine (5.75 g, 53.72 mmol, methanol (MeOH) solution) in tetrahydrofuran (THF) (100 mL) was stirred at room temperature for 2 hours. The reaction mixture was then concentrated, followed by the addition of sodium bicarbonate (NaHCO3) (aq., 20 mL), and the resulting solution was extracted with ethyl acetate (EtOAc) (3×50 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to afford ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (4.68 g, 96%) as a yellowish solid. MS (ES+) C9H13N3O2S requires: 227. found: 228 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:18]
Reactant: CCO
Reactant: O=C(O)CCc1ccc(O)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
To an ice-cooled solution of 3-(p-hydroxyphenyl)-propionic acid (8.3 g, 50.0 mmol) in ethanol (100 mL) was dropwise added thionyl chloride (3.7 mL, 50.7 mmol). The mixture was stirred at room temperature over night, concentrated in vacuo and the residue purified by kugelrohr distillation, to give 9.6 g (99%) of 3-(4-hydroxy-phenyl)-propionic acid ethyl ester as a colourless oil.