Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:4][CH2:3]2.[CH:47]1(S(Cl)(=O)=O)C[CH2:48]1>>[CH:46]1([S:43]([NH:42][CH2:41][CH2:40][NH:39][C@:5]23[CH2:35][CH2:34][C@@H:33]([C:36]([CH3:38])=[CH2:37])[C@@H:6]2[C@@H:7]2[C@@:2]([CH3:1])([CH2:3][CH2:4]3)[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)(=[O:45])=[O:44])[CH2:48][CH2:47]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNS(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=S(=O)(Cl)C1CC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCNS(=O)(=O)C3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using cyclopropanesulfonyl chloride as the reagent in Step 1. The product was isolated as a colorless oil (3.5 mg, 34%). LCMS: m/e 677.52 (M+H)+, 2.32 min (method 11). 1H NMR (400 MHz, CHLOROFORM-d) δ 9.55 (br. s., 1H), 7.98 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.3 Hz, 2H), 6.76 (br. s., 1H), 5.99 (br. s., 1H), 5.21 (d, J=5.0 Hz, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 3.92-3.71 (m, 1H), 3.69-3.55 (m, 1H), 3.23 (br. s., 2H), 2.91-2.70 (m, 1H), 2.63-2.44 (m, 1H), 2.25-1.02 (m, 26H), 1.70 (s, 3H), 1.18 (s, 3H), 1.02 (s, 3H), 0.97 (s, 3H), 0.92 (s, 3H), 0.92 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:12][CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[C:17]1([C:15]23[CH2:14][CH2:13][CH2:12][N:1]2[C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[O:5]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(CCCCl)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: O=C1OC2(c3ccccc3)CCCN2c2ccccc21

Procedure:
A mixture of 26.1 g of 2-aminobenzoic acid, 36.5 g of 4-chloro-1-phenyl-1-butanone, 0.5 g of p-toluenesulfonic acid and 250 ml of xylene were refluxed with a water trap. After the reaction was complete, the solvent was removed by distillation and the remaining solid was recrystallized from ethanol. Yield: 41.1 g (81.5%), melting point 152° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH3:22])=[C:17]([CH:19]([OH:21])[CH3:20])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([CH3:22])=[C:17]([CH:19]([O:21][C:30]3[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=3)[CH3:20])[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C(C)Oc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[4-(1-Hydroxy-ethyl)-5-methyl-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.46 mmol), 4-methanesulfonyl-phenol (0.08 g, 0.46 mmol) and PPh3 (0.14 g, 0.55 mmol) in THF (5 mL) was added DEAD (0.1 g, 0.55 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed. The residue was purified by flash chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 7.79 (2H, m), 6.94 (2H, m), 5.59 (1H, q, J=6 Hz),), 4.2-4.04 (2H, m), 3.04-2.94 (1H, m), 2.98 (3H, s), 2.86-2.72 (2H, m), 2.39 (3H, s), 2.04-1.96 (2H, m), 1.67 (3H, d, J=6 Hz), 1.66-1.58 (2H, m), 1.42 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH2:23][CH2:24]O)[O:19][C:18]2=[O:33])[CH3:16])=[CH:11][CH:10]=1.N1C=CC=CC=1.P(Br)(Br)[Br:41]>C(Cl)Cl>[Br:41][CH2:24][CH2:23][C@@:20]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:19][C:18](=[O:33])[N:17]([C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:10][CH:11]=2)[CH3:16])[CH2:22][CH2:21]1
Reactant: BrP(Br)Br
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCBr)(c2ccc(F)cc2)OC1=O
Reaction time: 2 h
Yield: 41.8 %

Procedure:
To a solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (250 mg, 0.55 mmol) in methylene chloride (10 mL) was added pyridine (0.5 mL) and PBr3 (75 mg). The formed mixture was stirred for 2 h. The mixture was washed with water. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to afford (S)-6-(2-bromoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (60 mg, 23%). 1H NMR: (400 MHz, CDCl3): δ=1.45 (d, 3H), 2.12-2.38 (d, 4H), 2.43 (m, 1H), 2.94 (m, 2H), 3.49 (m, 1H), 5.22 (m, 1H), 6.83 (m, 2H), 6.95 (m, 4H), 7.19 (m, 1H), 7.22 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].P([O-])(O)(O)=O.[K+]>CS(C)=O.C(OC(C)C)(=O)C.[Cu]>[CH2:13]([O:12][C:10](=[O:11])[C:9]([F:16])([F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:14]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Brc1ccccn1
Agent: [Cu]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)C
Product: CCOC(=O)C(F)(F)c1ccccn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 67107.4 %

Procedure:
To the solution of 2-bromopyridine (18 mL, 0.2 mmol) and ethyl bromodifluoroacetate (27 g, 0.22 mol) in DMSO (70 mL) was added copper powder (29 g, 0.46 mol). The mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with isopropyl acetate (100 mL). A solution of potassium dihydrogen phosphate (1.27 M, 150 mL) was added and stirred for 30 min. the copper salt was removed by filtration and washed with isopropyl acetate (100 mL). The filtrate layer was separated. The organic layer was washed with water (2×100 mL) and dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 5%-40% methyl t-butyl ether in hexanes in 40 min) afforded difluoro-pyridin-2-yl-acetic acid ethyl ester (27 g, 68%) as a colorless oil. LC-MS m/e 202 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.ClC1C=CC(CC2C=C(C=O)SC=2)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O>[CH:9]1([C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=2)[CH2:11][CH2:10]1
Reactant: O=Cc1cc(Br)co1
Reactant: OB(O)C1CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cc(C2CC2)co1
Yield: 30.9 %

Procedure:
The title compound was synthesized from 4-bromo-furan-2-carbaldehyde (300 mg, 1.71 mmol) and cyclopropylboronic acid (171 mg, 1.99 mmol), using the conditions to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde, with the exception that the reaction was run in toluene (7.5 mL) and water (0.5 mL), and triphenylphosphine was replaced with tricyclohexylphosphine (48 mg, 0.17 mmol). Purification by flash chromatography (0-60% EtOAc in heptane) provided 4-cyclopropylfuran-2-carbaldehyde as an orange oil 72 mg (31%). 1H NMR (400 MHz, CDCl3) δ ppm 0.55-0.61 (m, 2H), 0.90-0.97 (m, 2H), 1.69-1.77 (m, 1H), 7.00 (d, J=0.78 Hz, 1H), 7.49 (d, J=0.59 Hz, 1H), 9.58 (d, J=0.49 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](C(O)=O)=[CH:4][CH:3]=1.C(Cl)Cl.[C:18](OC(=O)C)(=[O:20])[CH3:19].[C:25]([O:28]C(O)=O)(=[O:27])C>C(N(CC)CC)C.O1CCCC1>[C:18]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:25]([OH:28])=[O:27])[CH:3]=1)(=[O:20])[CH3:19]
Reactant: O=C(O)c1ccc(O)c2ccccc12
Reactant: CC(=O)OC(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1cc(C(=O)O)cc2ccccc12

Procedure:
To a suspension of 2.3 g. of 4-hydroxy-1-naphthoic acid in 100 ml. of methylene chloride and 100 ml. of tetrahydrofuran, a mixture of 1.5 g. of triethylamine, 1.6 g. of 4-N-dimethylaminopyridine and 1.5 g. of acetic anhydride is added. The reaction mixture is heated at 50° for one hour. The solution is extracted with ethyl acetate, the organic layer washed with water and dilute hydrochloride acid and evaporated to dryness to yield 2.1 g. of the acetoxy carboxylic acid.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@@H:2]([C:14]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6]NC(C(F)(F)F)=O.[CH3:24][N:25](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48]CN(C(C)C)C(C)C>C(Cl)Cl.C(OCC)(=O)C>[NH2:25][CH2:24][C:6]1[CH:48]=[C:2]([CH:3]=[CH:4][CH:5]=1)[C:14]([OH:16])=[O:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NCc1cccc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 457.7 %

Procedure:
NMeArg(Tos)-Gly-OBzl (14.40 g, 29.4 mmol), Boc-D-Lys(Tfa) (10.00 g, 29.4 mmol), and HBTU (11.37 g, 62.0 mmol) were dissolved in methylene chloride (40 ml). After cooling to 0° C., DIEA (10.44 g, 62.0 mmol) was added and the reaction was allowed to proceed 20 minutes at 0° C. and 2 days at room temperature. The reaction mixture was diluted with ethyl acetate (800 ml), extracted with 200 ml portions of 0.2 N HCl (1×), sat. NaHCO3 (1×), and saturated NaCl (2×), dried (MgSO4), and evaporated under reduced pressure to a yellow solid. Purification by flash chromatography (silica gel; 5:1 EtOAc:acetonitrile) gave the title compound as a colorless solid (20.34 g, 85%). MP 78-85° C.; DCI-MS: [M+NH4 ]=831.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:19]([C:23]1[NH:24][C:25]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[C:26]([Cl:28])[N:27]=1)[CH2:20][CH2:21][CH3:22].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.[Cl-].[Na+].O>[CH3:18][O:17][C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:24]2[C:25]([CH2:29][O:30][Si:31]([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33])=[C:26]([Cl:28])[N:27]=[C:23]2[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:4][CH:5]=1)=[O:16]
Reactant: CCCCc1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 4'-bromomethylbiphenyl-2-carboxylate (2.05 g) in dry THF (10 mL) was added dropwise to a solution of 2-butyl-4-chloro-5-(t-butyldimethylsilyloxymethyl)-1H-imidazole (2.03 g) and NaN(TMS)2 (1.48 g) in dry THF (20 mL) at 0° C. and the reaction mixture was stirred at room temperature overnight. It was diluted with brine and the organic layer was collected, dried over MgSO4, and evaporated under reduced pressure. The residue was purified by flash chromatography (EtOAc, silica) to separate the two regioisomeric alkylation products. The major isomer, 4'-[[2-butyl-4-chloro-5-(t-butyldimethylsilyloxymethyl) -1H-imidazol-1-yl]methyl][1,1'-biphenyl-2-yl]carboxylic acid methyl ester (1.4 g) was used in the next step and the regiochemistry of this alkylation product was proven by NOE experiments at the stage of the hydrazide.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:14]1[CH:30]=[CH:29][C:17]([CH:18]=[CH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)=[O:13].C(O)(=[O:33])C.OO>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[CH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)=[CH:29][CH:30]=1)(=[O:33])=[O:13]
Reactant: CC(=O)O
Reactant: O=C(O)c1ccc(C=Cc2ccc(S(=O)Cc3ccc4ccccc4n3)cc2)cc1
Agent: OO
Solvent: ClCCl
Product: O=C(O)c1ccc(C=Cc2ccc(S(=O)(=O)Cc3ccc4ccccc4n3)cc2)cc1
Temperature: 25 °C

Procedure:
To 3 mmol of the sulfinyl compound from Step A in acetic acid (40 mmol) is added 30% hydrogen peroxide (2 ml). The mixture is stirred at ambient temperature and assayed by TLC. Upon disappearance of the sulfinyl starting compound, the reaction mixture is diluted with dichloromethane, washed with dilute aqueous sodium bisulfite and water, dried and evaporated to give 4-(4-(2-quinolinylmethylsulfonyl)styryl)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: CSc1ccc(Cl)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: CSc1ccc(Cl)c(C(=O)Cl)c1

Procedure:
A mixture of 2.03 g of 2-chloro-5-(methylthio)benzoic acid and 10 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are removed under vacuum and 20 ml of toluene added and removed under vacuum (2 times) to give 2.2 g of brown needles.
Reaction SMILES: CO[C:3](=[O:15])[CH2:4][N:5]1[CH2:9][CH:8]2[CH2:10][CH2:11][C:12](=[O:13])[N:7]2[C:6]1=[O:14].[NH3:16]>CO>[O:14]=[C:6]1[N:7]2[C:12](=[O:13])[CH2:11][CH2:10][CH:8]2[CH2:9][N:5]1[CH2:4][C:3]([NH2:16])=[O:15]
Reactant: COC(=O)CN1CC2CCC(=O)N2C1=O
Reactant: N
Solvent: CO
Product: NC(=O)CN1CC2CCC(=O)N2C1=O
Reaction time: 24 h

Procedure:
A solution of tetrahydro-3,5-dioxo-1H-pyrrolo-[1,2-c]imidazole-2(3H)-acetic acid methyl ester (1.0 g, 0.004 mol) in methanol, 150 ml, is saturated with anhydrous ammonia. The mixture is allowed to stand 24 hours at room temperature. The solution is concentrated at reduced pressure to yield tetrahydro-3,5-dioxo-1H-pyrrolo[1,2-c]imidazole-2(3H)-acetic acid amide.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46][O:47]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1.C1C[O:64]CC1>>[CH:46]([OH:47])=[O:64].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: C1CCNCC1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCCCC5)c4)c4ccccc43)cn12
Product: O=CO
Yield: 46 %

Procedure:
A solution of Intermediate 154a (66 mg, 88 μmol) and piperidine (44 μL, 0.45 mmol) in THF (2 mL) was heated at 60° C. overnight in a sealed vessel. The reaction mixture was concentrated in vacuo and the residue purified by MDAP (Method 7) to give the title compound as a white solid (31 mg, 46%). LCMS (Method 5): Rt 3.77 min, m/z 746 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.2 Hz), 1.24-1.34 (11H, m), 1.39-1.55 (6H, m), 1.61-2.18 (4H, m), 2.34-2.43 (4H, m), 2.63 (2H, t, J=6.1 Hz), 2.86-2.94 (1H, m), 3.11-3.19 (1H, m), 3.27-3.36 (1H, m), 4.09 (2H, t, J=5.9 Hz), 4.77 (1H, m), 5.52 (1H, t, J=4.0 Hz), 6.32 (1H, s), 6.93-6.98 (1H, m), 7.04-7.13 (3H, m), 7.19 (1H, dd, J=9.5 Hz, 2.6 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J=9.9 Hz), 7.69 (1H, d, J=1.8 Hz), 8.12 (1H, s), 8.17 (1.5H, s).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[N:10]([C:15]([C:17]2[CH:39]=[C:38]([O:40][CH3:41])[C:20]3[N:21]([CH3:37])[C:22]([C:24]4[N:32]([CH2:33][CH:34]5[CH2:36][CH2:35]5)[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH:25]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.CO>[NH2:7][C@@H:8]1[CH2:9][N:10]([C:15]([C:17]2[CH:39]=[C:38]([O:40][CH3:41])[C:20]3[N:21]([CH3:37])[C:22]([C:24]4[N:32]([CH2:33][CH:34]5[CH2:36][CH2:35]5)[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH:25]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[C@H:11]([CH3:14])[CH2:12][CH2:13]1
Reactant: COc1cc(C(=O)N2C[C@@H](NC(=O)OC(C)(C)C)CC[C@H]2C)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)N2C[C@@H](N)CC[C@H]2C)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Reaction time: 2.5 h
Yield: 90.2 %

Procedure:
To a flask containing tert-butyl((3S,6R)-1-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-6-methylpiperidin-3-yl)carbamate (47 mg, 0.082 mmol) in dichloromethane (DCM) (1 mL) was added TFA (0.253 mL, 3.28 mmol) and the reaction was stirred for 2.5 h. The reaction mixture was concentrated in vacuo to afford a brown oil. This was dissolved in methanol and loaded onto an SCX cartridge (5 g). It was eluted with methanol (3 column volumes) and product eluted as free base with 2M ammonia in methanol. The filtrate from the ammonia fractions was concentrated in vacuo to yield a yellow oil—((2R,5S)-5-amino-2-methylpiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone (35 mg, 0.074 mmol, 90% yield). The free base (35 mg) was dissolved in dichloromethane (DCM) (1 mL) in a vial and HCl (2M in Et2O) (0.037 mL, 0.074 mmol) was added. The resultant suspension was sonicated for 5 min and allowed to stand for 15 min.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:6])[CH2:4][CH3:5].[H-].[Na+].CO[C:11](=O)[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].O>CN(C)C=O>[CH2:4]([C:3]1[N:6]=[C:11]([CH2:12][CH2:13][NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[O:1][N:2]=1)[CH3:5]
Reactant: CCC(=N)NO
Reactant: COC(=O)CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1noc(CCNC(=O)OC(C)(C)C)n1
Temperature: 50 °C
Reaction time: 0.1 h

Procedure:
2.00 g (22.70 mmol) N-hydroxy-propionamidine are placed in 10 ml dimethylformamide and molecular sieve. 0.999 g (24.97 mmol) sodium hydride (60% in mineral oil) are added. The mixture is stirred for 0.1 hours at 50° C., then 5.00 g (24.60 mmol) methyl3-tert-butoxycarbonylamino-propionate in 20 ml dimethylformamide are added. The reaction mixture is stirred for 3 hours at 50° C. After cooling 15 ml of water are added, and the mixture is suction filtered through Celite. The 2 phases of the filtrate are separated and the organic phase is evaporated down. The residue is purified by chromatography.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: COC(=O)C(C)(C)CC(CCCCN)CCCc1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.34 g methyl 8-amino-2,2-dimethyl-4-[3-(3-pyridyl)propyl]-octanoate in 5 ml dry methylene chloride is added a catalytic amount of 4-dimethylaminopyridine followed by 0.2 ml triethylamine and the mixture is cooled to 0°; 0.208 g (0.96 mmol) p-chlorophenylsulfonyl chloride is added, the reaction mixture is allowed to warm to room temperature and stirred for 48 h. The mixture is diluted with methylene chloride and washed with saturated sodium bicarbonate, water and brine. The organic phase is dried, filtered and evaporated to yield an amber oil which is purified by flash chromatography using 1:1 ethyl acetate/hexane to yield methyl 8-(p-chlorophenylsulfonamido)-2,2-dimethyl-4-[3-(3-pyridyl)propyl]-octanoate; IR (CH2Cl2): 3381, 1729, 1164 cm-1 ; NMR (CDCl3): delta 3.57 (s,3H), 2.9 (q,2H), 2.53 (t,2H), 1.12 (s,6H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=O)=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C([N:24](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N>CCCCCC.ClCCl>[C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([NH2:24])=[O:21])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Agent: N
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: NC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Reaction time: 1 h

Procedure:
[2-(1-cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetic acid (100 mg) and triethylamine (53 mg) were added to dichloromethane (2ml). After addition of diphenylphosphoryl azide (145 mg) with stirring under ice cooling, the mixture was stirred at room temperature for 1 hour. Conc. aqueous ammonia (5 ml) was added to the reaction mixture and stirring was further continued for 1 hour. Hexane (5 ml) was added and crystals deposited were filtered off. The crystals were recrystallized from dichloromethane and methanol to obtain the title compound as needles, m.p. 244°-245° C., yield 64 mg (64.6%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]1[CH2:11][CH2:12][CH:13]=O.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([C@:23]23[CH2:28][C@H:27]2[CH2:26][NH:25][CH2:24]3)=[CH:19][CH:18]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:49]C(Cl)C>>[ClH:49].[O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]1[CH2:11][CH2:12][CH2:13][N:25]1[CH2:26][C@H:27]2[C@:23]([C:20]3[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:30])[F:29])=[CH:22][CH:21]=3)([CH2:28]2)[CH2:24]1
Reactant: N#Cc1cn(CCC=O)c(=O)[nH]c1=O
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: CC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cl
Product: N#Cc1cn(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of 2,4-dioxo-1-(3-oxo-propyl)-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (Prep35, 90 mg, 0.47 mmol) in dichloroethane (8 mL), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 106 mg, 0.47 mmol), AcOH (42 mg, 0.7 mmol) and NaBH(AcO)3 (198 mg, 0.94 mmol) were added and the mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum, the residue redissolved in ethyl acetate and the obtained mixture washed with aqueous saturated NaHCO3 solution. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with DCM-MeOH—NH4OH (97-3-1) to give the free base of the title compound as a white solid (70 mg, 38% yield).