Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([CH3:10])[C:6](=[O:9])[NH:7][N:8]=1)[CH3:2].[Cl:11][S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13]>C(Cl)Cl>[Cl:11][S:12]([NH:15][C:16]([N:7]1[C:6](=[O:9])[N:5]([CH3:10])[C:4]([O:3][CH2:1][CH3:2])=[N:8]1)=[O:17])(=[O:14])=[O:13]
Reactant: CCOc1n[nH]c(=O)n1C
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: CCOc1nn(C(=O)NS(=O)(=O)Cl)c(=O)n1C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
28.8 g (0.20 mol) of 5-ethoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one are introduced into 250 ml of methylene chloride, and the mixture is cooled to -10° C. 28.3 g (0.20 mol) of chlorosulphonyl isocyanate are added to this mixture, and the reaction mixture is stirred for 30 minutes without cooling. The solvent is then carefully removed by distillation under water pump vacuum. 53 g (93% of theory) of 2-chlorosulphonylaminocarbonyl-5-ethoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one are obtained as a crystalline residue of melting point 106° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16]>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH:16][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: NCc1ccccc1Cl
Reactant: Oc1ccc2nc(Cl)oc2c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Oc1ccc2nc(NCc3ccccc3Cl)oc2c1

Procedure:
2-Chloro-benzooxazol-6-ol (1 eq) and 2-chloro-benzylamine (2 eq) was dissolved in NMP. Using a Personal Chemistry microwave system, the mixture was reacted at 180° C. for six minutes. The crude reaction mixture was diluted with ethyl acetate and washed once with brine and once with 1N HCl, or washed twice with brine, depending on the amine used. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated. This material was purified by silica gel column using hexane and ethyl acetate. MH+=275.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH:8]2[C:10](=[CH:11][C:12]([O:14][CH2:15]C)=[O:13])[CH:4]([CH2:5][CH2:6][CH2:7]2)[CH2:3]1.[Mg].[Cl-].[NH4+]>CO>[CH3:1][N:2]1[CH2:9][CH:8]2[CH:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:4]([CH2:5][CH2:6][CH2:7]2)[CH2:3]1
Reactant: CCOC(=O)C=C1C2CCCC1CN(C)C2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)CC1C2CCCC1CN(C)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.7 %

Procedure:
37.13 g of ethyl (3-methyl-3-azabicyclo[3.3.1]non-9-ylidene)acetate was dissolved in 815 ml of methanol. After adding 20.24 g of magnesium, the resulting mixture was stirred at room temperature for 18 hours. Then a saturated aqueous solution of ammonium chloride was added to the reaction mixture followed by extraction with ethyl acetate. The ethyl acetate layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After concentrating the solvent under reduced pressure, 34.32 g of crude methyl (3-methyl-3-azabicyclo[3.3.1]non-9-yl)acetate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([CH2:12][CH3:13])[CH:15]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CCc1cccc(N)c1
Product: CCc1cccc(NC(=O)c2cc(Cl)ccc2O)c1

Procedure:
This material was prepared according to the method of Example 1 using 5-chlorosalicylic acid and 3-ethylaniline, with reagents and solvents employed in similar molar ratios. 1HNMR (500 MHz, DMSO-d6): δ 1.20 (t, 3H), 2.62 (q, 1H), 7.02 (m, 2H), 7.28 (m, 1H), 7.47 (m, 1H), 7.54 (m, 1H), 7.56 (br s, 1H), 7.90 (m, 1H), 10.34 (s, 1H).
Reaction SMILES: [Li]CCCC.[I:6][C:7]1[S:8][C:9](I)=[CH:10][CH:11]=1.[Cl:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:13][C:14]1[N:19]=[C:18]([C:9]2[S:8][C:7]([I:6])=[CH:11][CH:10]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Clc1ncccn1
Reactant: Ic1ccc(I)s1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: C1CCOC1
Product: Clc1nccc(-c2ccc(I)s2)n1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
nBuLi (16 mL, 1.6 M solution in hexane, 25 mmol) was added to a stirred solution of 2,5-diiodothiophene (7.0 g, 21 mmol) in THF (80 mL) at −50° C. The solution was stirred for 10 min at −50° C. before 2.9 g (25 mmol) of 2-chloropyrimidine was added. The reaction solution was stirred for 1 h at −20° C., then cooled to −50° C. and quenched by addition of 2 mL of AcOH in 10 mL of MeOH. Solid 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10.4 g, 46 mmol) was added and the reaction solution was warmed to 0° C. and stirred for 1 h. The reaction mixture was then poured into 100 mL of a 0.5 M solution of sodium ascorbate, diluted with 250 mL of 1 M aqueous Na2CO3 and the crude product removed by filtration and washed repeatedly with water. The residue was azeotroped with toluene to give the product. MS (M+H)+ 323.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:24]1[CH:25]=[C:26]2[C:31](=[O:32])[NH:30][C:28](=[O:29])[C:27]2=[CH:33][CH:34]=1)([OH:23])=[O:22].CCN(C(C)C)C(C)C>C(#N)C>[C:1]([N:30]1[C:31](=[O:32])[C:26]2=[CH:25][C:24]([C:21]([OH:23])=[O:22])=[CH:34][CH:33]=[C:27]2[C:28]1=[O:29])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc2c(c1)C(=O)NC2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(O)c1ccc2c(c1)C(=O)N(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2=O

Procedure:
To trityl chloride resin (5 g; 10.25 retool; 200-400 mesh: 1% divinylbenzene-crosslinked polystyrene) presoaked in 80 mL dry acetonitrile for 30 min., 5 g (26 mmol) 4-carboxyphthalimide (2) from Example 2 and 6 mL (34 mmol) DIPEA were added, and the suspension was refluxed for 72 h. Following filtration, the polymer was washed with 300 mL DMF and then 300 mL CH2Cl2. The loading was determined by weight difference, and confirmed to be 0.5 mmol/g resin by TFA-induced cleavage of 4-carboxyphthalimide from the resin.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[I:11].[C:12]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])[CH2:13][C:14]([CH3:16])=O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:19]([O:18][C:12](=[O:17])/[CH:13]=[C:14](/[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[I:11])\[CH3:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: Nc1ccc(CCO)cc1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C/C(=C\C(=O)OCc1ccccc1)Nc1ccc(CCO)cc1I
Yield: 99.9 %

Procedure:
To a solution of 4-amino-3-iodophenethyl alcohol from Step A (10 g, 38 mmol) and benzyl acetoacetate (7.3 g, 38 mmol) in benzene (150 mL) was added p-toluenesulfonic acid (361 mg, 1.9 mmol). The mixture was heated at reflux overnight using a Dean Stark condenser. The mixture was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 16.6 g (99%) of the crude desired product as a light brown oil: MS(APCI+): m/z 438.1 (MH+). The compound was taken to Step C without further purification.
Reaction SMILES: [N:1]1[NH:2][N:3]=[CH:4][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC.I[C:23]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>CN(C=O)C.[Cu]I.O>[CH3:32][C:29]1[CH:30]=[CH:31][C:23]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26]
Reactant: c1cn[nH]n1
Reactant: Cc1ccc(I)c(C(=O)O)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)O)c1

Procedure:
To a solution of 2H-1,2,3-triazole (CAS number 288-36-8; 1.99 g, 28.93 mmol) in DMF (7.0 ml) at 0-10° C. was added cesium carbonate (4.7 g, 14.45 mmol), trans-1-N,2-N-dimethylcyclohexane-1,2-diamine (0.127 g, 1.45 mmol), copper(I) iodide (0.068 g, 0.36 mmol) and 2-iodo-5-methylbenzoic acid (CAS number 52548-14-8; 3.79 g, 14.46 mmol). The reaction was subjected to microwave irradiation at 125° C. for 15 minutes, and then poured into water (20 ml) and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (0-3% methanol/DCM) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=O)[CH2:12][N:13]2[CH2:30][CH2:29][C:16]3([C:20](=[O:21])[N:19]([C:22]4[CH2:23][O:24][C:25](=[O:28])[C:26]=4[CH3:27])[CH2:18][CH2:17]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:32].[CH3:33][NH2:34].CCO.[BH4-].[Na+]>C1COCC1>[CH3:33][NH:34][CH:11]([C:10]1[CH:9]=[CH:8][C:7]2[C:6](=[O:32])[O:5][CH2:4][C:3]=2[C:2]=1[CH3:1])[CH2:12][N:13]1[CH2:14][CH2:15][C:16]2([C:20](=[O:21])[N:19]([C:22]3[CH2:23][O:24][C:25](=[O:28])[C:26]=3[CH3:27])[CH2:18][CH2:17]2)[CH2:29][CH2:30]1
Reactant: CN
Reactant: CC1=C(N2CCC3(CCN(CC(=O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(CN1CCC2(CC1)CCN(C1=C(C)C(=O)OC1)C2=O)c1ccc2c(c1C)COC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 8-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxoethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (25 mg, 0.057 mmol) and methyl amine (4 mg, 0.114 mmol) in anhydrous THF was added Ti(O-iPr)4(35 μL, 0.114 mmol). The reaction was sealed and shaken at ambient temperature for 16 hr. To this reaction, EtOH (200 proof, 0.5 mL) was added followed by adding NaBH4 (11 mg, 0.171 mmol) portion-wise within 30 min. The reaction was shaken for 3 hr and quenched with water (0.5 mL). The reaction was partitioned between EtOAc (4 mL×2) and ammonium (2N, 1.5 mL). The organic phase was combined and evaporated under reduced pressure. The residue was dissolved in DMSO (1.5 mL) and filtered. The crude product was purified by using reversed-phase HPLC (Acetonitrile with 0.1% TFA: water with 0.1% TFA from 10% to 60%) to give the title compound. LC-MS (IE, m/z): 454 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O.[F-].[Cs+]>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>[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1F
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3F)ccc2c1
Temperature: 85 °C
Yield: 62.8 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-yl ester (1.0 g, 1.9 mmol), 2-fluorophenyl boronic acid (532 mg, 3.8 mmol), trans[dichlorobis(triphenylphosphine)]palladium II (266 mg, 0.38 mmol) and cesium fluoride (2.6 g, 17.1 mmol) in 150 mL degassed acetonitrile and heat at 85° C. for 2 hours. Cool the reaction, filter and purify on an SCX column, eluting with 2N ammonia/methanol. Concentrate and purify on a silica column eluting with 1 0-10% gradient of methanol/methylene chloride to give 560 mg (63%) of the title compound: mass spectrum (ion spray) m/z=470 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=O.[CH:52]([C:54]1[C:59](=[O:60])[N:58]([CH2:61][CH2:62][CH3:63])[C:57](=[O:64])[N:56]2[CH2:65][CH2:66][S:67][C:55]=12)=O>C(Cl)Cl>[O:64]=[C:57]1[N:56]2[CH2:65][CH2:66][S:67][C:55]2=[C:54](/[CH:52]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:59](=[O:60])[N:58]1[CH2:61][CH2:62][CH3:63]
Reactant: CCCn1c(=O)c(C=O)c2n(c1=O)CCS2
Reactant: CCOC(=O)CBr
Agent: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCn1c(=O)c(/C=C/C(=O)OCC)c2n(c1=O)CCS2
Yield: 78.7 %

Procedure:
A solution of the Wittig reagent prepared from triphenylphosphine (5.3 g) and ethyl bromoacetate (3.4 g), (carboethoxymethylene)triphenylphosphorane (6 g) and 8-formyl-6-propyl-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione (3.76 g) in methylene chloride (15 ml) was refluxed in for 7 hours. The reaction solution was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel. The resulting crude crystals were recrystallized from methylene chloride -isopropyl ether to give colorless needles (3.82 g, 79%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[NH:22][CH:23]=[C:24]([C:26]3[C:27]([O:41][CH:42]4[CH2:45][CH2:44][CH2:43]4)=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]([C:36]([O:38][CH3:39])=[O:37])[C@@H:31]([CH3:40])[CH2:30][CH2:29]4)[N:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH:42]1([O:41][C:27]2[C:26]([C:24]3[N:25]=[C:21]([CH:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)[NH:22][CH:23]=3)=[CH:35][CH:34]=[C:33]3[C:28]=2[CH2:29][CH2:30][C@H:31]([CH3:40])[N:32]3[C:36]([O:38][CH3:39])=[O:37])[CH2:43][CH2:44][CH2:45]1
Reactant: COC(=O)N1c2ccc(-c3c[nH]c(C4CCN(C(=O)OC(C)(C)C)CC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1c2ccc(-c3c[nH]c(C4CCNCC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-imidazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.050 g, 0.09 mmol) in dichloromethane (6 mL), and the reaction mixture stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum, and the residue was purified via preparative-HPLC (Waters I): Column: Waters HSS C18, 2.1×50 mm, 1.8 um; Mobile Phase water (0.05% ammonium bicarbonate) and acetonitrile (5% to 95% acetonitrile in 10 min, flow rate: 20 mL/min); Detector: UV254&220 nm. This afforded methyl (S)-5-cyclobutoxy-2-methyl-6-(2-(piperidin-4-yl)-1H-imidazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.0039 g, 10%) as an off-white solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.15-1.26 (m, 2H), 1.32-1.68 (m, 3H), 1.95-2.55 (m, 8H), 2.97-3.19 (m, 3H), 3.40-3.47 (m, 2H), 3.77-3.82 (m, 2H), 4.13-4.25 (m, 1H), 4.51-4.71 (m, 3H), 7.28-7.47 (m, 2H), 8.55-8.61 (m, 1H). MS (ESI, pos. ion) m/z 425 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([CH3:23])[CH2:5][S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Na+]>>[CH3:23][CH:4]([CH2:5][S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([OH:24])=[O:2]
Reactant: CCCCCCCCCCCCCCCCSCC(C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCSCC(C)C(=O)O
Yield: 91 %

Procedure:
The racemic α-methyl-β-hexadecylmercapto-propionic acid methyl ester described in Example 33 was saponified with 2 N sodium hydroxide under reflux. There was obtained racemic α-methyl-β-hexadecylmercaptopropionic acid, in 91% yield, melting point 53°-56° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]#[N:10])=[CH:4][CH:3]=1.Cl[C:18]1[N:23]2[N:24]=[CH:25][CH:26]=[C:22]2[N:21]=[C:20]([CH2:27][CH3:28])[CH:19]=1>C(O)C>[C:9]([CH:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:18]2[N:23]3[N:24]=[CH:25][CH:26]=[C:22]3[N:21]=[C:20]([CH2:27][CH3:28])[CH:19]=2)=[CH:7][CH:6]=1)#[N:10]
Reactant: N#CC(c1ccccc1)c1ccc(N)cc1
Reactant: CCc1cc(Cl)n2nccc2n1
Solvent: CCO
Product: CCc1cc(Nc2ccc(C(C#N)c3ccccc3)cc2)n2nccc2n1
Temperature: 25 °C

Procedure:
2.1 g (10.1 mmol) 2-(4-Aminophenyl)-2-phenylacetonitrile (prepared by catalytic hydrogenation of phenylcyanomethylenequinone oxime according to the method of R. B. Davis, D. D. Carlos, G. S. Mattingly, J. Org. Chem. 1965, 30, 2607) and 1.8 g (9.9 mmol) 7-Chloro-5-ethylpyrazolo[1,5-a]pyrimidine (Example 1, Step B) were dissolved in 50 ml dry ethanol and heated with reflux for 10 h. Solid materials, which precipitated after cooling to room temperature, were filtered, the filtrate evaporated in vacuo, the residue treated with 10% aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo to afford the crude title compound as an oil, which was pure enough for the next step as detected by its 1H-NMR spectrum.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=O)=[N:9][NH:10][CH:11]=1)=[O:5].[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[CH3:27][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:12]([C:8]2[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:2]=3[F:1])=[CH:11][NH:10][N:9]=2)=[O:14])[CH2:22][CH2:23]1
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2n[nH]cc2NC(=O)c2c(F)cccc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.1 %

Procedure:
A mixture of 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (134 mg, 0.50 mmol), 4-amino-N-methylpiperidine (50.0 μl, 0.45 mmol), EDAC (104 mg, 0.54 mmol) and HOBt (73.0 mg, 0.54 mmol) in DMF (3 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic portion was dried (MgSO4) and reduced in vacuo to give 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (1-methyl-piperidin-4-yl)-amide as a white solid (113 mg, 69%). (LC/MS: Rt 2.52, [M+H]+364.19).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(C(C)C)C(C)C)C1C=CC=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1>C1COCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:32])=[CH:26][CH:25]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCCCCCCN
Agent: CC(C)N(Cc1ccccc1)C(C)C
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Heptan-1-amine (1 g, 8.679 mmol) was dissolved in dry THF under N2 and polymer supported N-benzyl-N,N-diisopropylamine (4.955 g, 26.038 mmol) was added. The mixture was stirred for 30 min and cooled to 0° C. and (4-chlorophenyl)acetyl chloride (1.969 g, 10.415 mmol) was added. The solution was stirred overnight at room temperature. The excess of (4-chlorophenyl)acetyl chloride was removed by filtering the mixture through an NH2 cartridge. The solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 1.045 g of 2-(4-chlorophenyl)-N-heptylacetamide (yield 45.0%).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccccc2Cl)C1
Yield: 82.7 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-chlorophenylboronic acid (143 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml) and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) were stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (180 mg, 82.5%) as an oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12](=[S:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1C=CC=CC=1.C(O)C>[C:5]1([C:3]2[N:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:18][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(N)=S
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
A mixture of 2-bromo-1-phenylethanone (1.790 g, 8.99 mmol) and ethyl 2-amino-2-thioxoacetate (Example 4A, 1.20 g, 9.01 mmol) in benzene (80 mL) and ethanol (10 mL) was stirred at room temperature for 18 h. The mixture was heated at 80° C. for 1 h. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (300 mL) and saturated aqueous sodium bicarbonate (100 mL). The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual clear oil was chromatographed on silica gel (4×10 cm, elution toluene-ethyl acetate 0-2-4%) and gave a yellow oil (1.588 g). This was distilled in vacuo (bp: 105-115° C./0.1 torr, bulb to bulb distillation, air bath temperature) to provide the title material (1.409 g, 67%) as a pale yellow syrup which solidified to an almost colorless solid upon standing. LC (Method C): 2.009 min. HRMS (ESI) calcd for C12H12NO2S [M+H]+ m/z 234.0583, found 234.0597. 1H NMR (CDCl3, 400 MHz) δ ppm: 1.48 (t, J=7.2 Hz, 3H), 4.52 (q, J=17.2 Hz, 2H), 735-7.49 (m, 3H), 7.75 (s, 1H), 7.93-8.00 (m, 2H).