Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:16][N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][CH2:13][N:12](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][CH2:10][N:9](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][CH2:7][N:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][CH2:4][N:3]1S(C1C=CC(C)=CC=1)(=O)=O.OS(O)(=O)=O.C(O)C.C(OCC)C>CC#N>[CH3:1][CH:2]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC(C)N(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CC#N
Solvent: CCOCC
Product: CC1CNCCNCCNCCNCCN1
Temperature: 100 °C
Reaction time: 70 h
Yield: 28 %

Procedure:
This compound was synthesized following the procedure of European Patent 0 287 465 A1, Oct. 19, 1988. A mixture of 2-methyl-1,4,7,10,13-penta(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 2D (20.6 g, 0.0206 mole) and concentrated H2SO4 (75 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 70 h. To the resulting brown solution ethanol (100 ml) was added dropwise with stirring at 0° C., followed by ethyl ether (1 l). The off-white oily solid was filtered and washed thoroughly with ethyl ether. The solid was then dissolved in H2O (100 ml) and the resulting solution was washed with ethyl ether. The pH of the solution was adjusted to 10-11 with 10 N NaOH and the solvent was removed in vacuo. Ethanol (2×500 ml) was then added and removed in vacuo. The resulting brown oily solid was extracted with hot THF (2×500 ml) and filtered. The filtrates were combined and the solvent was removed in vacuo. The residue was dissolved in THF (100 ml) and filtered to remove insoluble impurities. The solvent was removed in vacuo to give the crude product as a yellow crystalline solid which was then dissolved in CH3CN and filtered to remove impurities. Crystallization occurred upon cooling the filtrate to -20° C. Recrystallization from cold (-20° C.) CH3CN gave 1.30 g (28% yield) of the product as an off-white crystalline solid: mp 73-5° C.; 1H NMR (CDCl3) δ 1.02 (d, J=6.2 Hz, 3 H), 1.71 (br s, 5 H), 2.36 (m, 1 H), 2.72 (m, 18 H); Anal. calcd. for C11H27N5 : C, 57.60; H, 11.87; N, 30.53: Found: C, 57.68; H, 11.34; N, 30.48.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][CH:10]=[CH2:11])[C:3]=1[O:12][CH3:13].[N:14]([O-])=O.[Na+].O.O.Cl[Sn]Cl>>[CH2:9]([C:4]1[C:3]([O:12][CH3:13])=[C:2]([NH:1][NH2:14])[CH:7]=[C:6]([Cl:8])[CH:5]=1)[CH:10]=[CH2:11]
Reactant: O=N[O-]
Reactant: C=CCc1cc(Cl)cc(N)c1OC
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: C=CCc1cc(Cl)cc(NN)c1OC
Yield: 82.6 %

Procedure:
The title compound was prepared by the general procedure described above for Preparations 2a-i using 2-amino-4-chloro-6-allylanisole (18 g), NaNO2 (9.02 g), and SnCl2.2H2O(3.48 g). Workup gave 16 g (82%) of (3-allyl-5-chloro-2-methoxyphenyl)hydrazine which was used without further purification.
Reaction SMILES: C[O-].[Na+].[CH:4](OCC)=[O:5].[C:9]1([C:17]([CH2:19][C:20]2[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[CH:22][CH:21]=2)=[O:18])[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=1.O1CCCC1>C(O)C>[CH:4]([CH:19]([C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[CH:26][CH:27]=1)[C:17](=[O:18])[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=1)=[O:5]
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(C=O)c2ccc(OC)cc2)cc1
Reaction time: 1 h

Procedure:
A solution of sodium methoxide (11.9 g, 0.22 mole) in 80 ml ethanol was cooled in an ice bath and treated with ethyl formate (20 ml, 0.24 mole). A solution of desoxyanisoin (51.2 g, 0.2 mole) in 275 ml warm tetrahydrofuran was then added while maintaining the reaction temperature below 5°. The reaction mixture was stirred for 1 hour at 0° and then stirred overnight at room temperature.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[Cl:37][C:38]1[C:39]([C:48]([F:51])([F:50])[F:49])=[N:40][N:41]([CH2:44][C:45](O)=[O:46])[C:42]=1[CH3:43]>>[Cl:37][C:38]1[C:39]([C:48]([F:50])([F:49])[F:51])=[N:40][N:41]([CH2:44][C:45]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[N:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[CH2:32][CH2:33]2)=[O:46])[C:42]=1[CH3:43]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: c1cnc(N2CCNCC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ncccn2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2-Pyrimidinyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: MS (ES) M+H expected=389.1, found=389.0; HPLC retention time=3.99 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using a 4.5 minute gradient of 20% to 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C@H:4]([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N1([S:21](Cl)=[O:22])C=CN=C1>ClCCl>[CH3:12][C@H:11]1[C:13](=[O:15])[O:14][S:21](=[O:22])[N:10]1[C@@H:4]([CH2:3][CH2:2][CH3:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=S(Cl)n1ccnc1
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Solvent: ClCCl
Product: CCC[C@@H](C(=O)OCC)N1[C@@H](C)C(=O)OS1=O
Reaction time: 1 h

Procedure:
Introduce into a reactor 200 g of N-[(S)-ethoxycarbonyl-1-butyl]-(S)-alanine and 1.5 liters of dichloromethane and then, at 0° C., add 325 g of 1H-imidazole-1-sulphinyl chloride. Subsequently, bring the reaction mixture to ambient temperature and then, after stirring for 1 hour, filter off the precipitate formed. The filtrate obtained is evaporated to dryness to yield the expected product in the form of an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[O:13][CH2:14][C:15]([CH2:33][OH:34])([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=2)[N:16]=1>C(Cl)Cl>[CH3:11][C:12]1[O:13][CH2:14][C:15]([CH:33]=[O:34])([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=2)[N:16]=1
Reactant: CCCCCCCCc1ccc(CCC2(CO)COC(C)=N2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCCCCCc1ccc(CCC2(C=O)COC(C)=N2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.6 %

Procedure:
A solution of 0.059 mL (0.8 mmol) of oxalyl chloride in 1.5 mL of CH2Cl2 at −78° C. was treated with 0.12 mL (1.6 mmol) of DMSO. The resulting mixture was stirred cold for 10 min, 118 mg of (+/−)-2-methyl-4-hydroxymethyl-4-(2-(4-octylphenyl)ethyl)oxazoline (from EXAMPLE 2, Step A) was added and resulting mixture was stirred cold for 30 min. TEA (0.28 mL, 2.0 mmol) was added and the resulting mixture was warmed to rt. The mixture was partitioned between 30 mL of ether and 10 mL of water. The organic layer was separated, dried and concentrated to afford 118 mg (100%) of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([NH:17][C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19](O)=[O:20])=[O:16])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:26][C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[CH2:4][CH3:5])[CH3:2].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[C:52]([O:56][C:57](=[O:60])[CH2:58][NH2:59])([CH3:55])([CH3:54])[CH3:53].Cl>CN(C=O)C.O.C(Cl)CCl>[C:52]([O:56][C:57](=[O:60])[CH2:58][NH:59][C:19](=[O:20])[C@@H:18]([NH:17][C:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]([CH2:26][C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[N:8][C:9]=2[CH:14]=1)=[O:16])[CH2:22][CH:23]([CH3:24])[CH3:25])([CH3:55])([CH3:54])[CH3:53]
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@@H](CC(C)C)C(=O)O)ccc21
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)OC(C)(C)C)ccc21
Reaction time: 16 h
Yield: 32.2 %

Procedure:
To a solution of 100 mg of (S)-2-{[1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-4-methyl-pentanoic acid in 1 ml of dry DMF 12 mg of HOAT, 41 mg of EDC and 0.13 ml of DIPEA were added at 0° C. After 15 min 30 mg of glycine tert.-butylester-hydrochloride and 0.03 ml of DIPEA were added and the reaction was stirred at it for 16 h. The reaction was then poured into water and the pH was adjusted to 3 by the addition of 2 M aqueous hydrochloric acid. The reaction was extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated. The crude product was purified by HPLC to yield 32 mg (32%) of ((S)-2-{[1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-4-methyl-pentanoylamino)-acetic acid tert.-butyl ester.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O(CCCNC(C)(C)CC1C=CC([O:47][CH3:48])=CC=1)C1C=CC=CC=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:47][CH3:48])[CH:23]=[C:22]([Cl:1])[CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cc(Cl)cc(OC)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 378 (M-15,.1), 275 (5), 274 (34), 273 (16), 272 (100), 163 (5), 121 (17), 114 (8).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].C(N(CC)CC)C.[Mg+2].[Cl-].[Cl-].[CH2:23]=[O:24].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(#N)C>[OH:10][C:5]1[C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:23]=[O:24]
Reactant: C=O
Reactant: Oc1ccccc1OC(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=Cc1cccc(OC(F)(F)F)c1O
Reaction time: 120 h
Yield: 41.3 %

Procedure:
A solution of 2-trifluoromethoxyphenol (5.13 g, 28.8 mmol) in anhydrous acetonitrile (150 mL) in oven-dried glassware was treated with triethylamine (15.0 mL, 108 mmol) and MgCl2 (4.11 g, 43.2 mmol) which had been dried under vacuum with heating. Paraformaldehyde (5.18 g, 172 mmol), which had been dried under vacuum with P2O5, was then added and the solution was heated to reflux. After 5 days, the reaction was quenched with 1 N HCl (200 mL). The mixture was extracted using Et2O (2×100 mL). The combined organics were washed with brine (2×150 mL), dried (Na2SO4) and concentrated to a yellow solid. Purification by column chromatography (silica gel, 98:2 to 95:5 hexanes/EtOAc) gave the title compound (2.45 g, 41%) as a yellow powder: 1H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 7.75-7.65 (m, 2H), 7.08 (t, J=7.9 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:5]=1[C:6]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].C(N(CC)CC)C.Br[CH2:28][CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1.O>CN(C)C=O>[CH3:2][O:3][C:4]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:5]=1[C:6]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:28][CH2:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: COc1ccc(C(=O)C2CCNCC2)c(OC)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)C2CCN(CCc3c[nH]c4ccccc34)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirring solution of 8.0 g of 4-(2,4-dimethoxybenzoyl)piperidine hydrochloride and 6 ml of triethylamine in 250 ml of dimethylformamide is added a solution of 6.4 g of 3-(2-bromoethyl)indole in 50 ml of dimethylformamide. The reaction mixture is permitted to stir at ambient temperature for 72 hours and then 500 ml of water is added dropwise and extracted with chloroform. The combined extracts are dried and most of the chloroform removed leaving a dark oil. The oil is subjected to column chromatography on a silica gel column and eluting with a 3% methanol in chloroform solution to give 3-{2-[4-(2,4-dimethoxybenzoyl)piperidyl]ethyl}indole. The indole is recrystallized thrice from an ethanol-water mixture to give the pure indole, mp 110°-112° C.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3S[CH2:22][CH2:21][C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][C:18]=3[CH:29]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].OO.[S:32]([O-:35])([O-])=[O:33].[Na+].[Na+].O>C(O)(=O)C>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[S:32](=[O:35])(=[O:33])[CH2:22][CH2:21][C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][C:18]=3[CH:29]=2)=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: O=S([O-])[O-]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3)cc1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3(=O)=O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
Ethyl 7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (45 g, 109.1 mmol) was suspended in 405 ml of acetic acid and was heated to 60° C. to dissolve. A solution of 30% hydrogen peroxide (25.35 g, 223.6 mmol) in 45 ml of acetic acid was dropped slowly at 60-70° C. After the dropping, the mixture was stirred at 65-70° C. for 3 hours. At that temperature, 40 ml of an aqueous sodium sulfite solution was dropped and disappearance of the peroxide was checked with iodo-starch paper. After dropping 275 ml of water at that temperature, the mixture was cooled and stirred for 2 hours and then was stirred at 0-10° C. for 30 minutes. After filtration, the residue was washed with an ice-cooled, mixed solution of acetic acid/water (45 ml/31.5 ml) and subsequently with 225 ml of water. After vacuum drying (40° C.), 45.9 g (Yield 94.6%) of ethyl 7-(4-propoxyethoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate was obtained as white crystals.
Reaction SMILES: [OH:1][C@@H:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([OH:27])=O)[CH:6]=1)[CH2:3][OH:4].[NH2:28][C@@H:29]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:30]([NH2:32])=[O:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:32][C:30](=[O:31])[C@@H:29]([NH:28][C:25](=[O:27])[C:7]1[CH:6]=[C:5]([C@H:2]([OH:1])[CH2:3][OH:4])[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[N:8]=1)[CH2:33][CH:34]([CH3:36])[CH3:35]
Reactant: O=C(O)c1cc([C@H](O)CO)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)c1cc([C@H](O)CO)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Reaction time: 8 h

Procedure:
To a solution of (S)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinic acid (assume 0.44 mmol) in DMF (5 mL) was added (S)-2-amino-4-methylpentanamide (0.074 g, 0.44 mmol), DIEA (0.20 mL, 1.1 mmol) and HBTU (0.201 g, 0.53 mmol). The reaction was stirred overnight then partitioned between 50 mL EtOAc and 50 mL brine. The organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel eluting with 25-75% acetone in hexanes. The product fractions were isolated and evaporated in vacuo. The residue was triturated with 5 mL 50% EtOAc/hexanes, filtered and rinsed with additional 50% EtOAc/hexanes. The solid was dried under vacuum at 50° C. to yield N—((S)-1-amino-4-methyl-1-oxopentan-2-yl)-4-((S)-1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinamide (compound 63) as an off-white powder (0.105 g, 0.22 mmol, 50% yield, LC/MS: m/z=482.2 [M+H]+, 1H NMR (400 MHz, DMSO-d6): δ 8.64 (d, J=9.2 Hz, 1H), 8.20 (d, J=8.4 Hz, 2H), 8.05 (s, 1H), 8.00 (s, 1H), 7.62 (s, 1H), 7.32-7.24 (m, 2H), 7.21-7.11 (m, 5H), 5.63 (d, J=4.8 Hz, 1H), 4.88-4.82 (m, 1H), 4.76-4.69 (m, 1H), 4.62-4.53 (m, 1H), 3.63-3.49 (m, 2H), 1.76-1.56 (m, 3H), 0.96-0.89 (m, 6H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51][CH:50]=1>CN(C=O)C>[N:49]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH:61][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51][CH:50]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2cncnc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cncnc2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 8.6 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-pyrimidin-5-yl-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.002 g of product in 9% yield: LCMS (ESI) m/z 360 (MH+).
Reaction SMILES: [NH2:1][C:2]([CH2:12][F:13])([CH2:6][C:7]1[NH:11][CH:10]=[N:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:14](Cl)(=[O:16])[CH3:15].Cl.C(O)(=O)C>[OH-].[Na+]>[C:14]([NH:1][C:2]([CH2:12][F:13])([CH2:6][C:7]1[NH:11][CH:10]=[N:9][CH:8]=1)[C:3]([OH:5])=[O:4])(=[O:16])[CH3:15]
Reactant: NC(CF)(Cc1cnc[nH]1)C(=O)O
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)NC(CF)(Cc1cnc[nH]1)C(=O)O
Temperature: 5 °C

Procedure:
A solution of 1.87 g (0.01 mole) of 2-amino-2-fluoromethyl-3-(5-imidazolyl)propionic acid in 10 ml of 2 N sodium hydroxide solution is cooled to 5° C. To this solution, maintained at 5° C., are added simultaneously from two syringes 1.0 g (0.013 mole) of acetyl chloride and 26 ml 2 N sodium hydroxide dropwise. After 2 hours the solution is neutralized by the addition of 8 ml of 5 N hydrochloric acid followed by 0.5 ml of acetic acid. The mixture is cooled to 0° C. and the resultant N-acetyl 2-amino-2-fluoromethyl-3-(5-imidazolyl)propionic acid filtered off.
Reaction SMILES: C([NH:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:23])([CH3:22])[C:14](=[O:21])[N:15]2[CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[NH2:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:23])([CH3:22])[C:14](=[O:21])[N:15]2[CH:18]([CH3:19])[CH3:20])=[CH:11][CH:10]=1
Reactant: CC(C)N1C(=O)C(C)(C)c2ccc(NCc3ccccc3)cc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)N1C(=O)C(C)(C)c2ccc(N)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Palladium on activated carbon (10%, 276 mg, 259 μmol) was added to a solution of 6-(benzylamino)-1-isopropyl-3,3-dimethylindolin-2-one (1.60 g, 5.18 mmol) in ethanol (75 ml). The mixture was stirred at room temperature under an hydrogen atmosphere (balloon) for 16 hours. As reaction was incomplete, the catalyst was filtered off and washed with ethanol. The solvent was evaporated and ethanol (75 ml) was added to the residue. Palladium on activated carbon (276 mg, 259 μmol) was added and hydrogenation (balloon) continued for 6 hours at 50° C. and 12 hours at room temperature. The catalyst was filtered off, washed with ethanol and the solvent was evaporated. The residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as light yellow solid (892 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:37][CH:38]=[CH2:39])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([O:18]CC)=[O:17].[OH-].[Li+].CO>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[C:4]([CH2:37][CH:38]=[CH2:39])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([N:32]1[CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: C=CCc1c(OCCCOc2cccc(OCC(=O)OCC)c2CCC)ccc(C(=O)N2CCCC2)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCc1c(OCCCOc2cccc(OCC(=O)O)c2CCC)ccc(C(=O)N2CCCC2)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound of Example 58 (95 mg, 0.176 mmol) and 352 μl (0.352 mmol) of 1M lithium hydroxide were added to 2.0 ml of methanol. The reaction mixture was stirred at room temperature for 4 hours and the solvent was removed under vacuum. Water (5.0 ml) was added to the residue, and the mixture was acidified with 10% hydrochloric acid then extracted three times with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed under vacuum to give a gum. Chromatography of the gum on silica gel with 50/50 ethyl acetate/hexane as eluant followed by drying under vacuum overnight gave the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][N:19]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][C:11]=1[F:17])(=[O:9])=[O:8].[F:30][C:31]1([F:44])[CH2:36][CH2:35][C@H:34]([OH:37])[C@@H:33]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:32]1.[H-].[Na+]>CN(C=O)C>[F:44][C:31]1([F:30])[CH2:36][CH2:35][C@H:34]([O:37][C:13]2[CH:14]=[CH:15][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:3]=3[O:2][CH3:1])[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)(=[O:9])=[O:8])=[C:11]([F:17])[CH:12]=2)[C@@H:33]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:32]1
Reactant: Cn1nccc1[C@H]1CC(F)(F)CC[C@@H]1O
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 39.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (167 mg, 0.40 mmol) prepared in Example 29a, the (1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (71.5 mg, 0.33 mmol) prepared in Example 88 g, sodium hydride (63%; 25.2 mg, 0.66 mmol) and DMF (2.0 mL), to yield the title compound (79.7 mg, 39%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH:20]=[N:19][N:18]=[N:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:17]2[N:18]=[N:19][CH:20]=[N:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: c1nnn[nH]1
Product: CC(C)(C)OC(=O)N1CCC(Cn2ncnn2)CC1

Procedure:
By a similar manner to Reference Example 29, 1-tert-butoxycarbonyl-piperidin-4-methanol (2.15 g, 10.0 mmol) was reacted with 1H-tetrazole (2.10 g, 30 mmol) to give 1tert-butoxycarbonyl-4-(2H-tetrazol-2-ylmethyl)piperidine as pale yellow oily substance (1.35 g, 50%) and 1-tert-1butoxycarbonyl-4-(1H-tetrazol-1-ylmethyl)piperidine as pale yellow solid substance (1.23 g, 46%).