Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][C:5]([C:9]3[O:10][C:11]4[C:17]([C:18]([O:20]C)=O)=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[NH3:22]>CO>[N:1]12[CH2:8][C:5]([C:9]3[O:10][C:11]4[C:17]([C:18]([NH2:22])=[O:20])=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: N
Reactant: COC(=O)c1cccc2nc(C34CCCN(CC3)C4)oc12
Solvent: CO
Product: NC(=O)c1cccc2nc(C34CCCN(CC3)C4)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 27 %

Procedure:
Methyl 2-(1-azabicyclo[3.2.1]octan-5-yl)benzo[d]oxazole-7-carboxylate (80 mg, 0.28 mmol) was added to ammonia in methanol (15 ml) and the mixture was stirred at room temperature for 3 days. Then the solid was filtered, washed with methanol, the residue solution was concentrated under vacuum. Then the residue was purified by flash column chromatography to give 2-(1-azabicyclo[3.2.1]octan-5-yl)benzo[d]oxazole-7-carboxamide (20.6 mg, yield: 27%) 1H-NMR (400 MHz, CD3OD) δ: 1.18 (s, 1H), 1.63-1.67 (m, 1H), 1.82 (s, 1H), 1.94-1.98 (m, 1H), 2.10-2.15 (m, 2H), 2.23-2.28 (m, 1H), 2.38-2.44 (m, 1H), 2.91-2.93 (m, 2H), 3.12-3.18 (m, 1H), 3.20-3.30 (m, 1H), 7.34-7.37 (t, J=8 Hz, 1H), 7.72-7.77 (m, 2H), LC-MS (m/z): 272 (M+1)+.
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]2[C:11]([C:12](=O)[CH2:13][CH2:14][O:15]2)=[CH:10][CH:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].CN([CH:26]=[O:27])C.P(Cl)(Cl)([Cl:30])=O>ClC=C(Cl)Cl.C(Cl)Cl>[C:1]([C:5]([NH:7][C:8]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]2[C:11]([C:12]([Cl:30])=[C:13]([CH:26]=[O:27])[CH2:14][O:15]2)=[CH:10][CH:9]=1)=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCCC2=O
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: ClC=C(Cl)Cl
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC(C=O)=C2Cl
Temperature: 60 °C

Procedure:
A suspension of methyl 7-tert-butylcarbonylamino-4-oxochroman-8-carboxylate (Intermediate 77, 1.32 g) in trichloroethylene (25 mL) was treated with DMF (1.5 mL), followed by dropwise addition of phosphorus oxychloride (0.998 g). The resultant mixture was heated at 60° C. for 2 hours. A further amount of phosphorus oxychloride (0.200 g) was added and the mixture was heated at 60° C. for 40 minutes. After cooling, the mixture was diluted with DCM and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with DCM and the combined organic layers were washed with brine, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-25% to give methyl 7-tert-butylcarbonylamino-4-chloro-3-formyl-2H-chromene-8-carboxylate (1.175 g) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=2)O)[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([CH:7]=1)[CH2:8][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:23])[CH3:24])[CH:19]([CH3:20])[CH3:21])=[CH:12][CH:11]=1
Reactant: CC(C)[Si](C#Cc1ccc(C(O)c2cc(Br)ccc2F)cc1)(C(C)C)C(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[Si](C#Cc1ccc(Cc2cc(Br)ccc2F)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5.6 g (5-bromo-2-fluoro-phenyl)-{4-[(triisopropylsilyl)-ethynyl]-phenyl}methanol and 4.1 ml triethylsilane in 50 ml dichloromethane is cooled in an ice bath. Then 4.7 ml trifluoroacetic acid are slowly added dropwise, and the solution is stirred for 4 h at ambient temperature. The solution is diluted with dichloromethane and washed with aqueous sodium hydrogen carbonate solution. After drying over sodium sulfate the solvent is removed and the residue is purified using silica gel (cyclohexane).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH:7][C:8]2[C:9]([C:20]([OH:22])=O)=[N:10][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:13]=2)[CH:4]=[N:3][CH:2]=1.[CH3:23][NH:24][C:25]([C:27]1[N:28]([CH3:33])[N:29]=[CH:30][C:31]=1[NH2:32])=[O:26]>>[CH3:33][N:28]1[C:27]([C:25](=[O:26])[NH:24][CH3:23])=[C:31]([NH:32][C:20]([C:9]2[C:8]([NH:7][C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)=[N:13][CH:12]=[C:11]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])[N:10]=2)=[O:22])[CH:30]=[N:29]1
Reactant: O=C(O)c1nc(OCC(F)(F)F)cnc1Nc1cncnc1
Reactant: CNC(=O)c1c(N)cnn1C
Product: CNC(=O)c1c(NC(=O)c2nc(OCC(F)(F)F)cnc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 3-(pyrimidin-5-ylamino)-6-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid (114 mg, 0.36 mmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (67 mg, 0.43 mmol) according to the method described in example 64, step 6 as yellow solid (92 mg, 56%).
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5]([C:7]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:10](=[O:20])[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:8]=1)=O.O=C1N(C2C=CC=CC=2)[N:33]=C(C(N)=O)C(SC2C=CC=CC=2)=C1.COC(OC)N(C)C>>[C:21]1([N:9]2[C:10](=[O:20])[CH:11]=[C:12]([S:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:7]([C:5]3[N:4]=[CH:3][NH:2][N:33]=3)=[N:8]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)c1nn(-c2ccccc2)c(=O)cc1Sc1ccccc1
Reactant: CN(C)C=NC(=O)c1nn(-c2ccccc2)c(=O)cc1Sc1ccccc1
Agent: COC(OC)N(C)C
Product: O=c1cc(Sc2ccccc2)c(-c2nc[nH]n2)nn1-c1ccccc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Preparation of N,N-dimethyl-N′-[(6-oxo-1-phenyl-4-phenylsulfanyl-1,6-dihydropyridazin-3-yl)carbonyl]formamidine: A mixture of 6-oxo-1-phenyl-4-phenylsulfanyl-1,6-dihydropyridazine-3-carboxamide (193 mg, 0.6 mmol) and N,N-dimethylformamide dimethyl acetal (1 mL) was stirred at 120° C. for 1 h and then evaporated in vacuo. The residue was crystallized on treatment with Et2O (10 mL) to yield the desired product as a white crystalline substance (196 mg, 88%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:9]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: CN1CCC(c2cn(S(=O)(=O)c3ccc(F)cc3)c3ccccc23)CC1

Procedure:
(17.0 mg, 46%), from 3-(1-methyl-4-piperidinyl)-1H-indole (Example 5d, 21.5 mg, 0.1 mmol) and 4-fluorophenylsulfonyl chloride (29.2 mg, 0.15 mmol), HRMS-FAB+ for C20H21N2O2SF, calculated MH+ : 373.13861; found: 373.13669.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][C@H:14]([OH:18])[C:15]([OH:17])=[O:16])=O)C1C=CC=CC=1.S(Cl)([Cl:21])=O.[C:23](OCC)(=O)[CH3:24].CO>C(O)C.[Pd]>[ClH:21].[CH2:23]([O:17][C:15](=[O:16])[C@@H:14]([OH:18])[CH2:13][CH2:12][NH2:11])[CH3:24]
Reactant: CCOC(C)=O
Reactant: O=C(NCC[C@H](O)C(=O)O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)[C@@H](O)CCN
Product: Cl

Procedure:
Add 4-benzyloxycarbonylamino-2(S)-hydroxybutyric acid (2.57 g) to absolute ethanol (30 ml) containing thionyl chloride (2.0 ml) and heat the resulting mixture under reflux for 20 hours. Cool, filter and concentrate the reaction mixture in vacuo to give a pale yellow oil. Chromatograph this oil on a column of silica gel (500 ml) using ethyl acetate as eluant to obtain a yellow oil, [α]D26 =+0.4° (MeOH). Hydrogenate the product (1.4 g) in absolute ethanol (50 ml) containing 10% Pd/C (0.50 g) at 50 psi for 2 hours. Filter the mixture and concentrate the mixture in vacuo to give the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](OCC)=[CH:4][CH:3]=1.[Li][CH2:12][CH2:13][CH2:14]C.CON(C)[C:19]([C:21]1[S:22][CH:23]=[CH:24][C:25]=1[CH3:26])=[O:20].Cl>C1COCC1>[CH3:26][C:25]1[CH:24]=[CH:23][S:22][C:21]=1[C:19]([C:2]1[CH:3]=[CH:4][C:5]([CH2:12][CH2:13][CH3:14])=[CH:6][CH:7]=1)=[O:20]
Reactant: [Li]CCCC
Reactant: CCOc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1sccc1C
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)c2sccc2C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 4-bromophenetole (1.86 mL, 13.0 mmol) in anhydrous THF (15 mL) was added dropwise (over a 5-min period) a solution of n-BuLi (6.0 mL, 2.5 M in hexane) under nitrogen atmosphere at −78° C. The resulting mixture was stirred at −78° C. for 1 hour, and then a solution of the Weinreb amide 43 (1.85 g, 10.0 mmol) in anhydrous THF (5.0 mL) was added dropwise (over a 10-min period). The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was poured into a 1 M HCl solution (25 mL) and extracted with EtOAc (50 mL). The organic phase was subsequently washed with brine, dried over MgSO4 and evaporated under vacuum. The residue was further purified by silica column chromatography (Biotage) to provide (4-ethoxyphenyl)(3-methylthiophen-2-yl)methanone (44, 1.52 g, 6.16 mmol, 62%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]([C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([OH:35])[CH:26]=1)=[O:24])[NH2:22]>C(O)(C)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:22][NH:21][C:23]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([OH:35])[CH:26]=3)=[O:24])[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1O
Solvent: CC(C)O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1O
Temperature: 0 °C
Yield: 80.7 %

Procedure:
1-[5-(4-tert-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.578 mmol, 157.5 mg) synthesized in Synthetic Example 3, methyl 4-hydrazinocarbonyl-2-hydroxybenzoate (0.578 mmol, 121.6 mg) synthesized in Reference Synthetic Example 43 and p-tosylic acid monohydride (30 mol %, 30 mg) were dissolved in isopropyl alcohol (15 mL) and stirred under heating with reflux for 8 hours, and the reactor was cooled to 0° C. The reaction solution was filtered and dried by means of a vacuum pump to give the desired product as a white solid (216.6 mg, yield 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl.CCOCC>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:31])[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 mL, 0.29 mmol) were dissolved in THF (2 ml). Benzoyl chloride (0.03 ml, 0.29 mmol) was added dropwise and the reaction was stirred at room temperature for 1 h. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. The resulting precipitate was filtered and dried under vacuum to provide 19 (33 mg, 40% yield) as a pale yellow solid. LC-MS (M+H=312, obsd.=312).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[Cl:13]Cl.CCN(C(C)C)C(C)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>>[Cl:13][C:11]1[CH:2]=[C:3]([CH:8]=[CH:9][C:10]=1[Cl:12])[C:4]([NH:6][NH:7][C:26](=[O:27])[CH2:25][Cl:24])=[O:5]
Reactant: ClCl
Reactant: NNC(=O)c1ccc(Cl)cc1Cl
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)NNC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a solution of compound 8 (370 mg, 0.934 mmol) in 5 ml of CH2 Cl2 was added DIPEA (180 mg, 1.4 mmol) at 0° C. and stirred for 10 minutes. Then chloroacetyl chloride (116 mg, 1.02 mmol) was added slowly at the same temperature and the mixture was warmed to ambient temperature and stirred overnight. Solvent was removed to give the crude compound which was used in the next step without any further purification. The crude compound was heated to reflux in toluene (25 ml) using Dean-Stark for 12 hours. Then the toluene was distilled and the crude material purified by column chromatography using EtOAc:Hexane (45:55) as an eluent to afford compound 9 as a pale yellow gummy material (212 mg). Yield: 50%.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[I-].C([N+]1(C)[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)C>C(O)C.O>[C@@H:2]1([N:1]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CCc2ccccc21
Reactant: CC[N+]1(C)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCN([C@H]2CCc3ccccc32)CC1

Procedure:
(S)-1-Aminoindane (37 mmol) was dissolved in ethanol (65 ml). Potassium carbonate (3.7 mmol) and 1-ethyl-1-methyl-4-oxo-piperidinium iodide (56 mmol) dissolved in water (30 ml) were added and the mixture was refluxed for 30 mil. Water was added, ethanol was removed in vacuo and the residue was extracted with ethyl acetate. Organic phases were pooled, dried with sodium sulfate and concentrated. Chromatography on silica gel (ethyl acetate) yielded the desired product as an oil. 7.1 g (90%) of (S)-1-indan-1-yl-piperidine-4-one, MS: m/e=216.4 (M+H+).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][N:5]([C@H:15]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:16]([O:18]CC2C=CC(OC)=CC=2)=[O:17])[CH2:4]1)=O.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:35][CH:34]=1.Cl>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:43][CH2:44][N:45]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=4)[CH2:6][N:5]([C@H:15]([CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:16]([OH:18])=[O:17])[CH2:4]3)[CH2:46][CH2:47]2)=[CH:37][CH:38]=1
Reactant: COc1ccc(COC(=O)[C@@H](CC2CC2)N2C[C@H](c3cccc(F)c3)[C@@H](C=O)C2)cc1
Reactant: Fc1ccc(CCCC2CCNCC2)cc1
Agent: Cl
Product: O=C(O)[C@@H](CC1CC1)N1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2cccc(F)c2)C1
Yield: 111.9 %

Procedure:
The title compound was prepared from 33.5 mg (0.07 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclopropyl)propanoic acid, 4-(methoxy)benzyl ester (from EXAMPLE 21, Step E) and 20.5 mg (0.07 mmol) of 4-(3-(4-fluorophenyl)propyl)-piperidine.HCl (from EXAMPLE 96, Step B) using a procedure analogous to that described in EXAMPLE 1, Step J to provide 40 mg (80%) of the title compound: RF: 0.47 (1:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 0.01-0.07 (m, 2H), 0.34-0.47 (m, 2H), 0.68 (m, 1H), 0.96-3.41 (m, 26H), 3.80 (s, 3H), 5.12 (ABq, J=11.9, 21), 6.82-7.34 (m, 12H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: Cc1cccc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1-n1nccn1
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: Cc1cccc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 459 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.45-6.50 (m, 9H), 4.65-2.70 (m, 5H), 2.10-0.75 (m, 11H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C@@H:5]([O:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]1=[O:26].C(=O)(SC)O[O:29][CH:30]([O:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]([CH3:33])[CH3:32].[C:43](OO)(=[O:45])C>ClCCl.C(O)(=O)C>[CH3:38][CH:36]([CH3:37])[C:35]([O:34][C@H:30]([O:29][C:43]([O:1][N:2]1[C:6](=[O:7])[C@@H:5]([O:8][C:9](=[O:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:4]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]1=[O:26])=[O:45])[CH:31]([CH3:32])[CH3:33])=[O:39]
Reactant: O=C(O[C@@H]1C(=O)N(O)C(=O)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: CSC(=O)OOC(OC(=O)C(C)C)C(C)C
Reactant: CC(=O)OO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)C(=O)O[C@H](OC(=O)ON1C(=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
To a stirred solution of compound (27) (35 g, 98.6 mmol) and thiocarbonate (11) (34.6 g, 148 mmol) in dichloromethane at 0° C. was dropwise added a 32% solution of peracetic acid (300 mmol) in acetic acid over 2 h. The reaction temperature was kept below 35° C. during the addition of peracetic acid. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The resulting white precipitate was filtered and washed sequentially with water and a mixture of ether and hexane (1:2), then dried under vacuum to afford the crude title compound. This product was crystallized once from a mixture of ethyl acetate and hexane (1:1) to afford the title compound (25) (13.7 g, 25% yield). The diastereomeric purity of the product was determined to be 98.4% d.e. by HPLC using a chiral column. 1H NMR (CDCl3, 400 MHz): δ 1.06 (d, 6H), 1.22 (d, 3H), 1.22 (d, 3H), 2.20 (m, 1H), 2.64 (hept., 1H), 6.01 (br. s, 2H), 6.64 (d, 1H), 7.47 (m, 4H), 7.63 (m, 2H), 8.07 (m, 4H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 10C to give the title compound. 1H NMR (400 MHz, DMSO-d6, Temp=90° C.) δ ppm 11.09-11.16 (m, 1H), 8.30 (d, J=7.1 Hz, 1H), 7.99 (d, J=1.3 Hz, 1H), 7.92-7.96 (m, 1H), 7.84-7.88 (m, 1H), 7.26-7.46 (m, 4H), 3.80-3.83 (m, 4H), 3.64-3.65 (m, 1H), 3.65 (d, J=5.0 Hz, 1H), 3.09-3.13 (m, 4H); MS (APCI+) M/Z 399 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:17]2[CH:16]3[CH2:18][CH2:19][CH:13]([CH2:14][CH:15]3[NH:20][CH:21]=[O:22])[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:4].O.[CH3:24]I>C1(C)C(C)=CC=CC=1>[CH2:3]([N:5]1[C:17]2[CH:16]3[CH2:18][CH2:19][CH:13]([CH2:14][CH:15]3[N:20]([CH3:24])[CH:21]=[O:22])[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:4]
Reactant: CI
Reactant: CCn1c2c(c3ccccc31)C1CCC2C(NC=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCn1c2c(c3ccccc31)C1CCC2C(N(C)C=O)C1
Reaction time: 18 h

Procedure:
To a stirred suspension of sodium hydride (0.5 g of 57% oil dispersion, 0.011 mole) in dry xylene (15 ml), a solution of N-(9-ethyl-2,3,4,9-tetrahydro-1,4-ethano-1H-carbazol-2-yl)-formamide (0.9 g, 0.0034 mole, described in Example 6) in dry xylene (15 ml) was added dropwise under nitrogen. The suspension was refluxed with stirring for 18 hr. The reaction mixture was cooled. The water condenser was replaced by a dry ice/acetone condenser and methyl iodide (1.7 ml) was added. The reaction mixture was refluxed for 5 hr. Additional 1.7 ml of methyl iodide was added. The solution was refluxed for 4 hr and stirred at 20° C. for 18 hr. The reaction mixture was cooled in ice, and water was added dropwise to destroy the excess hydride. The compound was extracted with ethyl acetate and the organic layer was washed with water, dried and evaporated to afford the title compound as a yellow oil (ca. 1.2 g): IR (CHCl3) 1650 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([CH2:18][OH:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>C(Cl)Cl.CCOCC>[CH:25]1([C:28]([O:19][CH2:18][C:14]2[N:15]=[CH:16][C:17]3[N:5]([CH2:4][C:3]4[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:2]=4[Cl:1])[C:6]4[C:11]([C:12]=3[CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:29])[CH2:27][CH2:26]1
Reactant: O=C(Cl)C1CC1
Reactant: OCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(OCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1)C1CC1
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
A solution of [9-(2,5-dichlorobenzyl)-9H-β-carbolin-3-yl]methanol (357 mg, 1.0 mmol) and cyclopropyl carbonyl chloride (133 mg, 1.27 mmol) in methylene chloride (5 mL) was allowed to stand for 10 minutes. The solvent was evaporated, and the residue partitioned between aqueous Na2CO3 and methylene chloride. The extract was dried over Na2SO4, filtered and evaporated, affording a resin. This was dissolved in ether and filtered through a plug of silica gel, treated with ethereal hydrogen chloride, evaporated, and the residue recrystallized from ethanol/ethyl acetate/ether, affording 270 mg (58%) of the title compound as a yellow solid. 1H NMR (CDCl3) δ8.85 (s, 1H), 8.44 (s, 1 H), 8.25 (d, J=7.9 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.35-7.28 (m, 3H), 7.10 (dd, J=8, 2.3 Hz, 1H), 6.37 (d, J=2.3 Hz, 1H), 5.62 (s, 2H), 5.46 (s, 2H), 1.74 (m, 2H), 1.56 (m, 1H), 0.84-0.71 (m, 4H); MS (APCI; (M+H)+) m/z 425.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:43][NH:44][C@@H:45]([CH2:52][CH2:53][CH3:54])[CH2:46][N:47]1[CH2:50][CH:49]([OH:51])[CH2:48]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:44]([C@@H:45]([CH2:52][CH2:53][CH3:54])[CH2:46][N:47]1[CH2:48][CH:49]([OH:51])[CH2:50]1)[CH3:43])=[O:7]
Reactant: CCC[C@@H](CN1CC(O)C1)NC
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.3 %

Procedure:
3,4-Difluorobenzoic acid (0.184 g, 1.16 mmol), TBTU (0.373 g, 1.16 mmol) and DIPEA (0.303 mL, 1.74 mmol) was stirred in DCM (2 mL) for 40 min before (S)-1-(2-(methylamino)pentyl)azetidin-3-ol (Compound J4) (0.1 g, 0.58 mmol) was added. The resultant mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue dissolved in a mixture of MeOH (3 mL) and NaOH (aq. 1 mL, 1M). The resultant mixture was stirred at rt for 90 min before the MeOH was removed on a vacuum centrifuge. The crude product was extracted with DCM and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (102 mg, 56%). Mixture of rotamers: (600 MHz, DMSO-d6) δ 0.67-0.76, 0.79-0.91, 0.92-1.04, 1.06-1.48, 2.30-2.76, 3.23-3.42, 3.43-3.53, 4.05-4.17, 4.37-4.47, 5.17-5.26, 7.14-7.27, 7.36-7.56. Total no of protons: 22. HRMS (M+H)+: calculated 313.1728. found 313.1714.