Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:10]=[C:9]2[C:18](O)=[O:19].C(Cl)(=O)C([Cl:25])=O>ClCCl.CN(C)C=O>[F:1][CH:2]([F:21])[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:10]=[C:9]2[C:18]([Cl:25])=[O:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(C(F)(F)F)nc2c(OC(F)F)cccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(C(F)(F)F)nc2c(OC(F)F)cccc12
Reaction time: 8 h

Procedure:
A solution of 8-difluoromethoxy-2-trifluoromethylquinoline-4-carboxylic acid (0.50 g) in dichloromethane (30 ml) was stirred at room temperature under an atmosphere of nitrogen. Oxalyl chloride (0.28 ml) was added followed by N,N-dimethylformamide (1 drop) and stirring continued overnight. The solvent was removed in vacuo to give 8-difluoromethoxy-2-trifluoromethylquinoline-4-carbonyl chloride (650 mg) as an off white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([O:17][O:18][C:19]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[P:20]([OH:23])([OH:22])=[O:21])[CH2:11]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:11][C@@H:10]([O:17][O:18][C:19]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[P:20]([OH:23])([OH:22])=[O:21])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)C(OO[C@H](COCc1ccccc1)COS(C)(=O)=O)(C(C)C)P(=O)(O)O
Agent: [Na+]
Product: CC(C)C(OO[C@H](CN=[N+]=[N-])COCc1ccccc1)(C(C)C)P(=O)(O)O
Temperature: 105 °C
Reaction time: 5 h
Yield: 74.6 %

Procedure:
(R)-3-O-Benzyl-2-O-(diisopropyl phosphonomethoxyl)-1-O-(methanesulfonyl)glycerol (15, 9 g, 20.53 mmol) (J. J. Bronson, etc. J. Med. Chem. 1989, 32, 1457) and sodium azide (4 g, 61.58 mmol) were mixed in 40 mL of anhydrous N',N'-dimethylformamide. The resulting mixture was stirred at 105° C. for 5 hours. After the solvent was removed under reduced presuure, the residue was added 100 mL of methylene chloride. The mixture was filtered, and the solid was washed with methylene chloride. The filtrate was evaporated, and the residue was purified by flash chromatography on silica gel (methylene chloride:acetone=10:1 to 3:1) to give 6.15 g (78% yield) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:19][CH2:20][CH2:21][CH2:22][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:11]=2[O:10][CH2:9][C:8]1=[O:12]
Reactant: ClCCCI
Reactant: O=C1COc2c(F)cccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C1COc2c(F)cccc2N1CCCCl
Yield: 59.9 %

Procedure:
8-Fluoro-4H-benzo[1,4]oxazin-3-one (95MF45) (0.290g, 1.74 mmol), Cs2CO3 (0.848 g, 2.6 mmol) and 3-chloro-1-iodopropane (0.390 g, 1.91 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (95MF51(2082)) (0.254 g, 60%). 1H NMR (CDCl3) δ 7.01-6.95 (m, 1H), 6.88-6.82 (m, 2H), 4.66 (s, 2H), 4.13-4.08 (m, 2H), 3.63 (t, J=6.0 Hz, 2H), 2.19-2-12 (m, 2H); 13C NMR (CDCl3) δ 164.2, 152.1 (d, J=246.8 Hz), 133.9 (d, J=15.0 Hz), 130.6 (d, J=3.1 Hz), 122.6 (d, J=8.1 Hz), 111.8 (d, J=18.4 Hz), 110.1 (d, J=3.4 Hz), 67.8, 42.4, 39.5, 30.1.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:5]([CH2:36][CH3:37])[CH2:6][CH2:7][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:34][CH3:35])[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][C:19]([C:24](=O)[CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:18][CH:17]=3)=O)[CH3:4].O.NN>C(O)CO.O>[ClH:1].[ClH:1].[CH2:31]([N:28]([CH2:29][CH3:30])[CH2:27][CH2:26][CH2:25][CH2:24][C:19]1[CH:18]=[CH:17][C:16]2[N:15]([CH2:34][CH3:35])[C:14]3[C:22]([C:21]=2[CH:20]=1)=[CH:23][C:11]([CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:3][CH3:4])[CH2:36][CH3:37])=[CH:12][CH:13]=3)[CH3:32]
Reactant: CCN(CC)CCCC(=O)c1ccc2c(c1)c1cc(C(=O)CCCN(CC)CC)ccc1n2CC
Agent: Cl
Agent: NN
Solvent: OCCO
Solvent: O
Product: CCN(CC)CCCCc1ccc2c(c1)c1cc(CCCCN(CC)CC)ccc1n2CC
Temperature: 165 °C

Procedure:
A solution of 11.0 g (0.02 mole) of 3,6-bis(4-diethylaminobutryl)-9-ethylcarbazole dihydrochloride and 25 ml of an 85% aqueous hydrazine hydrate solution is dissolved in 200 ml of ethylene glycol and heated to a temperature of 165°C for a period of 18 hours. The reaction mixture is cooled and diluted with water whereupon the free base of the desired compound separates as an oil. The product is separated by decantation, washed with water, dissolved in diethyl ether and the ethereal solution dried over magnesium sulfate. The dried solution is concentrated to a small volume and placed on an aluminum oxide chromatographic column and eluted with methylene chloride. The eluate is converted to its hydrochloride salt and crystallized from a methanol-ethyl acetate solution. Recrystallization from acetone with two additional recrystallizations from a methylene chloride-acetone solution results in the preparation of 3,6-bis(4-diethylaminobutyl)-9-ethylcarbazole dihydrochloride having a m.p. 172°-4° C; and λmaxEtOH 240; and E1cm1% 907.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:26])[C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[CH:13]=[CH:12][N:11]=2)=[O:8])=[CH:5][N:6]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(O)CCC>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[C:17]([NH:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:7]([C:4]2[S:3][C:2]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:6][CH:5]=2)=[O:8])[CH:15]=1)=[O:26]
Reactant: O=C(Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1)c1cnc(Br)s1
Reactant: C1COCCN1
Solvent: CCCCO
Product: O=C(Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1)c1cnc(N2CCOCC2)s1
Temperature: 50 °C
Yield: 69.7 %

Procedure:
To a suspension of 2-bromo-N-(4-(2,6-dichlorobenzamido)pyridin-2-yl)thiazole-5-carboxamide (Example 7) (24.0 mg, 0.051 mmol) in 1-butanol (1 mL) was added morpholine (44.4 mg, 0.51 mmol). The mixture was heated at 50° C. for 6 hours. The mixture was then concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (Gemini, 3×10 cm, gradient: 5-85% CH3CN/H2O with 0.1% NH4OH over 10 min) to afford the desired product (17 mg, 69.4% yield). 1H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 10.68 (s, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 8.27 (d, J=5.5, 1H), 7.63-7.57 (m, 2H), 7.56-7.51 (m, 2H), 3.73-3.68 (m, 4H), 3.52-3.46 (m, 4H). LCMS (ESI) m/z: 478.2 [M+H+]
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(#N)C>[CH3:4][Si:3]([CH2:2][NH:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:6])[CH3:5]
Reactant: NCc1ccccc1
Reactant: C[Si](C)(C)CCl
Solvent: CC#N
Product: C[Si](C)(C)CNCc1ccccc1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
To a solution of chloromethyltrimethylsilane (1.34 kg, 10.96 mol) in acetonitrile (17.0 L) is added benzylamine (2.34 kg, 21.92 mol) and the reaction mixture is heated at reflux for 16 h. The reaction mixture is cooled to room temperature and the precipitate of benzylamine hydrochloride is removed by filtration. The filtrate is concentrated under vacuum to about 5 L and then diluted with water (5 L). The reaction mixture is extracted with hexane (2×5 L). The organic extracts are combined and washed with brine (5 L) and dried over MgSO4. The filtrate is concentrated under vacuum to give 1.77 kg (83%) of N-(trimethylsilylmethyl)benzylamine.
Reaction SMILES: [Cl:1][C:2]1[N:3](/[N:13]=C/C2C=CC(Cl)=CC=2)[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1.O.NN>COCCO>[Cl:1][C:2]1[N:3]([NH2:13])[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: Clc1ccc(/C=N/n2cc(-c3cccnc3)nc2Cl)cc1
Agent: NN
Solvent: O
Solvent: COCCO
Product: Nn1cc(-c2cccnc2)nc1Cl
Temperature: 130 °C
Yield: 77.9 %

Procedure:
To a solution of E-2-Chloro-N-(4-chlorobenzylidene)-4-(pyridin-3-yl)-1H-imidazol-1-amine (210 mg, 0.66 mmol) in 2-methoxyethanol (5 mL) was added 80% hydrazine hydrate (0.5 mL). The reaction mixture was heated to 130° C. for 1 hour and then the reaction mixture was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (100 mg, 78%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 8.50-8.49 (m, 1H), 8.06-8.03 (m, 1H), 7.43 (s, 1H), 7.34-7.30 (m, 1H), 4.87 (br, 2H); ESIMS m/z 195 [(M+H)]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7](N)=[CH:6][C:5]=1[Cl:12].N([O-])=[O:15].[Na+].O>Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([OH:15])=[CH:6][C:5]=1[Cl:12]
Reactant: O=N[O-]
Reactant: COC(=O)c1c(Cl)cc(N)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1c(Cl)cc(O)cc1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
4-Amino-2,6-dichlorobenzoic acid methyl ester (0.5 g) was suspended in 20% HCl (25 mL) and stirred for 30 min then cooled to 0-5° C. After slow addition of NaNO2 (188 mg), the mixture was stirred for 30 min at that temperature and added to boiling water (50 mL) . The mixture was then refluxed for 2 h, allowed to cool to room temperature and extracted with AcOEt, dried (MgSO4), filtered and evaporated. The residue was purified by preparative TLC (silica gel; eluent: CH2Cl2) to give 2,6-dichloro-4-hydroxybenzoic acid methyl ester (275 mg).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=O)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=O)[CH:19]=[N:20][CH:21]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:10]2[C:11](=[O:12])[O:13][C:7]([C:5]3[S:6][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:9]2)[CH:19]=[N:20][CH:21]=1
Reactant: COc1cncc(C=O)c1
Reactant: Cc1ccc(C(=O)NCC(=O)O)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cncc(C=C2N=C(c3ccc(C)s3)OC2=O)c1
Temperature: 90 °C
Yield: 56.6 %

Procedure:
To a screw-capped test tube, N-[(5-methyl-2-thienyl)carbonyl]glycine (60 mg, 0.3 mmol), 5-methoxy-3-pyridinecarboxaldehyde (45 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 51 mg of the above-captioned compound.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:47])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]([CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[N:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:47])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]([CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[NH:29][CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[N:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]
Reactant: Cc1c(-c2noc(-c3cnc(OC(C)C)c(Cl)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2CCCC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2noc(-c3cnc(OC(C)C)c(Cl)c3)n2)ccc2c1CCNC2CCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
Trifluoroacetic acid (1.0 ml) was added to a stirred solution of 4-(6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-2-{[(1,1-dimethylethyl)oxy]carbonyl}-5-methyl-1,2,3,4-tetrahydro-1-isoquinolinyl)butanoic acid (Preparation 34; 50 mg, 0.09 mmol) in dry dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvents were evaporated and the residue co-evaporated with toluene. Trituration of the residue with diethyl ether gave a gummy solid, which was purified by MDAP to give the title compound (26 mg) as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.I[C:26]1[CH:39]=[N:38][C:29]2[NH:30][C:31]3[CH:36]=[N:35][C:34]([Br:37])=[CH:33][C:32]=3[C:28]=2[CH:27]=1>[F-].[K+].C(#N)C.C(OCC)(=O)C>[Br:37][C:34]1[N:35]=[CH:36][C:31]2[NH:30][C:29]3[N:38]=[CH:39][C:26]([C:12]4[CH:11]=[CH:10][C:9]([CH2:8][N:5]5[CH2:4][CH2:3][C:2]([CH3:1])([CH3:24])[CH2:7][CH2:6]5)=[CH:14][CH:13]=4)=[CH:27][C:28]=3[C:32]=2[CH:33]=1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Reactant: CC1(C)CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Temperature: 80 °C
Yield: 32.5 %

Procedure:
A degassed mixture of 4,4-dimethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]piperidine (836 mg, 2.5 mmol), 3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (500 mg, 1.3 mmol), 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (109 mg, 0.13 mmol) in 1N aqueous potassium fluoride solution (25 mL) and acetonitrile (25 mL) was heated at 80° C. for 18 h. The cooled reaction mixture was diluted with ethyl acetate (100 mL) then washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 120 g column, ISCO, 0-15% methanol in DCM) to afford the title compound as an off-white solid (190 mg, 33%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.85 (d, J=2.2 Hz, 1H), 8.76 (d, J=2.2 Hz, 1H), 8.70 (d, J=0.9 Hz, 1H), 8.32 (d, J=0.9 Hz, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 3.82 (s, 2H), 2.77-2.63 (m, 4H), 1.52 (t, J=5.6 Hz, 4H), 1.00 (s, 6H).
Reaction SMILES: COC([CH:5]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:10][C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:24])=O.N1C=CC=CC=1.[I-].[Li+]>C(OCC)(=O)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]2[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[NH:7][C:6](=[O:24])[CH2:5]2)=[CH:13][CH:14]=1
Reactant: COC(=O)C1C(=O)Nc2ccccc2CC1c1ccc(OC)cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C2CC(=O)Nc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A solution of 1.0 g (3.08 mmol) of 2,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-1H-1-benzazepin-2-one [prepared by the method of Floyd, et al., J. Med. Chem., 35, 756-772 (1992)]in 10 mL of pyridine was treated with 1.65g (12.3 mmol, 4eq) of lithium iodide and the resulting mixture refluxed in an oil bath under a nitrogen atmosphere for 20 hours. The dark brown mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with 1N HCl (3×50 mL) and water, dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent followed by column chromatography on silica gel gave 520mg (63%) of the product. 1H NMR (200 MHz, CDCl3): 257 (dd; 4,8 Hz; 2H), 2.81 (dd; 7, 13 Hz; 1H), 3.13 (dd; 8, 14 Hz; 1H), 3.63 (dt; 14, 7 Hz; 1H), 3.74 (s, 3H), 6.82 (d, 8 Hz, 2H), 7.02 (d, 8 Hz, 1H), 7.14-7.34 (m, 5H), 8.03 (br s, 1H). FAB-MS: calculated for C17H17NO2 267; found 267 (100%).
Reaction SMILES: [C:1]([CH2:20][CH2:21][C:22]([OH:24])=[S:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[C:31](O)=[C:30]([Cl:33])[C:29]([Cl:34])=[C:28]([Cl:35])[C:27]=1[Cl:36].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:25][C:26]1[C:31]([O:24][C:22](=[S:23])[CH2:21][CH2:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:30]([Cl:33])[C:29]([Cl:34])=[C:28]([Cl:35])[C:27]=1[Cl:36]
Reactant: OC(=S)CCC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: S=C(CCC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a preferred embodiment of the preparation of the above first tetrapeptide hydrazide, the activated ester of 3-tritylthiopropionic acid, preferably the pentachlorophenyl ester, is prepared by combining substantially equimolar amounts of 3-tritylthiopropionic acid, pentachlorophenol and dicyclohexylcarbodiimide in an inert organic solvent, preferably tetrahydrofuran, at about 0° to 10° C. The mixture is stirred at about 0° to 10° C for about 1 hour and then at about 20° to 30° C for about 1 hour. The mixture is cooled to about 0° C, filtered and the filtrate evaporated. The residue is crystallized to obtain 3-tritylthiopropionic acid pentachlorophenyl ester. A solution of said last-named compound and a substantially equimolar amount of the tetrapeptide of formula H-Lys(Boc)-Asn-Phe-Phe-OMe acetate, prepared as described by H. U. Immer et al., cited above, in an inert organic solvent, preferably dimethylformamide or tetrahydrofuran, is treated with a substantially equimolar amount of an organic base, preferably triethylamine, at about 20° to 30° C. The mixture is stirred for 2 to 3 days at about 20° to 30° C and the solvent evaporated under reduced pressure. The residue is triturated with cold dilute aqueous citric acid and water, dried, and crystallized to give the tetrapeptide of formula Trt--SCH2CH2CO--Lys(Boc)--Asn--Phe--Phe--OMe. Said last-named compound is dissolved in an inert organic solvent, for example, methanol, ethanol, or preferably dimethylformamide. The solution is treated with an excess of hydrazine hydrate, for example 15 to 30 molar equivalents. The reaction mixture is kept at about 20° to 30° C for about 20 to 30 hours and evaporated under reduced pressure. The residue is triturated with cold water and dried to give said tetrapeptide hydrazide of formula (2, R = H) Trt--SCH2CH2CO--Lys(Boc)--Asn--Phe--Phe--NHNH2.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])=[C:4]([OH:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C[C:25](=[O:28])[CH2:26][CH3:27]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])=[C:4]([O:17][CH2:27][CH:26]2[O:28][CH2:25]2)[CH:3]=1
Reactant: CCC(C)=O
Reactant: CCOC(=O)CCC(=O)c1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCC(=O)c1ccc(Cl)cc1OCC1CO1
Yield: 86 %

Procedure:
A well stirred mixture of ethyl 3-(4-chloro-2-hydroxybenzoyl)propionate (9.6 g, 0.037 mole), potassium carbonate (5.96 g, 0.043 mole) epibromohydrin (14.4 ml, 0.173 mole) and dry butan-2-one (250 ml) was heated under reflux for 28 hours. Evaporation of the filtered solution under reduced pressure and purification of the residue by column chromatography gave ethyl 3-[4-chloro-2-(2,3-epoxypropoxy)benzoyl]-propionate as an oil (10.0 g, 86%). (Found: M+, 312/314. C15H17ClO5. requires M, 312/314).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](OC)=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a mixture of methyl 1-benzylpyrrolidine-3-carboxylate (11.67 g, 50 mmol) and tetrahydrofuran, at 0° C. was added lithium aluminum hydride (3.795 g, 100 mmol). The reaction was warmed to room temperature and refluxed for 24 hours. After cooling to 0° C., the reaction was quenched with saturated sodium sulfate and warmed to room temperature. Tetrahyrofuran (50 mL) and solid sodium sulfate were added to the mixture. After stirring for 1 hour, the mixture was filtered and the filtrate was concentrated and vacuum dried for 3 days to give the title compound as a colorless oil (8.49 g, 88%).
Reaction SMILES: [C:1]1([CH:7]([NH2:18])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](O)(=[O:30])[CH2:20][NH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>>[C:1]1([CH:7]([NH:18][C:19]([CH2:20][NH:21][C:22](=[O:23])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:30])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: NC(c1ccccc1)c1cccc(C(F)(F)F)c1
Product: O=C(CNC(=O)c1ccccc1)NC(c1ccccc1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from rac-C-phenyl-C-(3-trifluoromethyl-phenyl)-methylamine (CA [70428-92-1]) and hippuric acid.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2].[CH2:18](Br)[CH:19]=[CH2:20]>>[CH2:1]([C:3]1[N:4]([CH2:20][CH:19]=[CH2:18])[C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:13])[F:14])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: C=CCBr
Product: C=CCn1c(CC)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 149 from 2-ethyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and allyl bromide: 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=8.5 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 6.60 (s, 1H), 5.93 (ddt, J=17.7, 10.4, 4.3 Hz, 1H), 5.18 (app. d, J=10.3 Hz, 1H), 4.80-4.73 (m, 3H), 2.78 (q, J=7.4 Hz, 2H), 1.40 (t, J=7.4 Hz, 3H).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[CH:13]=[C:12]3[C:19]2[N:27]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)[CH2:4][O:3]1.Cl>CO>[CH3:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:7][C@@H:5]([OH:6])[CH2:4][OH:3])=[CH:17][CH:16]=2)[C:12]([C:19]2[N:27]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:29])=[O:30])[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:13]1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(OC[C@@H]5COC(C)(C)O5)cc34)cc3cccnc32)cc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(OC[C@@H](O)CO)cc34)cc3cccnc32)cc1
Yield: 39.5 %

Procedure:
A solution of 2-[5-({R}-(−)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [1.04 g, Reference Example 23(b)] in methanol (20 mL) was treated with hydrochloric acid (20 mL, 1M) then heated under reflux for 3 hours. The reaction mixture was concentrated in vacuo and the residue subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (2:1, v/v) to give the title compound (380 mg) as a clear oil. TLC: RF=0.2 (pentane/ethyl acetate: 1/2). MS: 492(MH+).