Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([O:15]C(=O)C)=[CH:5]1)(=O)C.O=O.[OH-].[Na+]>CO>[OH:15][C:6]1[CH:7]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][CH:5]=1
Reactant: CC(=O)Oc1cc(-c2ccccc2)n(C(C)=O)c1
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1c[nH]c(-c2ccccc2)c1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
A finely divided portion of N-acetyl-3-acetoxy-5-phenylpyrrole (2) (36.8 g; 0.15 mol) was freed of oxygen by stirring in a flowing argon stream for 10 minutes, then suspended in deoxygenated MeOH (379 mL), cooled to -6° C. (in a -15° C. methanol (MeOH)/dry-ice bath) under an inert gas atmosphere and rapidly treated with an ice cold deoxygenated solution of 2N NaOH (300 mL). The reaction temperature rose immediately upon addition of base to 18° C., and after ~3 minutes the reaction mixture became homogeneous. As the reaction mixture cooled, compound (3) separated as fine crystals. After 15 minutes a solution of cold deoxygenated 2M citric acid (150 ml) was added, the resulting mixture was stirred for 10 minutes, and then filtered. The solid was washed thoroughly with deoxygenated water (200 mL), taking care to minimize exposure of the product to air, then dried under vacuum overnight to yield the title compound (22.3 g; 93.6%) as light pink tiny needles.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:12](=[O:24])[CH:11]=2)[CH:7]=[C:6]([N+:25]([O-])=O)[C:5]=1[NH2:28]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:12](=[O:24])[CH:11]=2)[CH:7]=[C:6]([NH2:25])[C:5]=1[NH2:28]
Reactant: COC(=O)c1cc(C2=CC(=O)C(Cc3ccccn3)C(C)=C2)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C2=CC(=O)C(Cc3ccccn3)C(C)=C2)cc(N)c1N
Reaction time: 24 h

Procedure:
To a slurry of 10% palladium on carbon (0.045 g) in ethyl acetate (20 mL) was added 2-amino-5-(5-methyl-3-oxo-4-pyridin-2-ylmethyl-cyclohexa-1,5-dienyl)-3-nitro-benzoic acid methyl ester (0.176 g, 0.44 mmol). The resulting mixture was hydrogenated at 30 psi for 24 hours. The reaction was filtered, concentrated in vacuo, and the crude isolate purified (SiO2, 2 to 10% methanol in methylene chloride) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 2.5 (s, 3H), 3.99 (s, 3H), 5.3 (s, 2H), 5.38 (bs, 2H), 6.39 (s, 1H), 6.25 (s, 1H), 7.93-7.21 (m, 4H), 8.61 (s, 1H), 8.93 (s, 1H).
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[C:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][C:21](=[O:23])[CH3:22])=[CH:30][CH:29]=3)[CH2:36][CH2:35]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: CC(=O)Oc1ccc(N2CCNCC2)cc1
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2ccc(OC(C)=O)cc2)CC1
Yield: 89 %

Procedure:
Phenyl-N-(5,6-dimethyl 2methoxypyridin 3-yl)carbamate and 1-(4-acetoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:11][C:12]1[C:17]2[CH:18]=[CH:19][O:20][C:16]=2[C:15]([Cl:21])=[CH:14][CH:13]=1)C(OCC)=O)[CH3:2].[Cl-].[Na+]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:11][C:12]1[C:17]2[CH:18]=[CH:19][O:20][C:16]=2[C:15]([Cl:21])=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(Cl)c2occc12)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCc1ccc(Cl)c2occc12
Yield: 66.6 %

Procedure:
A mixture of 2-(7-chloro-benzofuran-4-ylmethyl)-malonic acid diethyl ester (2.47 g) and sodium chloride (0.656 g) in DMSO (12 ml) and water (0.5 ml) was heated at 200° for 4 h under nitrogen. The cooled mixture was partitioned between water (80 ml) and ether (3×50 ml) and the combined organic extracts washed with brine (3×50 ml) and dried (MgSO4). The solvent was evaporated to give the title compound as a brown oil (1.28 g)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[C:10]1[N:28]=[C:13]2[C:14]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][NH:18][C:14]1[C:13]2[N:12]([N:11]=[C:10]([NH:8][C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:28]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccccc1CNc1cccn2nc(Cl)nc12
Reactant: Cc1ccc(N)cn1
Product: COc1ccccc1CNc1cccn2nc(Nc3ccc(C)nc3)nc12

Procedure:
N(8)-(2-Methoxy-benzyl)-N(2)-(6-methyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 6-Methyl-pyridin-3-ylamine (83.90 mg, 0.7758 mmol) and (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methoxy-benzyl)-amine (200.00 mg, 0.69268 mmol) in a manner analogous to Example 2d. Product isolated as a red foam (23.23 mg, 9%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.51 (s, 1H), 8.74 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.97 (d, J=6.7 Hz, 1H), 7.23 (m, 2H), 7.15 (d, J=8.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.87 (t, J=15.1, 7.4 Hz, 1H), 6.75 (t, J=14.1, 7.1 Hz, 1H), 6.32-6.23 (m, 2H), 4.47 (d, J=5.9 Hz, 1H), 3.87 (s, 3H), 2.39 (s, 3H). MS=361. (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1C(=O)Cl

Procedure:
A suspension of 4-bromo-2-methylbenzoic acid (4.9 g, 22.8 mmol) in dichloromethane containing a few drops of N,N-dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (2.4 mL, 27.5 mol). After gas evolution subsided, the reaction mixture was refluxed for an additional 15 minutes and then evaporated to dryness in vacuo to provide the crude 4-bromo-2-methylbenzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[NH:20][N:19]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[CH:21]1([C:18]2[CH:17]=[C:16]([NH:15][C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)=[CH:3][CH:4]=4)[N:14]=3)[NH:20][N:19]=2)[CH2:23][CH2:22]1
Reactant: Nc1ccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)cc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)cc1)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
A solution of N2-(4-aminophenyl)-N4-(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine (0.011 g, 0.035 mmol; Shokat Lab: A. Statsyuk) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this 3-(trifluoromethyl)benzoyl chloride (0.005 mL, 0.036 mmol) diluted in CH2Cl2 (5 mL) was added drop wise. The reaction was allowed to warm and was left stirring for 1 hour. The reaction proceeded until completion as judged by TLC and LC-MS. The reaction mixture was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H20/0.1% TFA (1-100% gradient) to afford AD74. ESI-MS m/z [M+H]+ found 480.5, calculated 480.2.
Reaction SMILES: Cl.[CH2:2]([CH:4]1[CH2:8][CH:7]([CH2:9][OH:10])[CH2:6][CH:5]1[C:11]([OH:13])=[O:12])[CH3:3].[CH3:14][CH2:15]O>>[CH2:2]([CH:4]1[CH2:8][CH:7]([CH2:9][OH:10])[CH2:6][CH:5]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:3]
Reactant: CCC1CC(CO)CC1C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C1CC(CO)CC1CC
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
HCl gas was bubbled through a solution of 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylic acid (7.29 g, 42.3 mmol) in EtOH (60 mL) at about 25° C. for about 10 min. The reaction mixture was stirred at about 25° C. for about 72 h. The solvent was removed under reduced pressure. The crude residue was partitioned between water (30 mL) and DCM (3×30 mL). The combined organic extracts were concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc/heptane to give ethyl 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate (4.89 g, 58%) as a yellow oil: 1H NMR (CDCl3) δ 4.23-4.02 (m, 2H), 3.74-3.47 (m, 2H), 2.96-2.83 (m, 1H), 2.31-2.17 (m, 1H), 2.15-1.98 (m, 2H), 1.97-1.84 (m, 1H), 1.79-1.66 (m, 1H), 1.65-1.50 (m, 1H), 1.49-1.37 (m, 1H), 1.30-1.21 (m, 5H), 1.04-0.82 (m, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@H:16]([C:21]2[CH:37]=[CH:36][C:24]([O:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)=[CH:23][CH:22]=2)[C:17]([NH:19][OH:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].Cl>ClCCl.CCOCC>[NH2:28][CH2:27][CH2:26][O:25][C:24]1[CH:36]=[CH:37][C:21]([C@@H:16]([NH:15][S:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=2)(=[O:14])=[O:13])[C:17]([NH:19][OH:20])=[O:18])=[CH:22][CH:23]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)NO)c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)NO)c2ccc(OCCN)cc2)cc1
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Through a solution of 0.354 g (0.664 mmol) of the product of Example 199, tert-butyl 2-{4-[(1R)-1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(hydroxyamino)-2-oxoethyl]phenoxy}ethylcarbamate, in 10 mL of dichloromethane was bubbled hydrogen chloride gas for 10 minutes. The reaction was stoppered and let sit at room temperature for 30 minutes. The reaction was then diluted with 15 mL of ether and the resulting white precipitate was collected by filtration and dried in vacuo to give 0.283 g of (2R)-2-[4-(2-Aminoethoxy)phenyl]-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxyethanamide as a white solid. Electrospray Mass Spec 434.3 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)=[O:5].C1COCC1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:13][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=2[Br:1])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccccc1Br
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(NC(=O)c2ccccc2Br)c1
Yield: 65.5 %

Procedure:
2-Bromo-N-(3-nitrophenyl)benzamide (6.89 g, 21.5 mmol) was added to a 1 L flask with stir bar and dissolved with THF (143 mL). Sodium dithionite (37.4 g, 215 mmol) (aka sodium hydrosulfite) was added to a separate flask and dissolved with water (143 mL). The resulting cloudy solution was added to the solution of substrate, and the flask was sealed and flushed with nitrogen, then stirred vigorously for 16 h with a vent line to an oil bubbler. After this time LC-MS analysis showed complete conversion to a mixture of the desired product plus its N-sulfate. To hydrolyze the sulfated material, saturated aqueous ammonium chloride (30 mL) was added, and the mixture was refluxed for 4 h. The layers were then separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, then dried over Na2SO4, filtered, and concentrated. The crude material was then dissolved with dichloromethane and ethyl acetate, leaving an insoluble gum behind. The solution was purified by column chromatography (EtOAc/hexanes gradient), to yield the title compound as a pale yellow solid (4.10 g, 66%). LRMS (ESI+) (M+H): 291.96.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:20](O)[CH2:21][CH2:22][OH:23].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)C.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[O:19][CH2:20][CH2:21][CH2:22][OH:23])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(F)c2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(F)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
A solution of 3-(3-fluorophenylsulfonyloxy)-5-methylphenol (930 mg, 3.3 mmol, as prepared in the preceding step), 1,3-propanediol (0.75 mL, 10 mmol), 1,1'-(azodicarbonyl)dipiperidine (1.76 g, 7.0 mmol), and anhydrous tetrahydrofuran (20 mL) was cooled to 0° C. under nitrogen. Tri-n-butylphosphine (1.7 mL, 7.0 mmol) was added dropwise over 8.5 minutes. The mixture was stirred at 0° C. for 5 minutes then at ambient temperature for 5.5 hours. Diethyl ether (100 mL) was added, and the mixture was stirred for 15 minutes. The mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography through silica gel (25% to 35% ethyl acetate in hexane) to give the title compound as a yellow oil (877 mg, 78%). 1H-NMR (300 MHz, CDCl3) δ 7.65-7.68 (m, 1H), 7.50-7.60 (m, 2H), 7.35-7.41 (m, 1H), 6.63 (br s, 1H), 6.41 (br s, 1H), 6.38 (br t, 1H, J=2.1 Hz), 4.01 (t, 2H, J=6.0 Hz), 3.82 (br t, 2H, J=6.0 Hz), 2.25 (s, 3H), 1.99 (pentet, 2H, J=6.0 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C16H17FO5S: 363.1 (M+Na), 379.0 (M+K). Found: 362.8, 378.9.
Reaction SMILES: [CH2:1]([C:3]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N:12]=[C:13]=[S:14])=[CH:11][C:5]=2[O:4]1)[CH3:2].[CH3:16][NH:17][NH2:18]>C(O)C>[CH2:1]([C:3]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[S:14])[N:17]([CH3:16])[NH2:18])=[CH:11][C:5]=2[O:4]1)[CH3:2]
Reactant: CNN
Reactant: CCC1(C)Oc2ccc(N=C=S)cc2O1
Solvent: CCO
Product: CCC1(C)Oc2ccc(NC(=S)N(C)N)cc2O1
Yield: 66.9 %

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 2.1 g (0.0095 mole) of (2-ethyl-2-methyl-1,3-benzodioxol-5-yl) isothiocyanate with 0.44 g (0.0095 mole) of methylhydrazine in 50 ml of ethanol yielded 1.7 g of 4-(2-ethyl-2-methyl-1,3-benzodioxol-5-yl)-2-methyl-3-thiosemicarbazide as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:15])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[CH3:14])[CH2:2][CH3:3].[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[CH:25]=O>O1CCCC1>[CH2:1]([O:4][C:5](=[O:15])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:25][C:17]2[O:16][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH:18]=2)=[CH:9][C:8]=1[CH3:14])[CH2:2][CH3:3]
Reactant: CCCOC(=O)Nc1ccc(N)cc1C
Reactant: O=Cc1cc2ccccc2o1
Solvent: C1CCOC1
Product: CCCOC(=O)Nc1ccc(NCc2cc3ccccc3o2)cc1C
Reaction time: 1 h
Yield: 43 %

Procedure:
A mixture of 0.1 M solution of (4-amino-2-methylphenyl)-carbamic acid propyl ester (0.35 mL, 0.035 mmol) and 0.1 M solution of benzofuran-2-carbaldehyde (0.35 mL) in tetrahydrofuran (THF) was kept at 55° C. for 60 minutes. Volatiles were removed in vacuo. To the obtained residue 0.2 M sodium cyanoborohydride (NaBH3CN) (0.5 mL) in methanol and acetic acid (0.03 mL) were added. After sonication for 60 minutes the reaction mixture was evaporated in vacuo and the title compound was separated by preparative LC/MS to give 5.1 mg of colorless solid. Yield 43%. LC/MS (m/z) 339.2 ([M+H]+); RT=2.92, (UV, ELSD) 94%, 94%.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[NH:3]1.C(N(CC)CC)C.[CH3:16][C:17]1([CH3:29])[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([N:26]=[C:27]=[O:28])[C:20]=2[CH2:19][CH2:18]1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]([C:27]([NH:26][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH2:19][CH2:18][C:17]3([CH3:29])[CH3:16])=[O:28])[C:4]([CH3:8])=[N:3]1
Reactant: CC1(C)CCc2c(N=C=O)cccc21
Reactant: Cc1cc(=O)n(C)[nH]1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1=NN(C)C(=O)C1C(=O)Nc1cccc2c1CCC2(C)C
Temperature: 25 °C
Yield: 60.5 %

Procedure:
1.12 g (10 mmol) of 1,3-dimethylpyrazoline-5-one was suspended in 10 ml of toluene containing 1.11 g of triethylamine. To the suspension was added dropwise a solution of 1.87 g of 1,1-dimethylindane-4-yl isocyanate in 2 ml of toluene with stirring at room temperature, followed by further stirring at room temperature for 12 hours. Thereafter, the reaction mixture was extracted with water three times. The aqueous layers were made acidic with concentrated hydrochloric acid and cooled with ice. The precipitate produced was filtered and air-dried to obtain 1.81 g of 1,3-dimethyl-5-oxo-N-(1,1-dimethylindane-4-yl)4,5-dihydropyrazole-4-carboxamide (mp 141.4° C.). Then, thus obtained 1,3-dimethyl-5-oxo-N-(1,1-dimethylindane-4-yl)-4,5-dihydropyrazole-4-carboxamide was added to a mixture of 5 ml of phosphorus oxychloride and 907 mg of N,N-diethylaniline. The resultant mixture was stirred under reflux with heating for 1.5 hour. The obtained reaction mixture was poured into ice water and extracted with chloroform three times. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure and the residue was recrystallized with ethanol to obtain 0.96 g of 5-chloro-1,3-dimethyl-N-(1,1-dimethylindane-4-yl)pyrazole-4-carboxamide (mp 175.2° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=4)[CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc(-c3c(C)nnn3-c3ccc(F)cc3)c2)nc1
Temperature: 120 °C
Yield: 38.5 %

Procedure:
A mixture of 1-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-4-methyl-1H-[1,2,3]triazole (500 mg, 2.06 mmol), methyl 6-chloronicotinate (353 mg, 2.06 mmol) and potassium carbonate (568 mg, 4.11 mmol) in DMF (10 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 16 h. After cooling to room temperature the mixture was poured into water (150 mL) and the solid that formed was filtered off and dried to afford the title compound (300 mg, 39%) as a light brown solid. MS: m/e=379.3 [M+H]+.
Reaction SMILES: [CH3:1][S:2][CH:3]([CH2:13][CH2:14][CH2:15][CH:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[OH-].[Na+].I([O-])(=O)(=O)=[O:26].[Na+]>O>[CH3:1][S:2]([CH:3]([CH2:13][CH2:14][CH2:15][CH:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:26]
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)O)SC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)S(C)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
8-Methylthio-12-hydroxyheptadecanoic acid (Ex. 1) (6.7 g., 0.0202 mole) is dissolved in a solution of sodium hydroxide (1.0 g., 0.025 mole) in water (80 ml.). Sodium metaperiodate (4.7 g., 0.022 mole) is added and the resulting mixture is stirred at room temperature overnight (17 hours). The solids present are then filtered off and the filtrate is acidified with dilute hydrochloric acid to liberate the oily acid product. The oil is taken up in ether, washed with water and dried over sodium sulfate. The ether is evaporated in vacuo to leave the crude 8-methylsulfinyl-12-hydroxy-heptadecanoic acid as a viscous yellowish oil weighing 5.8 g. Purification is effected by chromatography on a column containing 125 g. of silica gel using 4% methanol is chloroform as eluant. There is obtained 2.2 g. of pure 8-methylsulfinyl-12-hydroxyheptadecanoic acid, a colorless viscous oil with Rf 0.14 on silica gel thin layer chromatograms with chloroform-methanol-acetic acid 96:3:1 as eluant; pmr (CDCl3) δ 0.90 (3H, t); 2.50 (3H, s CH3SO); 3.64 (1H, m HCO).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH:42]1([N:47]2[CH2:52][CH2:51][CH:50]([NH2:53])[CH2:49][CH2:48]2)[CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:53][CH:50]5[CH2:51][CH2:52][N:47]([CH:42]6[CH2:46][CH2:45][CH2:44][CH2:43]6)[CH2:48][CH2:49]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCN(C2CCCC2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C3CCCC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a mixture of 0.050 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.08 mL (0.44 mmole) of ethyldiisopropyl amine and 0.021 g (0.12 mmole) of 1-cyclopentyl-piperidin-4-ylamine in 1.5 mL of dimethylformamide was added 0.053 g (0.12 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-85:15) gave 0.029 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-cyclopentyl-piperidin-4-yl)-3-methoxy-benzamide (I-63).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:17]([OH:29])[C:18](=[O:28])[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])=O)C1C=CC=CC=1.[H][H]>[Pd].O.C(O)C>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:17]([OH:29])[C:18](=[O:28])[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21]
Reactant: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: C[C@@H](NC(=O)C(O)[C@H](CCCCN)NC(=O)OC(C)(C)C)c1ccccc1
Yield: 93.3 %

Procedure:
A slurry of 1.5 g of 10 wt % palladium on carbon in 3 mL of water was added to a solution of 15.28 g (29.70 mmol) of tert-butyl (1S)-5-{[(benzyloxy)carbonyl]amino}-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate in 200 mL of ethanol. The resulting slurry was stirred vigorously under 45 psi of hydrogen gas at 50° C. for 18 h. The catalyst was then filtered off, rinsing with 400 mL of ethanol. Concentration of the filtrate under vacuum afforded 10.52 g (93%) of tert-butyl (1S)-5-amino-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate as a colorless oil that crystallized upon standing under vacuum. 1H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J=8 Hz) and 8.08 (d, J=8 Hz) total 1H; 7.90-7.87 (m, ca 1H); 7.87-7.28 (m, 4H); 7.25-7.20 (m, 1H); 6.51 (d, J=9 Hz) and 6.17 (d, J=9 Hz) total 1H; 4.99-4.92 (m, 1H); 3.96 (d, J=4 Hz) and 3.90 (d, J=3 Hz) total 1H; 3.80-3.69 (m, 1H); 2.68-2.64 (m) and 2.53-2.57 (m) total 1H; 1.53-1.23 (m, 18H). ES-LCMS m/z 380 (M+H).