Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[OH:10].C(O)(=O)C.Cl>O>[C:21]1([C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)([C:5]2[NH:4][CH:8]=[CH:7][N:6]=2)[OH:10])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCn1ccnc1C(O)(c1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: OC(c1ccccc1)(c1ccc(C(F)(F)F)cc1)c1ncc[nH]1

Procedure:
A mixture of 9 g. (0.025 mol) of 1-(methoxymethyl)-α-phenyl-α-(p-trifluoromethyl-phenyl)imidazole-2-methanol, 70 ml. of glacial acetic acid, 7 ml. of concentrated hydrochloric acid and 7 ml. of water was refluxed for 3.5 hours. After cooling, the liquid was distilled off and 2 N sodium hydroxide solution and a small amount of ethanol were added to the residue. The alcohol was distilled off and the aqueous phase was extracted with diethyl ether. The ethereal solution was washed with water and dried over sodium sulphate and the solvent was distilled off. The residue was first crystallised from a mixture of toluene and petroleum ether (boiling range 40°-60° C.) and subsequently from isopropyl alcohol. α-Phenyl-α-(p-trifluoromethylphenyl)imidazole-2-methanol was obtained. Melting point 174°-175.5° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:37])([F:36])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])=[CH:24][CH:23]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]([F:36])([F:19])[F:37])=[CH:27][CH:26]=3)=[O:34])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccc(OC(F)(F)F)cc1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3ccc(OC(F)(F)F)cc3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(4-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=1.04 min; [M+H]+=461.10.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N:8]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)=[C:6]([N+:22]([O-])=O)[CH:5]=[N:4]1)[CH3:2].[C:25]([O:29][C:30]([NH:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[F:45][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]([F:44])[C:38]=1[C:36]1[S:37][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:34]([C:46](=[O:47])[NH:22][C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=2[N:8]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)[N:35]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CCn1ncc([N+](=O)[O-])c1N1CCC[C@H](NC(=O)C(F)(F)F)CC1
Product: CCn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@H](NC(=O)C(F)(F)F)CC1
Yield: 66 %

Procedure:
Following the procedure for Example 517 starting with (S)-N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid gave (S)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (151 mg, 66%). 1H-NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.75 (s, 1H), 7.95 (s, 1H), 7.45-7.34 (m, 1H), 7.12-7.02 (m, 2H), 6.37 (d, J=8 Hz, 1H), 4.23-4.16 (m, 1H), 4.05 (q, J=7 Hz, 2H), 3.43-3.31 (m, 2H), 3.25-3.15 (m, 2H), 2.22-2.05 (m, 2H), 2.03-1.89 (m, 2H), 1.89-1.72 (m, 2H), 1.55 (s, 9H), 1.46 (t, J=7 Hz, 3H).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([C:16](=[O:18])[CH3:17])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=[O:5])[CH3:4].CO.[OH-].[Na+]>O>[OH:5][CH:3]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([CH:16]([OH:18])[CH3:17])([CH2:9]3)[CH2:7]1)[CH2:13]2)[CH3:4]
Reactant: CC(=O)C12CC3CC(C1)CC(C(C)=O)(C3)C2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(O)C12CC3CC(C1)CC(C(C)O)(C3)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A total of 1 g of sodium borohydride was slowly added to a mixture of 5.6 g of 1,3-diacetyladamantane, 20 ml of methanol, and 3 ml of 0.1 N sodium hydroxide aqueous solution on a water bath. After stirring for 30 minutes at room temperature, the resultant mixture was neutralized with a 1 N hydrochloric ac4d aqueous solution. To the neutralized mixture was added 50 ml of water, and the resultant mixture was extracted with three portions of 100 ml of ethyl acetate. The obtained organic layer was concentrated to give 5.5 g of 1,3-bis(1-hydroxyethyl)adamantane.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:15][CH3:16])[CH2:4][NH:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[C:17]([C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:34][C:32]1[CH:33]=[C:25]2[C:26](=[CH:30][CH:31]=1)[C:27](=[O:28])[N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=1)[C:4]([C:3](=[O:2])[CH2:15][CH3:16])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCC(O)CNCc1ccc(C#N)cc1
Agent: Cl
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(C#N)cc1

Procedure:
In the same manner as in Example 458, Step 2, the title compound was synthesized from 4-[(2-hydroxybutylamino)methyl]benzonitrile hydrochloride and 2-benzoyl-4-chlorobenzoic acid.
Reaction SMILES: CS(C)=O.[C:5]([O:22]C)(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])[CH3:25]>O1CCCC1>[C:27]1([C:24](=[O:26])[CH2:25][C:5](=[O:22])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCC(=O)OC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCC(=O)CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.88 h

Procedure:
An apparatus as described in Example 1 is charged with 31.7 g of sodium-tert-butylate, 150 g of DMSO and 150 g of tetrahydrofuran (THF) and the mixture is cooled to 0° C. Then a mixture of 89 g of methyl palmitate and 36 g of acetophenone is added dropwise over 45 minutes. The reaction mixture is then stirred for ca. 45-60 minutes at 30° C., the solvent is removed by distillation on a rotary evaporator (bath temperature <60° C.), and the residue is taken up in 1000 ml of water. The aqueous solution is acidified with dilute hydrochloric acid and the precipitate is isolated by filtration, washed with water, and dried.
Reaction SMILES: [CH:1]([N:4]([P:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])Cl)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][CH:25]([OH:27])[CH3:26]>C(OCC)C>[CH:25]([O:27][P:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])([CH3:26])[CH3:24]
Reactant: CC(C)N(C(C)C)P(Cl)N(C(C)C)C(C)C
Reactant: CC(C)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)OP(N(C(C)C)C(C)C)N(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
Bis(diisopropylamino)chlorophosphine (19, 250.1 g, 937 mmol) was dissolved in anhydrous ethyl ether (3.6 L) and triethylamine (190 g, 1.87 mol) was introduced. The turbid mixture was cooled at 0° C. and a solution of 2-propanol (225 g, 287 mL) in ether (200 mL) was added via a funnel. The resulting cloudy mixture was stirred at room temperature for 5.5 hours. The reaction was complete by checking with 31P NMR (δ=116.10 ppm, S). White solid (triethylamine HCl salt) was removed by filtration. The filtrate was concentrated to furnish a pale brown liquid (272 g, quantitative) and used for next step without further purification. Note that the P(III)-reagent can be purified by vacuum distillation (bp 84-86° C., 5 mm Hg) if desired to furnish a colorless clear oil. 1H NMR (CDCl3): δ 3.91 (m, 1H), 3.51 (m, 4 H), 1.19 (d, 6 H, J=6 Hz), 1.16 (24 H, m). 31P NMR (CDCl3): δ 116.1.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:7])[CH2:5][OH:6].[Br:8][C:9]1[N:13]2[CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[C:16]([C:19]#[N:20])=[C:17](Cl)[C:12]2=[N:11][CH:10]=1>O>[Br:8][C:9]1[N:13]2[CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[C:16]([C:19]#[N:20])=[C:17]([O:6][CH2:5][CH:4]([CH3:7])[CH3:3])[C:12]2=[N:11][CH:10]=1
Reactant: CC(C)CO
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(Br)cnc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(Br)cnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
NaH (60% in mineral oil, 149 mg, 3.7 mmol) was carefully added to 2-methyl-1-propanol (10 mL) at 0° C. (ice bath). The mixture was stirred at RT for 10 min before 3-bromo-8-chloro-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (500 mg, 1.25 mmol) was added in one portion. The reaction mixture was heated at 70° C. and stirred for 1 h, then cooled to RT and poured into water (100 mL). The formed slurry was extracted successively with DCM (2×50 mL) and AcOEt (50 mL), and the combined organic fractions were dried over Na2SO41 filtered, and evaporated to dryness. The remaining residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, hexane/TBME 95.5→100% TBME) to yield the title compound (348 mg, 0.79 mmol, 63%). MS: 438 [M+1]+; HPLC: AtRet=3.36; TLC: RF 0.81 (hexane/TBME 1:1).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.[CH3:21][CH:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>>[Cl:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[CH3:21])[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1CCCN1
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Product: CC1CCCN1c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C#N

Procedure:
The title compound was prepared in analogy to example 27 step C from 2,6-dichloro-4-phenyl-quinoline-3-carbonitrile (prepared as described in example 27 step B) and 2-methylpyrrolidine. Yellow solid. MS (ESI): 348.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Br[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:33]1([CH2:32][O:31][C:29](=[O:30])[CH2:28][NH:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:21]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cccc(NCC(=O)OCc2ccccc2)c1
Yield: 71.9 %

Procedure:
A mixture of 1.08 g (3.0 mmol) of 3-(octadecyloxy)benzenamine, 0.52 ml (3.3mmol) of benzyl bromoacetate and 0.8 g (6.0 mmol) of potassium carbonate in40 ml of acetone was stirred at reflux under argon for 18 hours. The reaction mixture was filtered and the filtrate was concentrated at reducedpressure to an oil which was purified by chromatography on 150 g of silica gel using 20% ethyl acetate-hexane to give 1.1 g (72% yield, mp 55°-60°) of N-[3-(octadecyloxy) phenyl]glycine phenylmethyl ester.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].CN(C)C=O.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C@:21]1([O:45][CH2:44]1)[C@H:22]([N:24]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])=[CH:31][CH:30]=2)[C:25]1=[O:43])[CH3:23]>O>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C@@:21]([OH:45])([CH2:44][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[C@H:22]([N:24]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][C:37]([F:41])([F:42])[CH:38]([F:39])[F:40])=[CH:33][CH:34]=2)[C:25]1=[O:43])[CH3:23]
Reactant: C[C@@H](N1CCN(c2ccc(OCC(F)(F)C(F)F)cc2)C1=O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](N1CCN(c2ccc(OCC(F)(F)C(F)F)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 0.41 g of 1H-1,2,4-triazole, 0.19 g of 60% sodium hydride in oil and 12 ml of dimethylformamide was stirred at room temperature for 20 minutes, and added with 0.85 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone obtained in Step 3 and the resultant mixture was heated at 60° C. for 4 hours. After cooling, 20 ml of water was added to the reaction mixture and the mixture was extracted with 80 ml of ethyl acetate. The extract was washed with 20 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient eluent: hexane:ethyl acetate=1:2→1:5) to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy) phenyl]-2-imidazolidinone (Compound B) as a colorless powder.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[F:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccc(F)cc2)CC1

Procedure:
2-(3-Chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (28.1 g), triethylamine (14 cc) and 1-(4-fluorophenyl)piperazine (18.8 g) in toluene (300 cc) are heated for 8 hours at boiling point. The mixture is then cooled to a temperature of about 20.C and stirring is maintained for 15 hours at this temperature. The precipitate formed is separated by filtration and washed with toluene (2×50 cc). The filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.1-1.5 bar) with ethyl acetate as eluant, and recrystallized from boiling acetonitrile (150 cc). 2-{3-[4-(4-Fluorophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide is obtained, m.p. 95°-97° C.
Reaction SMILES: [NH:1]([C:3]1[C:8]([CH2:9][CH2:10][CH3:11])=[N:7][C:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][N:4]=1)[NH2:2].[NH:18]1[CH:22]=[C:21]([CH2:23][CH:24]([C:30](OCC)=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:20]=[CH:19]1>>[NH:18]1[CH:22]=[C:21]([CH2:23][CH:24]([C:30]2[N:4]3[CH:5]=[C:6]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[N:7]=[C:8]([CH2:9][CH2:10][CH3:11])[C:3]3=[N:1][N:2]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:20]=[CH:19]1
Reactant: CCCc1nc(-c2cccnc2)cnc1NN
Reactant: CCOC(=O)C(Cc1c[nH]cn1)C(=O)OCC
Product: CCCc1nc(-c2cccnc2)cn2c(C(Cc3c[nH]cn3)C(=O)OCC)nnc12

Procedure:
In a manner analogous to that described in Example 1, by condensing 2-hydrazino-3-propyl-5-(3-pyridyl)pyrazine with diethyl (imidazol-4-yl-methyl)malonate (J.Chem.Soc. 99, (1911) 1390) there is obtained ethyl rac-α-(imidazol-4-ylmethyl)-8-propyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 405 (M)+, which is converted into the above acid by saponification analogously to Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]([OH:12])[C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[H-].[Na+].CN(C=O)C.[CH3:21][CH2:22][CH2:23]Br>O>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]([O:12][CH2:21][CH2:22][CH3:23])[C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])c(O)c1C
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c([N+](=O)[O-])ccc(OC)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
2.0 g (10.93 mmol) of 3-methoxy-2-methyl-6-nitrophenol (prepared according to R. A. Raphael, P. Ravenscoft, J. Chem. Soc. Perkin Trans. I, (1988), 1823-1828) were added in portions under an argon atmosphere to a suspension of 525 mg (1 2.02 mmol) of NaH in 30 ml of abs. DMF cooled to 0° C. After stirring at 0° C. for 30 min, 1.17 ml (12.70 mmol) of n-propyl bromide were added dropwise. The reaction solution was stirred at 70° C. for 8 h. Subsequently, 70 ml of H2O were added with ice cooling, and the mixture was then concentrated to dryness. The residue was taken up in EA, and the solution was washed 3× with H2O, dried over Na2SO4, and concentrated. Drying in a high vacuum afforded 2.37 g of the title compound in the form of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:25](I)[CH3:26]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:25][CH3:26])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCI
Reactant: COC(=O)c1cc(Cl)cc(NC2CCCC2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCCC1
Temperature: 80 °C
Yield: 14.7 %

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclopentylamino)-2-methylbenzoate (0.62 g, 2.32 mmol) in dry DMF (10 mL), cesium carbonate (3.78 g, 11.6 mmol) and ethyl iodide (5.43 g, 34.8 mmol) were added and the resulting reaction mass was heated at 80° C. for 18 h. On completion, reaction mixture was cooled to room temperature and filtered. The residue was washed with ethyl acetate and filtrate concentrated and purified by column chromatography to afford desired methyl 5-chloro-3-(cyclopentyl(ethyl)amino)-2-methylbenzoate (0.101 g, 15%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([C:23]([F:25])([F:24])[F:26])[CH:16]=2)=[O:22])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(Nc1cc(F)cc(C(F)(F)F)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a solution of 3-Fluoro-5-trifluoromethyl-aniline (940 mg, 5.25 mmol, 1.05 eq.) in dry THF (20 ml) was added 4-Chloro-3-(trifluoromethyl)-phenylisocyanate (1.11 g, 5.0 mmol) at rt and the mixture was stirred overnight. Then it was diluted with cHexane (100 ml), washed twice with 2 N HCl, once with sat. NaHCO3 and brine (100 ml each) and adsorbed on Celite in vacuo. Flash chromatography on silica with cHexane/TBME (5:1 to 3:1) yielded 687 mg pure product (34%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O)=[CH:4][C:3]=1[CH3:16].[O-:17][C:18]#[N:19].[Na+].C(=O)([O-])O.[Na+].[OH-].[Na+]>ClCCl.C(O)(=O)C>[Br:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([N:9]2[C:10]([CH3:15])([CH3:14])[C:11](=[O:13])[NH:19][C:18]2=[O:17])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(NC(C)(C)C(=O)O)cc(C)c1Br
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a mixture of 2-((4-bromo-3,5-dimethylphenyl)amino)-2-methyl propanoic acid (5.79 g of the compound obtained from Reaction 1-1) in dichloromethane (62 mL) and acetic acid (62 mL), sodium cyanate (5.03 g, 59.8 mmol) was added at room temperature. The mixture was stirred at room temperature for three hours. A saturated solution of sodium hydrogen carbonate (400 mL) was added to adjust the pH to 7-8 using a 5 N aqueous sodium hydroxide, and this mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained solid was washed sequentially with ethyl acetate-hexane and then with dichloromethane-hexane to obtain 1-(4-bromo-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione (3.80 g, 66%).
Reaction SMILES: [C:1]1(=[O:36])[N:5]([C:6]2[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=2)[C:9]([O:11][CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][NH:17]C(OC(C)(C)C)=O)=[O:10])[C:4](=[O:35])[CH:3]=[CH:2]1.[ClH:37]>C(OCC)C>[ClH:37].[ClH:37].[C:4]1(=[O:35])[N:5]([C:6]2[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=2)[C:9]([O:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:1](=[O:36])[CH:2]=[CH:3]1
Reactant: CC(C)(C)OC(=O)NCCN(CCOC(=O)c1cccc(N2C(=O)C=CC2=O)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: NCCNCCOC(=O)c1cccc(N2C(=O)C=CC2=O)c1
Temperature: 25 °C

Procedure:
6 g (11.93 mmol) of N-(O-(3-maleinimidobenzoyl)-2-hydroxyethyl)-N,N′-bis-tertiarybutyloxycarbonyl-1,2-diaminoethane are diluted with 60 ml (5 eq) of a 1 M solution of HCl in diethylether while stirring at room temperature. After 48 h of stirring at room temperature, the fine-crystallinic precipitate is suctioned off over a G4 glass frit, freed of the HCl residues through multiple washing with anhydrous ether and dried under a vacuum. Obtained are 3.0 g (7.98 mmol) of the product as a fine-powdery yellow solid, corresponding to 66.9% of the theoretically possible yield. Elementary analysis for C15H19N3O4Cl2 (375.9 g/mol); calculated: C: 47.89%, H: 5.05%, N: 11.17%, Cl: 18.86%; found: C: 46.97%, H: 5.42%, N: 10.03%, Cl: 17.63%.
Reaction SMILES: Cl.[Br:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[CH:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20]>O1CCOCC1.CCOC(C)=O>[Br:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[CH:19]([NH2:21])[CH3:20]
Reactant: CC(NC(=O)OC(C)(C)C)c1c(Br)c2ccccc2n1-c1cccc(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(N)c1c(Br)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
Hydrogen chloride (4.0 M) in 1,4-dioxane (1.2 mL, 4.8 mmol) was added to a solution of tert-butyl {1-[3-bromo-1-(3-fluorophenyl)-1H-indol-2-yl]ethyl}carbamate (0.15 g, 0.35 mmol) in 1,4-dioxane (2.0 mL) The reaction was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated NaHCO3 solution, dried over MgSO4 and concentrated to give the crude product (0.12 g). LCMS calculated for C16H12BrFN (M-NH2)+: m/z=316.0. Found: 316.0.