Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C@@H:22]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]([NH:25][N:26]2[C:31](=[O:32])[NH:30][C:29](=[O:33])[NH:28][C:27]2=[O:34])=[O:24])[C:11](=[O:21])[NH:12][O:13]CC2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C@@H:22]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]([NH:25][N:26]2[C:27](=[O:34])[NH:28][C:29](=[O:33])[NH:30][C:31]2=[O:32])=[O:24])[C:11](=[O:21])[NH:12][OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)C[C@@H](C(=O)Nn1c(=O)[nH]c(=O)[nH]c1=O)[C@H](CCCC1CCCCC1)C(=O)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)Nn1c(=O)[nH]c(=O)[nH]c1=O)[C@H](CCCC1CCCCC1)C(=O)NO
Yield: 29.3 %

Procedure:
A solution of 0.107 g of 2(R)-[4-cyclohexyl-1(S)-(benzyloxycarbamoyl)butyl]-N-(2,4,6-trioxo-1,3,5-triazin-1-yl)-4-methylvaleramide in 5 ml of methanol was hydrogenated in the presence of 0.01 g of 10% palladium-on-carbon for 2 hours. The mixture was filtered and evaporated and the residue was triturated with diethyl ether to give 0.026 g of 2(R)-[4-cyclohexyl-1(S)-(hydroxycarbamoyl)butyl]-N-(2,4,6-trioxo-1,3,5-triazin-1-yl)-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [K].[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].[CH2:10](Cl)[CH:11]=[CH2:12]>O>[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:12][CH:11]=[CH2:10]
Reactant: COCCOCCO
Reactant: C=CCCl
Agent: [K]
Solvent: O
Product: C=CCOCCOCCOC
Temperature: 10 °C
Reaction time: 8 h

Procedure:
1,700 mls of dried peroxide free tetrahydrofuran, available from Fisher Scientific Company, 15 Jet View Drive, P.O. Box 8740, Rochester, NY 14624 and 158.7 g potassium metal, available from Fisher Scientific, are charged under dry nitrogen into a 5,000 ml three-neck round bottom flask equipped with mechanical stirrer. The solution is chilled to 10° C., using an icewater bath and 494 ml of diethylene glycol monomethyl ether, available from Chemical Samples Company, 4692 Kenny Road, Columbus, OH 43221, is added dropwise. The potassium metal reacts within 24 hours at which time 350 mls of allyl chloride available from Aldrich, 159 Forest Street, Metuchen, NJ 08840, is added dropwise at such a rate to maintain a gentle reflux. After the reaction is allowed to continue overnight, one liter of distilled water is added to the reaction vessel to dissolve the precipitated salts. The tetrahydrofuran layer is washed three times with a salt water solution (270 g NaCl to 1 liter H2O) to remove excess alcohol. The tetrahydrofuran is removed with a water aspirator and the product is distilled at reduced pressure. 410 g of diethylene glycol allyl methyl ether is obtained (b.p. 109° C./30 mm). The analytical data is consistent with a product of the general formula:
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH:1]1([CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCC1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(CC1CCCC1)OCc1ccccc1
Reaction time: 2 h
Yield: 90.2 %

Procedure:
A mixture of cyclopentylacetic acid (10.02 g, 78.2 mmol), benzyl alcohol (8.45 g, 78.2 mmol) and p-toluenesulfonic acid monohydrate (1.48 g, 7.82 mmol) in benzene (60 mL) was refluxed using a Dean-Stark water separator for 2h. After cooling, benzene was removed and the mixture was diluted with ether (50 mL) and washed successively with saturated NaHCO3 solution, saturated brine solution, dried and evaporated to give the compound (15.40 g) as an oil; 1H NMR (300 MHz, CDCl3)δ: 7.35(m, 5H), 5.10(s, 2H), 2.40(d, j=8 Hz, 2H), 2.26(m, 1H), 1.81 (m, 2H), 1.6 (m, 4H), 1.18(m, 2H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[C:12]2[N:13]([C:17]([C:21]([O:23]CC)=[O:22])=[C:18]([CH3:20])[N:19]=2)[CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O1CCOCC1>[CH2:3]([O:10][C:11]1[C:12]2[N:13]([C:17]([C:21]([OH:23])=[O:22])=[C:18]([CH3:20])[N:19]=2)[CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cccn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc2c(OCc3ccccc3)cccn2c1C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
253 ml of 2N aqueous sodium hydroxide solution were added to a solution of 15.7 g (50.59 mmol) of ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate in 253 ml of dioxane, and the mixture was stirred at room temperature for 14 hours. 101 ml of 6N hydrochloric acid were then added to the mixture. The solid formed was filtered off, washed with water and with methyl tert-butyl ether and then dried in a vacuum drying cabinet at 40° C. overnight. This gave 15.49 g (108% of theory) of 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid as a colourless solid. The yield was more than 100% owing to water of crystallization (1H NMR).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[CH:3][CH:2]=1>CO.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:3][CH:2]=1
Reactant: COC(=O)/C=C/c1ccnc2ccccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccnc2ccccc12
Yield: 62.1 %

Procedure:
A solution of 11c (3.14 g, 14.73 mmol) in 41 mL dry CH3OH was treated with 10% Pd-C (157.0 mg, 5 wt %) at room temperature under a hydrogen atmosphere (balloon) (8 h). The reaction mixture was then filtered through a Celite plug, washed with EtOAc (150 mL), and concentrated in vacuo. SGC chromatotron (SiO2, 4 mm, 15-50% EtOAc/hexanes) afforded 12c (1.97 g, 2.03 g theoretical, 97%). For 12c: --H NMR (CDCl3, 250 MHz) d 8.77 (d, 1H, J=4.4 Hz, Ar C2-H), 8.08 (d, 1H, J=7.9 Hz, Ar C5-H or C8-H), 7.98 (d, 1H, J=7.6 Hz, Ar C5-H or Ar C8-H), 7.68 (ddd, 1H, J=1.5, 7.6, 7.9 Hz, Ar C6-H or C7-H), 7.54 (br dd, 1H, J=7.6, 7.9 Hz, Ar C6-H or C7-H), 7.21 (d, 1H, J=4.4 Hz, Ar C3-H), 3.65 (s, 3H, OCH3), 3.38 (t, 2H, J=7.7 Hz, ArCH2), 2.75 (t, 2H, J=7.7 Hz, CH2 (C=O)); IR (neat) nmax 2952, 1738, 1594, 1572, 1510, 1435, 1367, 124, 1170, 1026, 848, 763 cm-1. See FIG. 18b.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[O:8])=[CH:5][C:4]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].[BH4-].[Na+]>CO.C(O)C>[OH:32][CH:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])[C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:3]=1[O:2][CH3:1])[C:7]([NH:9][C:10]1([C:19]([OH:21])=[O:20])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)=[O:8]
Reactant: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1C(=O)c1ccccc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1C(O)c1ccccc1C
Yield: 18.5 %

Procedure:
The compound of example 240 (70 mg, 0.163 mmol) was dissolved in a mixture of methanol (1.5 ml) and ethanol (1.5 ml) and cooled in an ice bath. Sodium borohydride (18.9 mg, 0.49 mmol) was added in two batches and the mixture reacted with ice cooling until completion (3 h). The volatiles were evaporated and the residue was partitioned between diethyl ether and 1 N hydrochloric acid. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried and evaporated. The residue was purified by RP HPLC (water/ACN gradient) to yield 13 mg of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:59][CH2:60][CH3:61])[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])=[O:9])[CH3:2]>CO>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:59][CH2:60][CH3:61])[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:14])=[O:9])[CH3:2]
Reactant: CCCc1nc(CC)c(C(=O)OCCC(=O)Nc2ccccc2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CCCc1nc(CC)c(C(=O)OCCC(=O)Nc2ccccc2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 64.6 %

Procedure:
A solution of 0.05 g N-phenyl-2-(aminocarbonyl)ethyl 4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl) )biphenyl-4-yl]methyl]imidazole-5-carboxylate in 2.5 mL MeOH was refluxed overnight under N2. The reaction was evaporated to dryness and the residue immediately purified by flash chromatography with 0-5% MeOH/CHCl3 gradient to give 0.0226 g of pure product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.C(N(CC)CC)C.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[N:10]([S:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:28])=[O:27])[CH:11]=[CH:12][C:3]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#Cc1cnc2[nH]ccc2c1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Temperature: 0 °C
Reaction time: 10 h

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (2.6 g, 14.64 mmol) and triethylamine (3.06 mL, 21.96 mmol) in tetrahydrofuran (100 mL) was cooled to 0° C. and benzenesulfonyl chloride (2.253 mL, 17.57 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 hour and at room temperature for 10 hours and the mixture was concentrated. Water was added and the mixture was extracted with dichloromethane (three times). The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was triturated with diethyl ether to afford the title compound. MS (ESI(+)) m/e 318 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17]([CH3:19])=O)[N:3]=1.SC[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccc(F)cc2)c1C#N
Reactant: SCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccc(F)cc1

Procedure:
From 2-amino-4-(4-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 352 (M+H+, 100).
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@H:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[N:14][N:15]=1)[CH3:10])(C)(C)C>O1CCOCC1>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[S:12][C:11]([C@@H:9]([NH2:8])[CH3:10])=[N:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nnc(-c2ccc(Cl)cc2)s1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1nnc(-c2ccc(Cl)cc2)s1
Reaction time: 3 h
Yield: 113.1 %

Procedure:
A solution of hydrogen chloride (4.0 M in 1,4-dioxane, 4 mL, 16 mmol, 9 equiv) was added to a solution of (S)-tert-butyl(1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)carbamate (600 mg, 1.77 mmol) in 1,4-dioxane (5 mL) at room temperature. The solution was stirred for 3 hours, by which time a white precipitate had formed. The reaction was concentrated in vacuo to give the hydrochloride salt of (S)-1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethanamine (480 mg, white solid) in 97% yield. The material was used without purification. 1H NMR (400 MHz, CD3OD) δ 8.00 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 5.10 (q, J=6.9 Hz, 1H), 1.82 (d, J=6.9 Hz, 3H). MS m/z 240.0 (M+H)+; Rt-0.54 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C([O-])(O)=O.[Na+]>C(Cl)CCl>[CH3:27][S:28]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1N1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CS(=O)(=O)Nc1ccccc1N1CCN(Cc2ccccc2)CC1
Yield: 95.7 %

Procedure:
To a round-bottomed flask equipped with magnetic stirring was added 2-[4-benzylpiperazinyl]phenylamine (34 g, 127 mmol) in ClCH2CH2Cl (100 mL) and pyridine (12 mL, 140 mmol). The reaction mixture was stirred for 5 min. To the reaction was added methanesulfonyl chloride (Aldrich) (11 mL, 139 mmol), and the reaction mixture was heated at reflux for 18 h. After cooling to RT a satd soln of NaHCO3 (50 mL) was added. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). All organic fractions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the sulfonamide as yellow oil (42 g). MS (ESI, pos. Ion) m/z: 346 (M+H); MS (ESI, neg. Ion) m/z: 344 (M−H). Calc'd for C18H23N3O2S: 345.15.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][NH:37][CH3:38]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:37]([CH3:38])[CH3:36])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: CNC
Product: CN(C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (730 mg, 1.44 mmol) and N,N-dimethylamine (2M in THF) (800 μl, 1.60 mmol) as starting materials.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[CH3:24][O:25][C:26](=[O:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=O)=[CH:29][CH:28]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:24][O:25][C:26](=[O:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31]2[C:19]3=[CH:18][C:17]4[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=4[CH:11]=[C:10]3[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:9]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CN(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccccc1N
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C2=Nc3ccccc3N(C)c3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of N-methyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-phenylenediamine (13) (0.48 mol), terephthalic acid monomethyl ester (0.48 mol), and POCl3 (0.95 mol) in dry toluene (1750 mL) is heated at 80° C. for 4 days. After cooling to room temperature, the mixture is diluted with EtOAc (1500 mL). The mixture is washed with 5 N NaOH, brine, dried over MgSO4 and evaporated in vacuo. The residue is suspended in hexane. The crystals are collected by filtration and washed with hexane to give the ester (15) (R4=CH3, Z=H) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.C1COCC1.[CH3:18][NH2:19]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[N:19][CH3:18]
Reactant: CN
Reactant: O=Cc1ccc([N+](=O)[O-])c(Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN=Cc1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
3-Chloro-4-nitrobenzaldehyde (251 mg 1.35 mmole) was dissolved in dichloromethane (2 mL) and methylamine, 2M in THF (0.88 mL, 1.76 mmole) was added along with 3A Sieves (400 mg). The reaction was stirred at room temperature for 18.5 hours. The sieves were filtered and washed with more dichloromethane. The filtrate was evaporated, however only partial conversion to the imine was observed. The residue was redissolved in dichloromethane (2 mL) and methylamine. 2M in THF (1.0 mL, 2.0 mmole) was added along with powdered 3A Sieves (400 mg). The reaction was stirred at room temperature for a further 16.5 hours. The sieves were filtered and washed and the filtrate evaporated to give the title compound as an oil which quickly crystallised (199 mg). 1H-NMR (CDCl3, 500 MHz): δ 3.60 (d, J=1.89 Hz, 3H), 7.73 (dd, J=1.89, 8.51 Hz, 1H), 7.93 (m, 2H), 8.30 (q, J=1.58 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]/[CH:10]=[CH:11]\[CH:12]([OH:14])[CH3:13])=[CH:5][CH:4]=1.C(Cl)Cl.CN(C)C=O.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24]>CCOCC.C(N(CC)CC)C>[Si:27]([O:14][CH:12]([CH3:13])/[CH:11]=[CH:10]\[S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29]
Reactant: COc1ccc(S/C=C\C(C)O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc(S/C=C\C(C)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
14.1 g (67.1 mmol) of rac-(Z)-4-[(p-methoxyphenyl)thio]-3-buten-2-ol in 250 ml of of methylene chloride and 25 ml of N,N-dimethylformamide are treated with 15.2 g (100 mmol) of t-butyldimethylchlorosilane and 13.6 g (18.7 ml) of triethylamine, the reaction mixture is stirred at room temperature for 6 hours and evaporated. The oil obtained is taken up in 500 ml of ether, washed three times with 100 ml of water each time, dried over sodium sulphate and filtered through silica gel. There is obtained 4-[[(Z)-3-(t-butyldimethylsilyloxy)-1-butenyl]thio]anisole.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:27])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:7]2[OH:26].[C:28]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[F:1][C:2]1[C:3]([O:27][CH3:28])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:7]2[OH:26]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(O)c(F)c2C(C)(C)C1=O
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc2c(c1F)C(C)(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of 1,1-dimethylethyl N-((8-fluoro-4,7-dihydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.1 g, 0.3 mmol, see Example 23), and K2CO3 (0.04 g, 0.3 mmol) in 4 mL ACN stirred at room temperature, was treated with MeI (0.06 g, 0.4 mmol), and the resulting mixture was stirred for 12 hours, M+Na=416. The mixture was concentrated in vacuo and purified by column chromatography eluting with 10-30% EtOAc/hexane to give 98 mg of the title compound as a white solid. MS (m/z)=416 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:51]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]1([C:62]([O:64][CH3:65])=[O:63])[CH2:61][CH2:60]1)#[CH:52]>CN(C=O)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>[CH3:65][O:64][C:62]([C:59]1([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[C:51]#[C:52][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[N:17][CH:18]=3)[N:3]=2)[CH2:61][CH2:60]1)=[O:63]
Reactant: C#Cc1ccccc1C1(C(=O)OC)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)nc3)ncc2C(F)(F)F)CC1
Temperature: 120 °C

Procedure:
A stirred suspension of tert-butyl 4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (K5) (152 mg, 0.332 mmol), PdCl2(PPh3)2 (12 mg, 0.017 mmol), PPh3 (9 mg, 0.03 mmol), CuI (6 mg, 0.03 mmol) and methyl 1-(2-ethynylphenyl)cyclopropanecarboxylate (K2) (80 mg, 0.40 mmol) in DMF (4.0 mL) was degassed with nitrogen for 10 minutes. Et3N (1.0 mL) was added and the resulting mixture heated under microwave irradiation at 120° C. for 20 minutes. The volatiles were removed in vacuo and the residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-60% EtOAc in petroleum benzine 40-60° C. then 10-45% EtOAc in petroleum benzine 40-60° C.) to give the title compound A10 as yellow oil (141 mg, 68%); 1H NMR (400 MHz, d6-DMSO) δ 10.53 (s, 1H), 8.84 (s, 1H), 8.77 (d, J=2.5 Hz, 1H), 8.12 (d, J=6.5 Hz, 1H), 7.61 (dd, J=7.6, 1.0 Hz, 1H), 7.54-7.38 (m, 3H), 7.28 (d, J=8.5 Hz, 1H), 4.05 (br, 2H), 3.51 (s, 3H), 2.94-2.72 (m, 3H), 1.81 (d, J=10.5 Hz, 2H), 1.63 (q, J=4.1 Hz, 2H), 1.61-1.49 (m, 2H), 1.41 (s, 9H), 1.29 (q, J=4.2 Hz, 2H). LCMS-A: rt 5.913 min; m/z 622 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:6]([N+:20]([O-])=O)[CH:5]=1)([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[NH2:20][C:6]1[CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:9]=[CH:8][C:7]=1[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)c1ccc(CCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1ccc(CCNC(=O)OC(C)(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.7 %

Procedure:
To a solution of 92 mg of tert-butyl [2-(4-isopropyl-2-nitrophenyl)ethyl]carbamate in 2 mL of ethanol was added 20 mg of 10% palladium-carbon, and the mixture was stirred under hydrogen atmosphere at room temperature for 5 hours. The insoluble was removed by filtration, and the filtrate was concentrated under reduced pressure to give 82 mg of tert-butyl [2-(2-amino-4-isopropylphenyl)ethyl]carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][OH:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc(-c2cccc(Cl)c2)on1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(-c2cccc(Cl)c2)on1
Temperature: 25 °C

Procedure:
[5-(3-chlorophenyl)isoxazol-3-yl]methanol (178.6 g, 852 mmol) in dichloromethane (2 L) was dropwise added to pyridinium chlorochromate (400 g, 1.86 mol) in dichloromethane (2 L). The resulting slurry was stirred over night at room temperature. The slurry was filtrated through celite and the filtrate was distilled off. To the remaining solution EtOAc was added. The organic layer was washed with water, saturated brine and concentrated, to give crude title compound, which was used directly in the next step. 1H NMR (DMSO-d6): 10.13 (s, 1H), 8.08 (br s, 1H), 7.95 (m, 1H), 7.61 (m, 3H). MS (M++1)=208.
Reaction SMILES: C1(CCCC(N2C[C@@H](O)C[C@H]2C(O)=O)=O)C=CC=CC=1.[C:21]1([CH2:27][CH2:28][CH2:29][C:30]([N:32]2[CH2:43][C@@H:42]([OH:44])[CH2:41][C@H:33]2[C:34]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:35])=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH2:27][CH2:28][CH2:29][C:30]([N:32]2[CH2:43][C@H:42]([OH:44])[CH2:41][C@H:33]2[C:34]([N:36]2[CH2:37][CH2:38][CH2:39][CH2:40]2)=[O:35])=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C([C@@H]1C[C@H](O)CN1C(=O)CCCc1ccccc1)N1CCCC1
Agent: O=C(O)[C@@H]1C[C@H](O)CN1C(=O)CCCc1ccccc1
Product: O=C([C@@H]1C[C@@H](O)CN1C(=O)CCCc1ccccc1)N1CCCC1

Procedure:
By employing N-(4-phenylbutanoyl)-cis-4-hydroxy-L-proline in place of N-(4-phenylbutanoyl)-trans-4-hydroxy-L-proline in the procedure of Example 1(a) given above, N-[N-(4-phenylbutanoyl)-cis-4-hydroxy-L-prolyl]pyrrolidine (SUAM 14496) was obtained.