Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:37])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>CO>[CH2:3]([NH:10][C:11](=[O:37])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCOC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCOC)c1
Temperature: 50 °C
Yield: 83.8 %

Procedure:
278 mg (6.95 mmol, 10 eq) of sodium hydroxide are added to a solution of 337 mg (0.695 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(2-methoxyethoxy)biphenyl-4-yl]propanoate in 10 ml of methanol. The reaction mixture is heated at 50° C. for 2 hours. The reaction medium is evaporated to dryness, taken up in water, acidified with 2N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and the oil obtained is chromatographed on silica gel (10 g FlashSmart column) eluted with ethyl acetate. 274 mg of 3-[3′-(3-heptyl-1-methylureido)-2-(2-methoxyethoxy)biphenyl-4-yl]propanoic acid are obtained in the form of a whitish oil. Yield=84%
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45](Cl)=[CH:44][C:43]=1[F:49].[CH2:51]([C:53]([OH:85])([CH2:83][CH3:84])/[CH:54]=[CH:55]/[C:56]1[CH:61]=[CH:60][C:59]([C:62]([CH2:80][CH3:81])([C:65]2[CH:70]=[CH:69][C:68](B3OC(C)(C)C(C)(C)O3)=[CH:67][CH:66]=2)[CH2:63][CH3:64])=[CH:58][C:57]=1[CH3:82])[CH3:52]>O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:68]2[CH:67]=[CH:66][C:65]([C:62]([CH2:80][CH3:81])([C:59]3[CH:60]=[CH:61][C:56](/[CH:55]=[CH:54]/[C:53]([CH2:83][CH3:84])([OH:85])[CH2:51][CH3:52])=[C:57]([CH3:82])[CH:58]=3)[CH2:63][CH3:64])=[CH:70][CH:69]=2)=[CH:44][C:43]=1[F:49]
Reactant: COC(=O)Cc1ccc(Cl)cc1F
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)OC)c(F)c3)cc2)cc1C)CC
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
A solution of palladium acetate (3.3 mg, 0.0146 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (12.0 mg, 0.0293 mmol) and potassium phosphate (62.3 mg, 0.29 mmol) in water (0.050 mL) and toluene (0.200 mL) was stirred for three minutes. A solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester (Example 40; 31.8 mg, 0.15 mmol) and (E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 50.0 mg, 0.1049 mmol) in toluene (0.250 mL) was added, and the mixture was stirred in a nitrogen atmosphere at 100° C. for 1.5 hours. After filtration through cotton plug, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (17% ethyl acetate/hexane) to give the title compound (40.1 mg, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:55])[NH:15][C@@H:16]([C:28](=[O:54])[N:29]([C@@H:31]([C:43]2[O:47][N:46]=[C:45]([C:48](OCCC)=[O:49])[N:44]=2)[CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH3:30])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:56][NH2:57]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:55])[NH:15][CH:16]([C:28](=[O:54])[N:29]([CH:31]([C:43]2[O:47][N:46]=[C:45]([C:48](=[O:49])[NH:57][CH3:56])[N:44]=2)[CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH3:30])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN
Reactant: CCCOC(=O)c1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: CCO
Product: CNC(=O)c1noc(C(Cc2ccc3ccccc3c2)N(C)C(=O)C(Cc2ccc3ccccc3c2)NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
4-((1R)-1-{N-[(1R)-1-(3-Propoxycarbonyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (0.80 g, 1.07 mmol) was dissolved in 33% methylamine in ethanol and stirred at 90° C. for 18 h in a closed reaction vessel. The reaction mixture was concentrated in vacuo and the residue as chromatographed on silica (60 g) using ethyl acetate and heptane (7:3) as eluent to give 0.15 g of 4-(1-{-N-[1-(3-methylcarbamoyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[S:16][C:17]4[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:18]=4[CH:19]=3)[C:9]([CH2:13][OH:14])=[C:10]([C:11]#[N:12])[N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:31]CN(C(C)C)C(C)C>ClCCl.CO>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[S:16][C:17]4[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:18]=4[CH:19]=3)[C:9]([CH2:13][O:14][CH3:31])=[C:10]([C:11]#[N:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(C)cc2cc(-c3c(CO)c(C#N)n4ncnc(N)c34)sc12
Reactant: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: COCc1c(-c2cc3cc(C)cc(OC)c3s2)c2c(N)ncnn2c1C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of Example 68 (60 mg, 164 μmol) in dichloromethane (5 ml) was treated with thionyl chloride (18 μl, 246 μmol). The mixture was stirred at rt for 15 min and then evaporated. The residue was dissolved in methanol (2 ml) and treated with DIPEA (57 μl, 328 μmol). The mixture was stirred first 2 h at 60° C., then refluxed overnight and finally heated to 150° C. for 30 min in a microwave device. After this, the mixture was evaporated, and the residue was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. TFA). The product thus obtained was dissolved in methanol and filtered through an anion exchange cartridge (Stratospheres SPE, PL-HCO3 MP-resin). The cartridge was eluted with methanol, and the filtrate was evaporated affording 18 mg (28% of th.) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)[CH:8]=1)([O-])=O>CCOC(C)=O.CCO.O=[Pt]=O>[N:11]1([CH2:10][CH2:9][N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1cnn(CCN2CCc3ccccc32)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cnn(CCN2CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)indoline (183 mg, 0.71 mmol) in EtOAc (0.7 mL, degassed) and EtOH (2 mL, degassed), PtO2 (14 mg, 0.07 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 18 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain the title compound as an oil, which was used in the next step without further purification. LC-MS conditions A: tR=0.51 min, [M+H]+=229.26.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH:12]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)=[CH:5][C:6](=[O:24])[O:7]2>C(O)C>[OH:1][C:2]1[CH:11]=[C:10]([CH:12]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:13])[CH:9]=[C:8]2[C:3]=1[CH:4]([C:25]1[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=1)[CH2:5][C:6](=[O:24])[O:7]2
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(-c3ccncc3)cc(=O)oc2c1
Solvent: CCO
Product: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(=O)CC2c1ccncc1

Procedure:
The coumarin of Example 2 (2.2 g) was hydrogenated in ethanol using 5% palladium on carbon as a catalyst. The resulting oil was purified on a Florisil column, eluting with chloroform to give the desired product.
Reaction SMILES: Br[C:2]1[C:11]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:10]2[C:5]([NH:6][C:7]([CH3:25])([CH3:24])[C:8](=[O:23])[N:9]2[CH3:22])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH2:35][O:36][CH3:37])[CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:21])=[C:14]([CH:19]=1)[O:13][CH2:12][C:11]1[C:2]([C:29]2[CH:30]=[CH:31][C:32]([O:34][CH2:35][O:36][CH3:37])=[CH:33][C:28]=2[O:27][CH3:26])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]([CH3:22])[C:8](=[O:23])[C:7]([CH3:25])([CH3:24])[NH:6]2
Reactant: Cc1ccc(F)cc1OCc1c(Br)ccc2c1N(C)C(=O)C(C)(C)N2
Reactant: COCOc1ccc(B(O)O)c(OC)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCOc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)N(C)C(=O)C(C)(C)N3)c(OC)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 96.8 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 3-1, 2.32 g, 5.70 mmol), 2-methoxy-4-methoxymethoxyphenylboronic acid (Reference Compound No. 7-1, 2.43 g, 11.5 mmol), cesium carbonate (9.46 g, 29.0 mmol), and bis(triphenylphosphine)palladium(II)dichloride (415 mg, 0.591 mmol) was suspended in anhydrous N,N-dimethylformamide (25 ml) and the mixture was stirred at 80° C. for 5 hours. After cooling down, ethyl acetate (150 mL) and water (150 mL) were added and partitioned. The organic layer was washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (2.73 g) as a colorless solid. (Yield 97%)
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1O[C@H]1CCl.[CH:26]1([C:32]2C=C[C:35]([OH:38])=[CH:34][CH:33]=2)CCCCC1.C(OCC)(=O)C#CCC>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:35](=[O:38])[CH:34]=[C:33]([CH2:32][CH3:26])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Agent: CCC#CC(=O)OCC
Agent: ClC[C@H]1CO1
Solvent: CCO
Product: CCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2
Temperature: 25 °C

Procedure:
To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (1.0 g, 3.64 mmol), prepared in accordance with the procedures as set forth in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-cyclohexylphenol, in ethanol (18.2 mL) was added ethyl 2-pentynoate (0.92 g, 7.28 mmol). The reaction mixture was heated at reflux for 14 hrs and then gradually cooled to room temperature. The resulting crystalline solid was isolated by filtration, washed with heptane 3 times, and dried under vacuum to afford 560 mg of (S)-2-(4-cyclohexyl-phenoxymethyl)-5-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as a white solid. [α]D25 −27.96 (c 0.526, CHCl3).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:7]=1[CH:6]=2)[CH3:2].Cl[CH2:18][CH2:19][CH2:20][S:21][C:22]1[N:23]([CH3:38])[C:24]([C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][C:31]([CH3:37])=[N:32]3)=[N:25][N:26]=1>>[CH2:1]([C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][N:11]([CH2:18][CH2:19][CH2:20][S:21][C:22]3[N:23]([CH3:38])[C:24]([C:27]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:28]=4[CH:29]=[CH:30][C:31]([CH3:37])=[N:32]5)=[N:25][N:26]=3)[CH2:12][CH2:13][C:7]=1[CH:6]=2)[CH3:2]
Reactant: CCc1nc2cc3c(cc2o1)CCNCC3
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Product: CCc1nc2cc3c(cc2o1)CCN(CCCSc1nnc(-c2cccc4nc(C)ccc24)n1C)CC3

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-ethyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (1.5 mmol) and 5-{5-[(3 chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline and was obtained as a faint yellow slightly hygroscopic solid (0.75 mmol).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[N:20][C:19](Br)=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27].CC(C)([O-])C.[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(CC)CC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[N:20][C:19]([NH:27][C:26]5[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=5[O:24][CH3:23])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1N
Reactant: O=C(Nc1cnc(Br)cn1)C1(c2ccc3c(c2)OCO3)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccccc1Nc1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cn1
Temperature: 80 °C
Yield: 39.5 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromopyrazin-2-yl)cyclopropanecarboxamide (72 mg, 0.2 mmol), 2-methoxyaniline (30 mg, 0.24 mmol), and potassium tert-butoxide (31 mg, 0.28 mmol) in 2:1 dioxane:Et3N (1.8 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.6 mg, 0.0020 mmol) and XANTPHOS (1.2 mg, 0.0020 mmol). The reaction mixture was heated to 80° C. for 18 hours. The reaction mixture was filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product (32 mg, 0.079 mmol, 39%). ESI-MS m/z calc. 404.1, found 405.3 (M+1)+; retention time 3.61 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([S:10]([C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:24])[C:22]#[CH:23]>CN(C)C=O>[CH3:9][N:8]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([NH:24][CH2:21][C:22]#[CH:23])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20]
Reactant: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(F)cc1
Reactant: C#CCN
Solvent: CN(C)C=O
Product: C#CCNc1ccc(S(=O)(=O)N(C)CC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
To a solution of 1.820 g (6.00 mmol) of of [(4-fluoro-benzenesulfonyl-methyl-amino]-acetic acid tert-butylester in 25 mL of dimethylformamide was added 5.0 mL (4.0 g, 72.89 mmol) of propargylamine. The mixture was heated to 80° C. and stirred for 48 h. The mixture was partitioned between 400 mL of dichloromethane and 200 mL of 20% aqueous NH4Cl solution. The organic layer was separated, washed with 200 mL of water, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Silica gel column chromatography of the residue, eluting with 1% MeOH/CH2Cl2, provides 1.067 g (53%) of 2-(methyl{[4-(prop-2-ynylamino)phenyl]sulfonyl}-amino)acetic acid, tert-butyl ester as a light brown oil. Electrospray Mass Spec 339.3 (M+H)+
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=[O:11])[O:9][C:7](=[O:8])[CH2:6]1)[C:2](=[CH2:4])[CH3:3].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([CH:5]1[CH2:6][C:7](=[O:8])[O:9][C:10]1=[O:11])[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: C=C(C)CC1CC(=O)OC1=O
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(C)CC1CC(=O)OC1=O
Reaction time: 2 h
Yield: 97.5 %

Procedure:
β-Methallylsuccinic anhydride (539 g, 3.50 mole) was dissolved in toluene (800 mL) in a 1700 mL Parr stainless steel bottle fitted with a heating jacket. 10% Pd/C (3.60 g) was added and the bottle was connected to a Parr 2 L shaker fitted with two 4 L hydrogen tanks. After several evacuations and refilling with hydrogen, the shaker was started with the heater controlled for 60° C. The initial pressure was 60 lbs. When the pressure fell to 10 lbs, the tanks were repressurized to 60 lbs. After two hours, the controller was reset to 70° C. and the reaction was continued for another 12 hours. The heat was then turned off and after another 5 hours, the shaker was stopped. The reaction vessel was evacuated and the reaction mixture was filtered and concentrated. Distillation of the residue through the Vigreux column described above (P=9-10 mm Hg, T=180° C.) gave isobutylsuccinic anhydride (532.9 g, 97.6% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([O:18]C)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].S(=O)(=O)(O)O>CC(C)=O.O>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([OH:18])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: COC1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Temperature: 70 °C
Yield: 76.6 %

Procedure:
A solution of 6-acetoxy-2-methoxy-2,5,7,8-tetramethylchroman (74.11 g, 266.25 mmol), and concentrated sulfuric acid (2.5 mL) in a mixture of acetone (375 mL) and water 300 mL) was added to a distillation apparatus and warmed at reflux. Distillant was collected until the still head temperature reached 92° C. (about 1.5 h). The slurry was allowed to cool to 70° C. and 240 mL of acetone was added. The resulting mixture was allowed to cool to ambient temperature and the solid that formed was collected filtration. The solid was recrystallized from acetone and dried in a vacuum oven at 60° C. to afford 53.9 g (76.7% yield) of the desired product as a tan solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][O:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O.[CH3:27]O>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][O:18][C:19]([CH3:24])([CH3:23])[C:20]([O:22][CH3:27])=[O:21])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: CC(C)(OCc1nn(Cc2ccccc2)c2ccccc12)C(=O)O
Agent: Cl
Solvent: O
Product: COC(=O)C(C)(C)OCc1nn(Cc2ccccc2)c2ccccc12

Procedure:
A suspension of 2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid (20 g; 0.062 mol) in methanol (300 ml) was treated at 0° C. with gaseous HCl for 4 hours. The mixture was then poured into water (500 ml) and the product was extracted with diethyl ether (3×250 ml). The combined organic phases were washed with 5% sodium bicarbonate solution (2×100 ml) and then with water (50 ml). The solvent was evaporated off under reduced pressure and the crude residue was purified by crystallization from hexane.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][CH:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:21]([OH:25])[C:22]([NH2:24])=[O:23].CCN(C(C)C)C(C)C>>[NH2:24][C:22](=[O:23])[CH:21]([OH:25])[CH:20]([NH:19][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[N:18][C:10]=1[C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)c1cccnc1-c1nc2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1nc2ccccc2o1
Yield: 85.9 %

Procedure:
Coupling of 2-(benzo[d]oxazol-2-yl)nicotinic acid (190 mg, 0.791 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (169 mg, 0.780 mmol) was performed by analogy to the method described for example 1.2 using DIPEA instead of triethylamine. The reaction yielded 279 mg of the title compound; ESI-MS [M+H+]=417.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][O:24]S(C4C=CC(C)=CC=4)(=O)=O)=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:36])([CH3:35])[NH:3]1.[CH3:38]O>>[CH3:38][O:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]3[CH2:7][C:2]([CH3:37])([CH3:1])[NH:3][C:4]([CH3:35])([CH3:36])[CH2:5]3)[N:14]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)cc1
Reactant: CO
Product: COCCCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1

Procedure:
The title compound was prepared from toluene-4-sulfonic acid 3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propyl ester (Step A of Example 190) in MeOH. Yield: 3 mg (6%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:19]([C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)#[N:20].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:18][C@H:15]2[CH2:14][CH2:13][C@H:12]([C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)=[O:11])[CH2:17][CH2:16]2)=[CH:23][CH:22]=1)#[N:20]
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@@H](O)CC2)CC1
Reactant: N#Cc1ccc(O)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C#N)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 1.0 g (3.93 mmol) of cis-(4-isopropyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone, 0.515 g (4.3 mmol) of 4-cyanophenol, 1.28 g (4.88 mmol) of triphenylphisphine in 6 ml THF, 1.11 g (4.82 mmol) of di-tert-butyl azodicarboxylate in 6 ml of THF was added at 0° C., and stirred for 72 hr at room temperature. After evaporation, the residue was purified by column chromatography on silica gel eluting with cyclohexane and ethyl acetate=from 1:1 to 1:3, then dichloromethane and methanol=19:1. The combined product fractions were evaporated to dryness to yield 0.26 g (19% yields) of the titled compound. MS (m/e): 356.2 (MH+).