Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>C(OCC)(=O)C>[ClH:22].[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2F)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC1(c2ccccc2F)CCNCC1
Reaction time: 3 h

Procedure:
To a stirring solution of 4-(2-fluoro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 4.06 mmol) in ethyl acetate (5 mL) was added hydrogen chloride (15 mL, 4N in 1,4-dioxane) and the resulting solution was stirred for 3 hours during which time a precipitate formed. The reaction mixture was concentrated at reduced pressure to give the crude product, 4-(2-fluoro-phenyl)-piperidin-4-ol hydrochloride, which was used in the next step without purification. To a solution of chlorosulfonyl isocyanate (0.35 mL, 4.06 mmol) in dichloromethane (10 mL) at 3° C. was added tert-butanol (0.39 mL, 4.06 mmol). After 25 minutes, pyridine (0.72 mL, 8.9 mmol) was added and the resulting mixture was stirred for 40 minutes during which time a precipitate formed. This slurry was added via pipette to a solution of crude 4-(2-fluoro-phenyl)-piperidin-4-ol hydrochloride (940 mg, 4.06 mmol) and triethylamine (0.62 mL, 4.47 mmol) in dichloromethane (6 mL) at 3° C. The resulting mixture was allowed to warm to ambient temperature over 4 hours. The reaction mixture was diluted with dichloromethane (100 mL) and washed with dilute hydrochloric acid (40 mL, 0.1N) followed by saturated aqueous sodium chloride (30 mL). The organic layer was concentrated at reduce pressure. The resulting oil was dissolved in ethyl acetate (5 mL) and to this solution was added hydrogen chloride (15 mL, 4N in 1,4-dioxane) and the resulting solution was stirred for 5 hours. The reaction mixture was concentrated at reduced pressure and the resulting solid was purified by column chromatography through a silica gel cartridge (12 g) eluting with ethyl acetate/hexane (1:9 to 2:5) to give the product as a white solid (420 mg, 38% over 3 steps). 1H NMR (DMSO-d6) δ 7.65 (m, 1H,), 7.30 (m, 1H), 7.24-7.09 (m, 2H), 6.75 (s, 2H), 5.28 (s, 1H), 3.31 (m, 2H), 2.92 (m, 2H), 2.22 (m, 2H), 1.68 (m, 2H). MS (ES+)=275 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]#[N:14])=[C:4]([CH3:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[Br:1][C:2]1[C:3]([C:13]#[N:14])=[C:4]([CH3:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(O)c(C(=O)O)cc(Br)c1C#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(C#N)c(C)c1O
Reaction time: 3 h
Yield: 53.8 %

Procedure:
To a solution of 5-bromo-4-cyano-2-hydroxy-3-methylbenzoic acid (7.40 g) in dichloromethane (70.0 mL) were added oxalyl chloride (3.91 g) and DMF (0.20 mL) under ice-cooling, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with THF. To this mixture was added dropwise a solution of triethylamine (5.66 g) in methanol (50.0 mL) under ice-cooling, and the mixture was stirred for 20 min. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (4.20 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Br)([CH3:4])([CH3:3])[CH3:2].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].C(Cl)Cl.O>C(#N)C.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>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccccc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Yield: 74 %

Procedure:
51.4 g of Bromobenzoic acid tert.-butyl ester, 21.6 g of trimethylsilylacetylene, 1.4 g of (Ph3P)2PdCl2 in 400 ml of absolute acetonitrile and 100 ml of triethylamine are stirred under reflux for 8 hours in an atmosphere of nitrogen. After the reaction product has been worked up with CH2Cl2 /H2O and distilled, 40.6 g of 4-(trimethylsilylethinyl)-benzoic acid tert.-butyl ester are obtained.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:19](=[C:20]([CH2:25]Cl)[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:25][C:1]#[N:2])[C:19]=3[CH:18]=[CH:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: ClCc1cccc2c(-c3ccc(Cl)cc3)nccc12
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CCc1cccc2c(-c3ccc(Cl)cc3)nccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5.0 g of sodium cyanide and 120 ml of dimethylsulfoxide was added 11.7 g of 1-(4-chlorophenyl)-5-chloromethylisoquinoline little by little. The mixture was stirred at room temperature for 2 hours, and poured into a mixture of ethyl acetate and 1% sodium bicarbonate aqueous solution. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried. The solvent was distilled off. Recrystallization of the residue from dichloromethane-hexane afforded 1-(4-chlorophenyl)isoquinoline-5-acetonitrile as slightly yellow prisms having a melting point of 131.5° to 132.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][O:35]1.O>CN(C)C=O>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][O:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCC3CCCO3)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A stirring mixture of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (200 mg) and potassium carbonate (236 mg) in dry N,N-dimethylformamide (2 ml) was heated with stirring at 60° C. for 1 h. 2-(2-Bromoethyl)tetrahydrofuran (122 mg) was added and the stirring mixture heated at 50° C. for 4 h. After allowing to cool, water was added and the mixture extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a phase separation cartridge and stripped to give a brown oil. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (20-60%) and the appropriate fractions combined and evaporated to remove acetonitrile. The remaining aqueous mixture was made basic with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to afford the title compound, yield 107 mg.
Reaction SMILES: [CH:1]1([CH:4]([C:24]2[C:29](=[O:30])[O:28][C:27]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:26]=3[C:25]=2[OH:37])[C:5]2[CH:6]=[C:7]([NH:11][S:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=[O:19])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:43]O>C(OCC)(=O)C>[CH:1]1([CH:4]([C:24]2[C:29](=[O:30])[O:28][C:27]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:26]=3[C:25]=2[OH:37])[C:5]2[CH:6]=[C:7]([NH:11][S:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([O:20][CH3:43])=[O:19])(=[O:13])=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2cccc(C(c3c(O)c4c(oc3=O)CCCCCC4)C3CC3)c2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(S(=O)(=O)Nc2cccc(C(c3c(O)c4c(oc3=O)CCCCCC4)C3CC3)c2)c1

Procedure:
A solution of the title compound from Example 292 (300 mg) and concentrated sulfuric acid (300 μL) in methanol (10 mL) is stirred for 2 days at room temperature, diluted with ethyl acetate, washed with water, brine, dried (anhydrous sodium sulfate), filtered, concentrated, and chromatographed on silica gel to give 225 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:8]1[S:9][C:10]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cccc(Cl)c2s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc2nc(CBr)sc12

Procedure:
A mixture of 7-chloro-2-methyl-benzothiazole (1.00 g, 5.45 mmol), N-bromosuccinimide (1.26 g, 7.08 mmol), benzoyl peroxide (0.1 g), and CCl4 (10 mL was heated to reflux under irradiation of a UV lamp for 14 h. The reaction mixture was cooled and filtered to remove the succinimide formed in the reaction, and the filtrate was evaporated to dryness. The resulting solid was purified by flash chromatography to give the title lamp (400 mg, 1.5 mmol). 1H-NMR (CDCl3): δ 7.94 (d, 1H), 7.47 (t, 1H), 7.42 (d, 1H), 4.82 (s, 2H, CH2). HPLC Rt: 7.19 min.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](O)=[O:28]>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:28]
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccccc1F
Product: O=C(Cc1ccccc1F)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(2-fluorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.46-7.49 (m, 1H), 7.35 (tdd, J=7.7, 5.7, 1.9 Hz, 1H), 7.18-7.23 (m, 2H), 3.81-3.84 (m, 5H), 3.44-3.59 (m, 1H), 3.05-3.14 (m, 4H); MS (ESI+) M/Z 383 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][CH:4]=1.Cl.[NH2:16][OH:17].N1C=CC=CC=1.C(O)C>O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[N:16][OH:17])=[CH:5][CH:4]=1
Reactant: O=C1CCc2ccc(C(F)(F)F)cc21
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: ON=C1CCc2ccc(C(F)(F)F)cc21

Procedure:
One gram of 6-trifluoromethyl-1-indanone was converted to the corresponding oxime by reaction with 1.92 g. of hydroxylamine hydrochloride in 4 ml. of pyridine and 20 ml. of anhydrous ethanol. The mixture was refluxed for 24 hours and then poured into cold water. The oxime precipitated and was separated by filtration. The filter cake was washed with hot water. 1.02 g. of a white powdery solid melting at 128°-32° C. comprising 6-trifluoromethyl-1-indanone oxime were obtained. The compound melted at 132°-7° C. after recrystallization from an ethyl acetatecyclohexane solvent mixture.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([OH:12])[CH:10]=[CH2:11].[H-].[Na+]>CS(C)=O>[CH2:9]([O:12][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1)[CH:10]=[CH2:11]
Reactant: C=CCO
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CCOc1nccnc1Cl
Temperature: 0 °C

Procedure:
59.6 g of 2,3-dichloropyrazine and 92.8 g of allyl alcohol are dissolved in 400 ml of dimethylsulphoxide. 9.6 g of sodium hydride are introduced into this solution over the course of 30 minutes at 0°-5° C., whilst stirring. The mixture is then stirred for 15 hours at room temperature. Thereafter the reaction mixture is poured into 2 liters of ice water and extracted by shaking with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a waterpump vacuum. The residue is distilled in a high vacuum. 2-Allyloxy-3-chloro-pyrazine, boiling point 42°-44° C./0.03 mm Hg, is thus obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:13])[C:8]([CH3:12])=[C:9]([OH:11])[N:10]=[C:5]2[S:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][N:22]=1>CN(C=O)C>[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][O:11][C:9]3[N:10]=[C:5]4[S:4][CH:3]=[C:2]([CH3:1])[N:6]4[C:7](=[O:13])[C:8]=3[CH3:12])=[CH:29][CH:28]=2)=[O:26])=[CH:23][N:22]=1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)nc1
Reactant: Cc1c(O)nc2scc(C)n2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(C(=O)c3ccc(Cl)nc3)cc2)nc2scc(C)n2c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
To a solution of 3,6-dimethyl-7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one (526 mg) and potassium carbonate (574 mg) in DMF (10 ml) was added 4-(6-chloronicotinoyl)benzyl bromide (852 mg) and the mixture was stirred at 80° C. for 2 hours. This reaction mixture was concentrated and the residue was diluted with water-ethyl acetate and extracted with ethyl acetate. The extract was purified by silica gel column chromatography (hexane: ethyl acetate =2:1) and recrystallized from ethyl acetate to provide the title compound as colorless solid (300 mg).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]([NH:5][C:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:13][CH:12]=2)[CH2:9][C:8](=[O:10])[CH2:7]1)=[O:4].[BH4-].[Na+]>C(Cl)Cl.CO>[F:42][C:2]([F:1])([F:43])[C:3]([NH:5][C:6]1([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)[CH2:9][CH:8]([OH:10])[CH2:7]1)=[O:4]
Reactant: O=C1CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)CC(O)C1)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,2,2-trifluoro-N-(3-oxo-1-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-2) (25 mg, 0.043 mmol) in CH2Cl2 (1 mL) and MeOH (1 mL) was added NaBH4 (2.0 mg, 0.052 mmol) at −78° C., and the mixture was stirred at −78° C. for 1 hour. The mixture was quenched with sat. NH4Cl, extracted with CHCl3, washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give 2,2,2-trifluoro-N-(3-hydroxy-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-3). MS (M+H)+: observed=581, calculated=581.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]([CH2:26][CH3:27])[CH2:10][C:11]([NH:13][C:14]1[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:23]([CH3:25])[CH3:24])=O)[CH3:8].O.[OH-].[Na+]>O1CCCC1>[CH2:26]([N:9]([CH2:7][CH3:8])[CH2:10][CH2:11][NH:13][C:14]1[C:19]([CH:20]([CH3:21])[CH3:22])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:23]([CH3:25])[CH3:24])[CH3:27]
Reactant: CCN(CC)CC(=O)Nc1c(C(C)C)cccc1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CCNc1c(C(C)C)cccc1C(C)C

Procedure:
To 200 mL of tetrahydrofuran under a nitrogen atmosphere add 8.8 g (0.23 mol) of lithium aluminum hydride. Add dropwise a solution of 33.8 g (0.12 mol) of 2-(diethylamino)-N-(2,6-bis(1-methylethyl)phenyl)acetamide in 150 mL of tetrahydrofuran. When the addition is complete allow the reaction to stir at reflux. Monitor the progress of the reaction by thin-layer chromatography on silica gel (CH2Cl2 :MeOH, 9:1). Upon completion of the reaction add 1 mL of water, 1 mL of 15% NaOH and 3 mL of water per gram of lithium aluminum hydride. The solid material is removed by suction filtration through celite and the solvent is removed in vacuo. Recrystallize the solid from hexane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:15][CH2:14]2)[CH3:11])=[O:25])=[CH:6][CH:7]=1
Reactant: CN(C[C@H]1CC[C@H](OCCCCO)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Product: CN(C[C@H]1CC[C@H](OCCCCOS(C)(=O)=O)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 4-(4-{[(4-chloro-phenoxy-carbonyl)-methyl-amino]-methyl}-cyclohexyloxy)-butyl ester as colorless viscous, MS: 448 (MH+, 1 Cl).
Reaction SMILES: [CH3:1][C:2](Cl)([CH2:4][CH2:5][C:6]([CH3:9])(Cl)[CH3:7])[CH3:3].[S:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>CCCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:3])[C:13]2[CH:14]=[CH:15][S:11][C:12]=2[C:6]([CH3:9])([CH3:7])[CH2:5][CH2:4]1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: c1ccsc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCCC
Product: CC1(C)CCC(C)(C)c2sccc21
Temperature: 40 °C

Procedure:
90 g of 2,5-dimethyl-2,5-dichlorohexane and 195 ml of thiophene are dissolved in 400 ml of hexane. 54 ml of titanium tetrachloride are slowly added dropwise thereto while cooling with ice, the mixture is warmed to 40° C. for 1.5 hours, again cooled with ice and the dark red mixture is treated cautiously with ice-water. The mixture is extracted three times with ether, the organic phase is washed with saturated sodium bicarbonate solution, dried and evaporated. The thus-obtained black oil is firsly filtered over silica gel (eluting agent hexane) and subsequently distilled in a water-jet vacuum. There are obtained 18.5 g of 4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thiophene as a colorless liquid, b.p. 95°-96° C./10 mm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.C[O-].[Na+].Br[CH2:19][C:20]([OH:22])=[O:21]>CO.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:19][C:20]([OH:22])=[O:21])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CBr
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)c1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-t-butylphenol, 37.5 gm, was added to 300 ml of ethanol. 57.2 gm of a 25% solution of sodium methoxide (2 equivalents) in methanol was then added to the system. The system was stirred at room temperature for approximately 0.5 hour. Afterwards, 29.5 ml of bromoacetic acid was added and the system then heated to reflux for 18 hours. The reaction was then stopped and the solvent removed by stripping. The resulting solid was dissolved in methylene chloride; dilute sodium hydroxide was added to give a basic pH. The resulting precipitate was dissolved in hydrochloric acid, and then extracted with methylene chloride. The methylene chloride was stripped and the resulting crude product air dried. Toluene was then added to the product. The toluene was removed by stripping and any remaining water was azeotroped off with the toluene to give 33.3 gm of 4-t-butylphenoxyacetic acid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:22])[NH2:23]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and (S)-2-amino-3-phenyl-propionamide hydrochloride (1:1) (CAN 5241-58-7, 118.84 mg, 0.64 mmol) as starting materials, and isolated (60 mg, 37.03%) as colorless sticky solid; LC-MS (UV peak area, ESI) 100%, 381.4 (M+H).
Reaction SMILES: I[C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=2[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(NOCc1ccccc1I)c1ccccc1NCc1ccncc1
Product: COc1ccc(-c2ccccc2CONC(=O)c2ccccc2NCc2ccncc2)cc1

Procedure:
Prepared by a similar procedure as described for preparation of example 363. Starting materials: N-(2-Iodo-benzyloxy)-2-[(pyridin-4-ylmethyl)amino]-benzamide (see example 360) and 4-methoxyphenylboronic acid (Aldrich).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[NH:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:35]([C:31]4[CH:30]=[C:29]5[C:34](=[CH:33][CH:32]=4)[NH:26][CH:27]=[CH:28]5)=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5[nH]ccc5c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1H-indole-5-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.