Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[CH3:9][C:10]([OH:14])([C:12]#[CH:13])[CH3:11]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[Cl:8][C:4]1[CH:3]=[C:2]([C:13]#[C:12][C:10]([CH3:11])([OH:14])[CH3:9])[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(Br)c1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 72 h
Yield: 93.8 %

Procedure:
Add triethylamine (75 mL), 1-bromo-3-chlorobenzene (24.1 g, 0.126 mol), and 2-methylbut-3-yn-2-ol (15 mL, 0.152 mol) to a degassed mixture of bis(triphenylphosphine)palladium (II) dichloride (49 mg, 7.1 10−5 mol) and copper (I) iodide (2.4 mg, 1.26 10−5 mol). Stir at 90° C. for 72 h. Cool the reaction mixture to room temperature. Filter, concentrate and dissolve in ethyl acetate. Wash with water and dry the organic phase over sodium sulfate. Filter, concentrate and purify the residue by silica gel chromatography, eluting with hexane:ethyl acetate 6:1, to give the title compound (23 g, 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Br[CH2:57][CH2:58][OH:59]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:57][CH2:58][OH:59])[CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CCO)CC5)cc4)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a stirred solution of 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 1 of example 124) (75 mg, 0.123 mmol), potassium carbonate (24 mg, 0.185 mmol) and DMF (5 ml) was added 2-bromoethanol (24 mg, 0.185 mmol) and the mixture stirred at RT for overnight. Then water was added, this was then extracted into 10% methanol in DCM, organic portion was dried over sodium sulfate and concentrated to give 60 mg (75% yield) of the titled compound. MS: m/z=651.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6].[CH3:12][C:13]([CH3:17])([CH3:16])[C:14]#[CH:15].O>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:12][C:13]([CH3:17])([CH3:16])[C:14]#[C:15][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6]
Reactant: C#CC(C)(C)C
Reactant: CC(=O)Nc1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1C#CC(C)(C)C
Temperature: 50 °C
Reaction time: 5 h
Yield: 100.3 %

Procedure:
Under argon, 25.7 g (120 mmol) of ortho-bromoacetanilide, 5.05 g (7.2 mmol) of bis(triphenylphosphine)palladium(II) chloride and 1.37 g (7.2 mmol) of copper(I) iodide were initially charged in 450 ml of triethylamine. At room temperature, 17.8 g (180 mmol) of 3,3-dimethyl-1-butyne were then added dropwise over a period of 10 min, and the mixture is stirred at 50° C. for 5 h. The reaction mixture was poured into 2 l of water and extracted 3 times with in each case 250 ml of diethyl ether, and the extracts were dried over sodium sulphate and concentrated. Column-chromatographic purification on silica gel 60 with methylene chloride gave 25.9 g of N-[2-(3,3-dimethylbut-1-ynyl)-phenyl]acetamide of logP (pH 2.3)=3.03.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C@@H:9]2[NH:12][C:11](=[O:13])[C@H:10]2[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Si:49](Cl)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]>CN(C=O)C>[C:1]1([CH:7]=[CH:8][C@@H:9]2[N:12]([Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[C:11](=[O:13])[C@H:10]2[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(N=C(NCCCC[C@@H]1C(=O)N[C@H]1C=Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. DMF (25 mL) solution of compound 33 (6.8 g, 12.3 mmol) was added triethylamine (2.05 g, 20 mmol) and tert-butyldimethylsilyl chloride (3.05 g, 20 mmol). The reaction mixture was warmed to room temperature and stirred for 1.5 h. The suspension was partitioned between Et2O and pH 7.0 aqueous buffer. The organic layer was dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography to afford 8.4 g (quantitative) of the title product.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.CN(OC)[C:15]([C@@H:17]1[CH2:21][C:20](=[O:22])[N:19]([C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:18]1)=[O:16].Cl>O1CCCC1>[C:25]1([C@H:23]([N:19]2[CH2:18][C@H:17]([C:15]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[O:16])[CH2:21][C:20]2=[O:22])[CH3:24])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Brc1ccccn1
Reactant: CON(C)C(=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@H](C(=O)c2ccccn2)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In an atmosphere of nitrogen and at −78° C., n-butyl lithium (1.5 mol/l tetrahydrofuran solution; 13.2 ml, 19.9 mol) was added dropwise to a tetrahydrofuran solution (40 ml) of 2-bromopyridine (1.94 ml, 19.9 mmol), and then the mixture was stirred for 10 minutes. At −78° C., to this was further added dropwise a tetrahydrofuran solution (20 ml) of N-methyl-N-methoxy-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-(R)-carboxamide (3.66 g, 13.2 mmol), and the mixture was stirred for 30 minutes. The reaction solution was mixed with 1 mol/l hydrochloric acid (200 ml), warmed up to room temperature and then extracted with diethyl ether (200 ml×2). The resulting organic layer was washed with saturated brine (100 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure and the residue was applied to a silica gel column chromatography (silica gel 100 g). By eluting with a n-hexane:ethyl acetate system of from (3:1) to (1:1), 1.97 g (52%) of the title Sound was obtained as a light yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[C:15]([CH2:17][CH2:18][CH3:19])[C:14]([O:20]C)=[CH:13][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:16]=[C:15]([CH2:17][CH2:18][CH3:19])[C:14]([OH:20])=[CH:13][C:4]=1[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CCCc1cc(OC)c(C(=O)c2ccccc2)cc1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCc1cc(O)c(C(=O)c2ccccc2)cc1O
Temperature: -78 °C
Yield: 99 %

Procedure:
0.37 gram (1.3 mmole, 1.0 eq.) of product from step E was dissolved in 5 ml of dichloromethane. The solution was stirred under nitrogen atmosphere at -78° C. and 3.2 ml of 1.0 M boron tribromide solution in hexanes (3.2 mmole, 2.5 eq.) was added dropwise over a 5-8 minute span. The reaction was allowed to slowly warm, and after 3 hours ice was added to the reaction mixture. After an additional 30 minutes some water was added and the mixture was diluted with dichloromethane. The layers were separated and the organic was washed twice more with water, dried over sodium sulfate, filtered and evaporated to give the title compound (0.33 gram, 100% yield) without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[N:8]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:12][CH:13]=2)[N:8]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nn(C2CCCCO2)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Ethyl6-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-indazole-3-carboxylate (148 mg) which can be prepared according to the method described in Reference example 20, etc. was dissolved in dehydrated DMF (5.2 mL; manufactured by Kanto Chemical Co., Inc.), added with potassium carbonate (227 mg; manufactured by Sigma-Aldrich Co.) and benzyl bromide (73.6 μL; manufactured by Wako Pure Chemical Industries, Ltd.), followed by stirring for overnight at 60° C. After cooling to room temperature, the reaction solution was added to water, and then extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with ethyl acetate, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography “COLUMN-A”; n-hexane:ethyl acetate=95:5→74:26) to obtain the title compound (187 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([OH:12])([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH:17]1([N:23]=[C:24]=S)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].BrN1C(=O)CCC1=O>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([CH3:10])([CH3:11])[O:12][C:24]([NH:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:16][S:13]2(=[O:14])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(c1cccc(Br)c1)S(N)(=O)=O
Reactant: S=C=NC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1c1cccc(Br)c1
Reaction time: 0.33 h
Yield: 30.5 %

Procedure:
A solution of 1.00 g of 1-(3-bromophenyl)-2-hydroxy-2-methylpropane-1-sulfonamide and 0.483 g of cyclohexyl isothiocyanate in 7 ml of NMP was admixed with 1.62 ml of a 2 N solution of sodium bis(trimethylsilyl)amide. After stirring for 20 minutes, 578 mg of N-bromosuccinimide were added and the mixture was stirred at room temperature for a further 60 minutes. The reaction solution was admixed with 150 ml of water and extracted twice with 150 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC, and the product-containing fractions were lyophilized. This gave the product (411 mg) with a molecular weight of 415.3 g/mol (C17H23BrN2O3S); MS (ESI): m/e=416 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=1[O:37][CH3:38]>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[C:29]([O:37][CH3:38])[CH:30]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COc1cc(B(O)O)ccc1F
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2ccc(F)c(OC)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 4-fluoro-3-methoxyphenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:19]([F:24])([F:23])C([O-])=O.[Na+]>CN(C)C=O.O>[F:23][CH:19]([F:24])[O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.1 %

Procedure:
To a solution of 2-methyl-4-nitrophenol (14 g, 91.50 mmol) in dimethylformamide (120 mL) and water (25 mL) was added Cs2CO3 (41.8 g, 128.22 mmol), and sodium 2-chloro-2,2-difluoroacetate (32 g, 209.84 mmol). The resulting solution was stirred for 20 minutes at room temperature, then for an additional 3 hours at 100° C. The reaction solution was cooled to room temperature before the addition of 100 ml of H2O. The resulting solution was extracted with EtOAc (4×100 ml) and the combined organic layers were washed with H2O (2×150 mL), dried over Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography to provide 16 g (86%) of 1-(difluoromethoxy)-2-methyl-4-nitrobenzene.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]1=[O:21])[CH3:2].Cl[C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.ClCCl>[Cl:33][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([O:9][C:7]1[CH:6]=[CH:5][C:4]([CH:10]3[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]3=[O:21])=[C:3]([CH2:1][CH3:2])[CH:8]=1)[CH:32]=[N:31]2
Reactant: Clc1ccc2nc(Cl)cnc2c1
Reactant: CCc1cc(O)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cc(Oc2cnc3cc(Cl)ccc3n2)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 140 °C

Procedure:
4-(2-Ethyl-4-hydroxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.100 g, 0.34 mmol) is added to a mixture of 2,6-dichloroquinoxaline (0.081 g, 0.41 mmol) and potassium carbonate (0.110 g, 0.69 mmol) in N,N-dimethylformamide (3 ml), and the mixture is heated at 140° C. under microwave irradiation for 40 minutes. The mixture is cooled to room temperature, then acidified by addition of 2M aqueous hydrochloric acid. The mixture is diluted with dichloromethane and passed through a phase separation cartridge. The organic phase is concentrated to around 2 ml, and purified by preparative reverse phase HPLC to give 4-[4-(6-choroquinoxalin-2-yloxy)-2-ethylphenyl]-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [CH2:1]([S:10][C:11]#[N:12])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([OH:23])(=[O:22])=[O:21])[CH:15]=1>[Cl-].[Zn+2].[Cl-].O>[C:4]1([C:2]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([OH:23])(=[O:21])=[O:22])[CH:15]=3)[S:10][CH:1]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: N#CSCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: O=S(=O)(O)c1cccc(Nc2nc(-c3ccccc3)cs2)c1

Procedure:
132 parts of phenacyl thiocyanate, 38 parts of zinc chloride and 129 parts of 1-aminobenzene-3-sulfonic acid are together stirred with 750 parts of water for 20 hours at the boil. After the mixture has cooled, the product is filtered off and dried.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15]([Mg]Br)[CH:16]=[CH2:17].[Cl-].[NH4+]>C(OCC)C>[CH2:17]([C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH:16]=[CH2:15]
Reactant: C=CC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h

Procedure:
800 ml solution of 25.0 g tert-butyl 4-oxo-1-piperidinecarboxylate in diethyl ether was cooled in ice/methanol, and 138 ml solution of allylmagnesium bromide (1 M in diethyl ether) was added dropwise thereinto. The reaction mixture was stirred for 3 hr and 10 min. The reaction solution was poured into a mixture of saturated aqueous ammonium chloride and ice. The diethyl ether layer was recovered and washed with brine. It was dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated, and the resulting residue was purified by silica gel column chromatography to give 15.9 g of tert-butyl 4-allyl-4-hydroxy-1-piperidinecarboxylate.
Reaction SMILES: O[CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[O:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:20]1([CH:2]2[O:19][C:5]([C:6]3[C:7]([O:12][C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)=[N:8][CH:9]=[CH:10][CH:11]=3)=[N:4][CH2:3]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(NCC(O)c1ccccc1)c1cccnc1Oc1cccnc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(C2CN=C(c3cccnc3Oc3cccnc3)O2)cc1
Temperature: 25 °C
Yield: 10.2 %

Procedure:
A solution of N-(2-Hydroxy-2-phenyl-ethyl)-2-(pyridin-3-yloxy)-nicotinamide (0.450 grams, 1.3 mmole) and phosphorus oxychloride (1.25 ml, 13 mmole) in toluene (5 ml) was stirred over night. The mixture was concentrated to dryness and dissolved in methanol (5 ml) and potassium carbonate (0.500 g) was added. The mixture was stirred at room temperature over night. The mixture was poured into water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over Na2SO4, and concentrated to give an oil that was purified by chromatography on silica gel eluting with ethyl acetate to give a colorless oil (0.042 g). HRMS 318.1269; 1H NMR (400 mHz, CDCl3) d 4.09 (dd, J=15.1 Hz, 8.1 Hz, 6H), 4.57 (dd, J=15.1 Hz, 10.3 Hz, 1H), 5.67 (dd, J=10.2 Hz, 7.9 Hz, 1H), 7.09-7.13 (m, 1H), 7.32-7.39 (m, 6H), 7.54-7.57 (m, 1H), 8.20-8.22 (m, 1H), 8.29-8.31 (m, 1H), 8.46 (dd, J=4.6 Hz, 1.0 Hz, 1H), 8.61-8.64 (m, 1H).
Reaction SMILES: Cl.[C:2]1([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]([C:26](=O)[CH3:27])[CH2:18][CH2:19][CH2:20][CH2:21][S:22]([OH:25])(=[O:24])=[O:23]>C(O)(=O)C>[CH3:27][C:26]1[C:17]([CH3:16])([CH2:18][CH2:19][CH2:20][CH2:21][S:22]([O-:25])(=[O:24])=[O:23])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N+:8]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(=O)C(C)CCCCS(=O)(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: CC1=[N+](c2ccccc2)c2ccccc2C1(C)CCCCS(=O)(=O)[O-]
Reaction time: 3 h

Procedure:
N,N-Diphenylhydrazine hydrochloride (0.01 mol, 2.2 g), 5-methyl-6-oxoheptanesulfonic acid (0.017 mol, 3.0 g) in glacial acetic acid (20 ml) were stirred at room temperature (˜20° C.) for an hour then at 100° C. for 3 hours (TLC check). The reaction mixture was cooled down and the solvent removed under vacuum. The residue was washed with diethyl ether and purified by flash column on silicagel. Yield: 2 g (56%). Structure confirmed by NMR spectrum.
Reaction SMILES: C([O:8][C:9](=[O:38])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:37])[CH2:16][CH2:17][C:18](=[O:36])[C@@H:19]([NH:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CO.[Pd]>[C:28]([NH:27][C@@H:19]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:18](=[O:36])[CH2:17][CH2:16][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:38])=[O:8])=[O:37])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [H][H]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)O)c1ccccc1

Procedure:
To a stirred solution of the (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-proline benzyl ester (100 mg, 0.1951 mmol) in dry EtOAc-MeOH (3:1 ratio) (10 mL) was added 10% Pd/C (100 mg) and the resulting mixture stirred at room temperature under 1 atmosphere of hydrogen for 24 h. Filtration of the black Pd residue and evaporation of the filtrate gave a pale yellow crude residue. Column chromatography on silica gel elution with 37% MeOH-EtOAc afforded the (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-proline 5a as a white solid powder (68 mg, 82%): mp 148-149° C. (lit.12 mp 151-153° C.); Rf 0.28 (37% MeOH-EtOAc); IR (KBr) ν 1765 (CO), 3300 (broad, COOH) cm−1; 1H NMR (300 MHz, CD3OD) δH 2.01 (2H, m, —CH2), 2.51 (4H, m, —CH2CO and —CH2CH2N), 2.78 (2H, m, —CH2CO), 3.02-3.38 (4H, m —CH2Ph and —CH2N—), 4.84 (1H, m, —CH—), 4.98 (1H, m, —CH—) and 7.08-7.68 (10H, m, Ar—H); 13C NMR (75 MHz, CD3OD) δC 22.6, 24.5, 28.6, 34.3, 36.2, 46.4, 59.9, 61.8, 126.6 (2C), 126.8 (2C), 128.4, 128.9 (2C), 129.0, 131.6, 133.5, 136.6, 136.9, 167.9, 171.0, 179.3 and 208.9; HRMS m/z calcd for C24H26N2O5 (M+) 422.18417, found 422.18417. [± The carboxylic acid and amide protons were not observed, presumably, due to rapid exchange with water in the deuteriated NMR solvent.]
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][C:12]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][OH:14].[H-].[Na+].O>CS(C)=O>[CH3:11][C:12]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][O:14][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CC(C)(CO)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(COc1ccc([N+](=O)[O-])cc1)c1ccccc1
Yield: 72 %

Procedure:
In 200 ml of dimethylsulfoxide are dissolved 23 g of 4-nitrochlorobenzene and 25 g of 2,2-dimethyl-2-phenylethylalcohol. To this solution is added 4 g of sodium hydride is added with stirring. After 24 hours stirring at room temperature and another 30 minutes stirring at 60° C, 500 ml of water is added and the mixture is extracted with ether. The extract is washed with water, dried and the solvent is evaporated. Recrystallization of the residue from 200 ml of methanol, gives 28.5 g of 4-(2,2-dimethyl-2-phenylethyloxy)nitrobenzene, melting point: 79°-80° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1.[H-].[Na+]>>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:16][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([C:10]([F:9])([F:19])[F:20])=[CH:18][CH:17]=2)[N:3]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: FC(F)(F)c1ccc(COc2cncc(Cl)n2)cc1
Yield: 93.5 %

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (444 mg, 3.00 mmol) and 4-trifluoromethylbenzyl alcohol (581 mg, 3.30 mmol) and NaH (55% in mineral oil, 144 mg, 3.30 mmol). Recrystallization from hexane gave 0.81 g (93%) of the title compound: mp 67-69° C.