Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:3]([CH2:4][N:5]2[C@@H:15]3[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]5[O:24][CH:9]6[C:10]([CH2:12][CH2:13][C@:14]3([OH:25])[C@:8]6([C:18]=45)[CH2:7][CH2:6]2)=[O:11])[CH2:2]1.[ClH:26]>O>[CH:22]1[C:17]2[CH2:16][C@H:15]3[N:5]([CH2:4][CH:3]4[CH2:1][CH2:2]4)[CH2:6][CH2:7][C@:8]45[C@H:9]([C:10]([CH2:12][CH2:13][C@@:14]34[OH:25])=[O:11])[O:24][C:19]([C:18]=25)=[C:20]([OH:23])[CH:21]=1.[ClH:26]
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)C1O5
Agent: Cl
Solvent: O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 72.5 °C

Procedure:
70 kg Naltrexone base is taken in 210 Lit DM water and pH was adjusted to ˜2.0 with Conc. HCl and heated to 70-75° C. to get clear solution, filtered to make particle free and slowly cooled to 2-5° C. in 6-8 hrs period, filtered and then dried. The base was generated from filtrate by treatment with sodium hydroxide and converted to HCl salt by repeating the above mentioned process. Yield: 59.8 kg
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH3:29][N:30]([CH3:44])[C:31]([CH3:43])([CH3:42])[CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>>[CH3:29][N:30]([CH3:44])[C:31]([CH3:43])([CH3:42])[CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:36][CH:35]=1
Reactant: CN(C)C(C)(C)COc1ccc(C=O)cc1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC(C)(C)N(C)C)cc2)c1
Yield: 73.7 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (34 mg) and 4-(2-dimethylamino-2-methylpropoxy)benzaldehyde (100 mg) according to an analogous synthetic method to Example 264 described below and purified by LC-MS, the title compound (33 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6](I)[CH:7]=1.COB(OC)OC.Br[C:22]([C:24]([F:27])([F:26])[F:25])=[CH2:23].C(=O)([O-])[O-].[K+].[K+]>CCCCCC.C([Li])CCC.O1CCCC1.O.C(OC)(C)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:22]([C:24]([F:27])([F:26])[F:25])=[CH2:23])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[F:13]
Reactant: C=C(Br)C(F)(F)F
Reactant: Fc1c(Cl)cc(I)cc1C(F)(F)F
Agent: COB(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(F)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Yield: 73.1 %

Procedure:
In a solution of 2.58 g of 3-chloro-2-fluoro-5-iodobenzotrifluoride and 0.68 g of tert-butylmethyl ether in 20 mL of hexane, 6.0 mL of n-butyl lithium (1.54M hexane solution) was added dropwise at −20° C. with stirring, and stirred at the same temperature for 30 minutes. Then, a solution of 0.88 g of trimethoxyborane in 10 mL of tetrahydrofuran was added dropwise. After the completion of the addition dropwise, it was stirred at the same temperature further for 30 minutes and then the temperature was raised to room temperature. Then, in the reaction mixture, 4.00 g of 2-bromo-3,3,3-trifluoropropene, 2.20 g of potassium carbonate, 15 mL of water and 0.03 g of 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ilidene (1,4-naphthoquinone) palladium (0) dimmer were added, and stirred under nitrogen atmosphere at 60° C. for 6 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, insoluble material was filtered off, and the organic phase was collected and the aqueous phase was extracted with 30 mL of diethyl ether twice. The combined organic phases were washed with water, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with hexane to obtain 1.70 g of the aimed product as yellow oily substance.
Reaction SMILES: C(O[C:6]([N:8](C)[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:6][NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][CH2:14]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
200 mg (0.53 mmol) of trans-Methansulfonic acid 5[-4-(tert-butoxy carbonyl-methyl-amino)-cyclohexyl)-pentyl ester, dissolved in 2 ml of CH2Cl2, was treated with 2 ml of TFA. After stirring for 20 min at RT, the solution was concentrated in vacuo to yield 245 mg of pure trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentylester.trifluoroacetic acid salt, MS: 278 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.I[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:22]=1.[C:41]1([C:47]#[CH:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[N+:30]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:22]=[C:21]2[C:48]#[C:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([O-:32])=[O:31]
Reactant: C#Cc1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc([N+](=O)[O-])ccc21
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1nc(C#Cc2ccccc2)c2cc([N+](=O)[O-])ccc21
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
5-Nitro-3-phenylethynyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole can be obtained in the following way: 0.16 g of triphenylphosphine, 0.54 g of tetrakis(triphenylphosphine)palladium(0) and 0.27 g of copper iodide are added to a solution, under argon, of 3 g of 3-iodo-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in 200 ml of acetonitrile. After stirring for 10 minutes, 1.57 ml of phenylacetylene and 2 ml of triethylamine are added, and the reaction mixture is then refluxed for 16 hours. After cooling to a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. The residue is taken up in 150 ml of dichloromethane and then washed with 2 times 120 ml of water. The aqueous phases are pooled and extracted with 100 ml of dichloromethane. The organic extracts are pooled, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue is purified by chromatography under argon pressure (50 kPa), on a column of 200 g of silica (particle size 40-63 μm), eluting successively with pure cyclohexane then with cyclohexane/ethyl acetate (98/2; 97/3; 95/5; 90/10 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. 2.31 g of 5-nitro-3-phenylethynyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole are thus obtained in the form of a brown solid melting at 88° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([OH:15])[CH2:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]([CH3:14])([CH3:13])[CH2:6]1)=O.O.[NH2:17][NH2:18]>CO>[CH3:11][C:9]1([CH3:12])[CH2:10][C:5]([OH:15])([C:3]([NH:17][NH2:18])=[O:2])[CH2:6][C:7]([CH3:14])([CH3:13])[NH:8]1
Reactant: NN
Reactant: COC(=O)C1(O)CC(C)(C)NC(C)(C)C1
Solvent: O
Solvent: CO
Product: CC1(C)CC(O)(C(=O)NN)CC(C)(C)N1

Procedure:
16.2 parts of 2,2,6,6-tetramethyl-4-hydroxypiperidine-4-carboxylic acid methyl ester (according to German Patent No. 91,122), 5 parts of hydrazine hydrate and 20 parts of methanol are boiled under reflux for 10 hours and the methanol is subsequently distilled off. The residue is recrystallised from cyclohexane. Yield: 15.3 parts of 2,2,6,6-tetramethyl-4-hydroxypiperidine-4-carboxylic acid hydrazide melting at 121° to 123° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[N:15]([CH3:36])[C:16]([C:18]2[CH:19]=[C:20]([S:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=2)=[O:17])=[C:4]([O:37][CH3:38])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:52][O:53][C:54](=[O:57])[CH2:55][NH2:56].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[N:15]([CH3:36])[C:16]([C:18]2[CH:19]=[C:20]([S:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([NH:56][CH2:55][C:54]([O:53][CH3:52])=[O:57])=[O:34])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=2)=[O:17])=[C:4]([O:37][CH3:38])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(SCCCCC(=O)O)cc(C(F)(F)F)c1
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)CCCCSc1cc(C(=O)N(C)c2cnc(C)cc2-c2ccc(F)cc2OC)cc(C(F)(F)F)c1

Procedure:
To a solution of 5-(3-((4-(4-fluoro-2-methoxyphenyl)-6-methylpyridin-3-yl)(methyl)carbamoyl)-5-(trifluoromethyl)phenylthio)pentanoic acid (0.15 g, 272 μmol, example 312) in DMF (1 mL) was added 1,1′-carbonyldiimidazole (66.3 mg, 409 μmol) and the clear solution was stirred at room temperature for 45 minutes before glycin methyl ester hydrochloride (37.6 mg, 300 μmol) was added. Reaction mixture was stirred at room temperature for 20.5 hours before DIPEA (35.2 mg, 47.6 μL, 272 μmol) and glycin methyl ester hydrochloride (37.6 mg, 300 μmol) was added. After 23 hours the reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed twice with water and once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of CH2Cl2:MeOHe (100:0 to 90:10). Colorless foam (0.142 g; 79%). MS (ESI): m/z=622.20 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:13](=[O:17])[CH:14]([CH3:16])[CH3:15]>>[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([CH:13]([OH:17])[CH:14]([CH3:16])[CH3:15])=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Reactant: CC(C)C=O
Product: CC(C)C(O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Prepared analogously to the method described for Example 1a) from 2.3 mL (15 mmol) of 5-bromo-2-chlorobenzotrifluoride and 1.3 mL (14 mmol) isobutyraldehyde. Yellow oil. Yield: 2.0 g (53%).
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:17]([O:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH2:33]Cl)=[CH:27][C:26]=1[Cl:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C.O>[CH2:17]([O:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH2:33][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:27][C:26]=1[Cl:35])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc(CCl)cc(Cl)c1OCc1ccccc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(CN(c2ccc(C#N)cc2)n2cnnc2)cc(Cl)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 h at this temperature and 2-benzyloxy-1-chloro-5-chloromethyl-3-methoxy-benzene (CAB02174, 1.49 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) and water (50 mL) were added. The organic layer was separated and washed with water (2×50 mL) and brine (30 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was suspended in 2-propanol (20 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 1.76 g (79%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]([O:31][CH2:32][CH3:33])=[O:30])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(-c2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 101.7 %

Procedure:
A mixture of 4-(4-bromophenyl)nitrobenzene (Journal of Organic Chemistry, 2005, 70(9), 3730) (800 mg, 2.88 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (69 mg) and caesium carbonate (2.81 g, 8.63 mmol) in toluene (40 mL) was deoxygenated then palladium(II) acetate (13 mg, 0.06 mmol) and diethyl malonate (0.480 mL, 3.2 mmol) were added. The reaction mixture was heated under reflux for 2 h, cooled and then filtered through diatomaceous earth and the filter washed with EtOAc. The filtrate was concentrated by evaporation and adsorbed onto silica then purified by chromatography, eluting with 0-25% EtOAc in isohexane, to give the title compound (1.047 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:29][CH:30]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1ccccc1)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc(NC(=O)C(Cc2ccccc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 33.3 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-phenylpropanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (571 mg) were condensed in chloroform (35 ml) in the presence of triethylamine (1.64 ml) and 1-methyl-2-chloropyridinium iodide (902 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)-3-phenylpropanamide (442.3 mg).
Reaction SMILES: [NH2:1][C:2]1[C:20]([Br:21])=[CH:19][C:5]([CH2:6][C@H:7]([C:16]([OH:18])=O)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[Br:22].[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:25][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2]1[C:3]([Br:22])=[CH:4][C:5]([CH2:6][C@H:7]([C:16]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:27]=[CH:28][N:23]=[CH:24][N:25]=3)[CH2:30][CH2:31]2)=[O:18])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:19][C:20]=1[Br:21]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(Br)c(N)c(Br)c1)C(=O)O
Reactant: c1cc(N2CCNCC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(Br)c(N)c(Br)c1)C(=O)N1CCN(c2ccncn2)CC1
Yield: 92 %

Procedure:
Prepared analogously to Example A15a) from 4-amino-3,5-dibromo-N-(1,1-dimethylethoxycarbonyl)-D-phenylalanine and 1-(4-pyrimidinyl)piperazine in the presence of TBTU in a yield of 92% of theory. Colourless, amorphous substance, Rf=0.42 (FM4; Macherey-Nagel POLYGRAM® SIL G/UV254, ready-made films for TLC).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:28])[CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[O:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[N+](=[CH2:31])=[N-]>CO.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:28])[CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:27]=[CH:26][CH:25]=[C:19]([O:20][CH2:21][C:22]([O:24][CH3:31])=[O:23])[CH:18]=3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)COc1cccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)c1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)COc1cccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of (2R)-(3-[3-[2-(3-chlorophenyl)-2-hydroxyethylamino]cyclohexyl]phenoxy)acetic acid (trans-H) obtained in Example 46 (1.0 g) in methanol (10 ml) there was added an excess of diazomethane in ether solution, and the mixture was stirred at room temperature for 30 minutes. After distilling off the solvent under reduced pressure, separation and purification by silica gel column chromatography (ethyl acetate:hexane=5:l) gave 0.91 g of (1R)-1-(3-chlorophenyl)-2-[3-(3-methoxycarbonylmethoxyphenyl)cyclohexylamino]ethanol (88% yield).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=2[N:20]([CH3:29])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:5][CH2:4]1.[Cl:33][C:34]1[C:47]([N:48]=[C:49]=S)=[C:46]([Cl:51])[CH:45]=[CH:44][C:35]=1[CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40].CC(C)N=C=NC(C)C>CN(C=O)C>[F:31][C:2]([F:1])([F:32])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([C:11]2[C:12]([N:20]([CH3:29])[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:13][C:14]3[N:18]([CH3:19])[C:49]([NH:48][C:47]4[C:46]([Cl:51])=[CH:45][CH:44]=[C:35]([CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[C:34]=4[Cl:33])=[N:17][C:15]=3[CH:16]=2)=[O:30])[CH2:7][CH2:8]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1cc(N(C)Cc2ccc(F)cc2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CN(Cc1ccc(F)cc1)c1cc2c(cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1)nc(Nc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1Cl)n2C

Procedure:
The title compound is prepared in analogy to 1e from N-(trans-4-trifluoromethyl-cyclohexyl)-2-[N-methyl-N-(4-fluorobenzyl)amino]-4-methylamino-5-amino-benzoic acid amide (68 mg, 0.15 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (48 mg, 0.15 mmol), DIC (23 μL) and DMF (2.0 mL).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].CCCCCC.C([Li])CCC.[CH3:21][S:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[O:30])(=[O:24])=[O:23]>C(OCC)(=O)C.C(OCC)C.O1CCCC1>[F:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[CH:29]([OH:30])[CH2:28][CH2:27][CH2:26][CH2:25][S:22]([CH3:21])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)CCCCC=O
Reactant: Fc1ccc(F)c(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCCCC(O)c1cc(F)ccc1F
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
A tetrahydrofuran (5 ml) solution of 1-bromo-2,5-difluorobenzene (0.151 ml, 1.34 mmol) was stirred at −78° C. To the resulting mixture was added a hexane solution (0.843 ml, 1.34 mmol) of n-butyl lithium. The reaction mixture was added to a tetrahydrofuran (5 ml) solution of 5-(methylsulfonyl)pentanal (183 mg, 1.11 mmol) at −78° C. and at the same temperature, stirring was conducted for 30 minutes. After elevating the temperature of the reaction mixture to room temperature, diethyl ether was added thereto. The resulting mixture was washed successively with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=1:2 eluate was concentrated under reduced pressure, whereby the title compound (116 mg, 0.42 mmol, 37%) was obtained as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.O.[OH-].[Li+]>CO>[CH:15]1([N:9]2[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cnn(C2CCCC2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(C2CCCC2)c1C(F)(F)F
Temperature: 80 °C
Yield: 62.9 %

Procedure:
Cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.237 g, 0.858 mmol) was dissolved in methanol (2.0 mL). Water (2.0 mL) and lithium hydroxide (0.027 g, 1.127 mmol) were added and the mixture was heated at 80° C. for 2 hours. After cooling to room temperature, the methanol was removed in vacuo. THF was added to the residue and then removed in vacuo to insure complete removal of the methanol. 6N HCl (0.2 mL) was added to the aqueous residue to pH 2-3 resulting in precipitation of a white solid. The solid was collected by filtration, washed with water and dried under high vacuum at 100° C. to give 1-cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.134 g, 63%).
Reaction SMILES: C(O)C.C([O:6][C:7](=O)/[C:8](=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]2)=[C:26]([O:36][CH3:37])[CH:25]=1)/[CH2:9][CH2:10][CH2:11][NH:12][C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@@H:14]1[OH:22])C.[OH-].[Na+].O>C(OCC)(=O)C>[OH:22][C@H:14]1[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:13]1[N:12]1[CH2:11][CH2:10][CH2:9]/[C:8](=[CH:23]\[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]3)=[C:26]([O:36][CH3:37])[CH:25]=2)/[C:7]1=[O:6]
Reactant: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCN[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCCN([C@@H]3c4ccccc4C[C@@H]3O)C2=O)ccc1-n1cnc(C)c1
Yield: 72.8 %

Procedure:
To an ethanol (2.0 mL) solution of (E)-5-[(1R,2S)-2-hydroxyindan-1-ylamino]-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valeric acid ethyl ester (120 mg), 2N sodium hydroxide solution (1.0 mL) was added. After carrying out heat-refluxing of the reaction solution for 30 minutes and confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate=1:1->ethyl acetate->ethyl acetate:ethanol=10:1), and 78.9 mg of the title compound was obtained.