Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:11][CH2:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.C1(=O)N(OC(N(C)C)=[N+](C)C)C(=O)CC1.C(N(CC)C(C)C)(C)C.[NH2:45][CH:46]([CH2:48][CH2:49][CH2:50][N:51]([CH2:54][CH3:55])[CH2:52][CH3:53])[CH3:47]>CN(C=O)C.[Cl-].[Na+].O>[CH2:54]([N:51]([CH2:52][CH3:53])[CH2:50][CH2:49][CH2:48][CH:46]([NH:45][C:13](=[O:15])[CH2:12][CH2:11][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH3:47])[CH3:55]
Reactant: CCN(CC)CCCC(C)N
Reactant: O=C(O)CCN1CCCc2ccccc21
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCC(C)NC(=O)CCN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a solution of Compound 4 (1.9 g, 9.3 mmol) in DMF (35 mL), 2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate (3.4 g, 11.2 mmol) and N,N-diisopropyl ethylamine (3.4 mL, 19.5 mmol) were added. Combined mixture was stirred at room temperature for 30 mins and then a solution of 2-amino-5-diethylaminopentane (2.2 g, 13.9 mmol) in DMF (5 mL) was added. After stirring the mixture for additional 1 hour, it was poured in brine (100 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with brine (3×100 mL) and dried over MgSO4. The solvent was removed under reduced pressure to provide Compound 5 as a dark yellow viscous liquid (2.64 g, 82.5%). This product was used without further purification. The structure of Compound 5 is given below:
Reaction SMILES: Cl[CH:2]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:3]1[CH:4]=[C:5]([CH:10]2[O:14]CCO2)[S:6][C:7]=1[CH2:8][CH3:9].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.[I-].[Na+].Cl>O1CCCC1.O.CN(C)C(=O)C>[CH:15]1([CH:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)[C:3]2[CH:4]=[C:5]([CH:10]=[O:14])[S:6][C:7]=2[CH2:8][CH3:9])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCc1sc(C2OCCO2)cc1C(Cl)C1CCCCC1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCc1sc(C=O)cc1C(Nc1ccc(C(=O)OC)cc1)C1CCCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a mixture of 2-{4-[chloro(cyclohexyl)methyl]-5-ethylthiophen-2-yl}-1,3-dioxolane (3.08 g) synthesized above, methyl 4-aminobenzoate (2.96 g), sodium iodide (2.98 g) and N,N-dimethylacetamide (60 mL) sodium carbonate (2.08 g) was added, and the mixture was stirred overnight at 100° C. under an argon atmosphere. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to give a yellow oil. To a solution of the obtained oil in tetrahydrofuran (40 mL) was added 1N hydrochloric acid (10 mL), and the mixture was stirred at room temperature for 1 hr. Tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate/hexane) to give the title compound (2.05 g, 54%) as a yellow solid.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[F:56][C:57]1[CH:58]=[C:59]([CH:63]=[CH:64][CH:65]=1)[C:60](Cl)=[O:61]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:54][C:49]1[CH:48]=[C:47]([CH:52]=[CH:51][C:50]=1[Cl:53])[CH2:46][O:45][C:42]1[CH:43]=[CH:44][C:39]([C@H:37]2[CH2:36][O:35][C:31]3=[CH:32][C:33]4[CH2:34][C@@H:25]([C:23]([NH:22][C@@H:6]([CH2:7][C:8]5[CH:9]=[CH:10][C:11]([C:14]6[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=6[CH3:21])=[CH:12][CH:13]=5)[C:5]([OH:4])=[O:55])=[O:24])[N:26]([C:60](=[O:61])[C:59]5[CH:63]=[CH:64][CH:65]=[C:57]([F:56])[CH:58]=5)[CH2:27][C:28]=4[CH:29]=[C:30]3[O:38]2)=[CH:40][CH:41]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3cccc(F)c3)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexa hydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (25 mg) was dissolved in 1:1 EtOAc and saturated aqueous NaHCO3 and 3-fluorobenzoyl chloride (3 eq.) were added. After stirring at room temperature for 1 hour, the layers were separated and the organic layer was dried over Na2SO4 and evaporated. The residue was purified by over silica (hexanes to 8:2 hexanes-EtOAc to 6:4 hexanes-EtOAc to 6:4 hexanes-EtOAc+2% MeOH to DCM+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z): 861.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2].OO.C(=O)([O-])[O-:34].[K+].[K+]>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:16](=[O:27])[C:17]2[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])(=[O:34])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2)cc1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C(N)=O)c2)cc1
Reaction time: 24 h
Yield: 166.6 %

Procedure:
To a solution of N1-(3-cyanobenzoyl)-N2-(4-tert-butylbenzoyl)-1,2-benzenediamine (200 mg, 0.5 mmol) in methyl sulfoxide (10 mL) was added 30% hydrogen peroxide solution (0.5 mL, 5.8 mmol) and potassium carbonate (17 mg, 0.13 mmol). After stirring for 24 h, the reaction mixture was diluted with water (20 mL), filtered, washed with water, and dried to give 90 mg (43%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][C:18]#[N:19]>CC(CC)=O>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:17][C:18]#[N:19]
Reactant: N#CCBr
Reactant: Cc1c(N)cccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: Cc1c(N)cccc1OCC#N
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.7 %

Procedure:
2-methyl-3-aminophenol (20.1 g, 0.163 mol) was dissolved in methylethylketone (MEK) (150 ml). Cesium carbonate (106 g, 0.326 mmol) was added in portions followed by dropwise addition of bromoacetonitrile (29.3 g, 0.245 mol) over 30 min. The mixture was stirred 14 hr at room temperature, then filtered through a coarse fritted funnel. The solids were washed with ethylacetate (2×100 ml) and the combined washings and filtrate were concentrated at reduced pressure to give 20.8 g (79% yield) of (2-methyl-3-aminophenoxy)acetonitrile which required no further purification.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([CH2:14][OH:15])[N:2]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:15][CH2:14][C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cc2c(cn1)[nH]c1ccccc12
Product: CC(=O)OCc1cc2c(cn1)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 9H-β-carboline-3-methanol (99 mg, 0.50 mmol) in acetic anhydride (10 mL) was stirred for 4 hours at room temperature, during which time the starting material dissolved. Removal of the acetic anhydride in vacuo afforded a tan solid (122 mg). Purification by flash chromatography on silica gel with ethyl acetate as the eluent afforded 82 mg (68%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ9.49 (s, 1H), 8.99 (s, 1H), 8.13 (d, J=8.0, 1H), 8.07 (s, 1H), 7.56-7.61 (m, 2H), 7.26-7.34 (m, 1H), 5.43 (s, 2H), 2.15 (s, 3H). LRMS calcd for C14H12N2O2 (M+H) 241, found 241.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][N:14]=2)[C:9]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[N:8][C:7]=1[CH3:23])=[O:5])C.[OH-].[Na+]>>[CH3:23][C:7]1[N:8]=[C:9]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:10]2=[N:11][CH:12]=[CH:13][N:14]=[C:15]2[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(C)nc(N2CCN(C)CC2)c2nccnc12
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(N2CCN(C)CC2)c2nccnc2c1C(=O)O

Procedure:
10 gm. of 7-methyl-5-(4-methyl-1-piperazinyl)pyrido[3,4-b]pyrazine-8-carboxylic acid ethyl ester are hydrolyzed with dilute sodium hydroxide solution to obtain 7-methyl-5-(4-methyl-1-piperazinyl)pyrido[3,4-b] pyrazine-8-carboxylic acid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=1)[C:11]#[N:12].[C:20]([O-])([O-])=O.[K+].[K+].CI.O>CS(C)=O>[Cl:19][C:15]1[N:14]=[C:13]([C:10](=[C:2]2[N:3]([CH3:20])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1]2)[C:11]#[N:12])[CH:18]=[CH:17][N:16]=1
Reactant: N#CC(c1ccnc(Cl)n1)c1nc2ccccc2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CS(C)=O
Product: CN1C(=C(C#N)c2ccnc(Cl)n2)Sc2ccccc21
Reaction time: 48 h
Yield: 5 %

Procedure:
To a solution of 1 (0.1 g, 0.35 mmol) in dry DMSO was added dry K2CO3 then methyl iodide and the suspension was shaken at rt. for 2 days. The precipitate formed by addition of water was filtered off then washed with water until neutral pH. The crude residue, dried under vacuum at 40° C., was triturated in warm acetonitrile, filtered off then dried under vacuum at 40° C., affording 5.6 mg (5%) of the title compound as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:23]=[CH:22][NH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)[N:13]=2)[CH:5]=[N:6][CH:7]=1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>[Cu]I.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>[CH3:20][C:16]1[N:15]=[C:14]([C:12]2[N:13]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:3]=3)[C:9]3[CH:23]=[CH:22][NH:21][C:10]=3[N:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(-c2nc(-c3cncc(Br)c3)c3cc[nH]c3n2)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: Cc1cccc(-c2nc(-c3cncc(C#C[Si](C)(C)C)c3)c3cc[nH]c3n2)n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a suspension of of 4-(5-bromo-pyridin-3-yl)-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Example 16) (1 eq, 0.451 mmol, 250 mg) in TEA/DMF (1:1, 6 ml) are added copper (I) iodide (0.1 eq, 0.045 mmol, 8.8 mg), PdCl2(PPh3)2 (0.1 eq, 0.045 mmol, 32.3 mg), and trimethylsilylacetylene (Sigma-Aldrich, St. Louis, USA) (1.5 eq, 0.68 mmol, 0.098 ml). The resulting mixture is stirred at 90° C. for 1 h. The solvents are removed in vacuo, then sat. aqueous NaHCO3 solution is added, and the mixture is extracted with EtOAc. The organic layer is washed with sat. aqueous NaCl solution, dried with MgSO4, and concentrated under reduced pressure. The crude product is purified by reversed phase HPLC and recrystallized in EtOAc giving the title compound; [M+H]+=384.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=C1CCN(C(=O)c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CCN(C(=O)c2ccccc2)CC1

Procedure:
16.4 g. of the above piperidine were dissolved in 300 ml of ethanol to which was added 1.0 g. of 10 percent Pd/C. The mixture was placed in a low pressure hydrogenation apparatus and hydrogenated at a pressure of about 60 psi. The catalyst was removed by filtration and the solvents evaporated from the hydrogenation mixture in vacuo. N-benzoyl-4-(carbethoxymethyl)piperidine formed in the above reaction remained as a residue and was purified by distillation. A yield of about 15.86 g. of the compound was obtained distilling in the range 176°-178° C. at 0.20 mm Hg. The compound also crystallized from hexane in colorless prisms, mp=47°-48° C. The compound had the following physical characteristics.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2>CN(C)C=O>[CH:15]1([N:8]2[C:7]3[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=3[NH:5][C:4]3=[CH:3][S:2][CH:1]=[C:10]3[C:9]2=[O:11])[CH2:14][CH2:13][CH2:12][CH:7]=[CH:6]1
Reactant: O=C1Nc2ccccc2Nc2cscc21
Solvent: CN(C)C=O
Product: O=C1c2cscc2Nc2ccccc2N1C1C=CCCC1
Reaction time: 2 h

Procedure:
To a mixture of 11.8 g. of 4,9-dihydro-10H-thieno [3,4-b][1,5]benzodiazepin-10-one in 175 ml. of dimethylformamide is added 2.8 g. of 50% sodium hydride in mineral oil from which the mineral oil has been removed. The mixture is stirred for two hours and then 11.9 g. of 3-bromocyclohexene is added. The reaction mixture is stirred overnight and poured into ice water. The brown syrup which separates is collected and extracted into methylene chloride. The extracts are washed with water, dried over sodium sulfate, filtered and evaporated to an oil. The oil is triturated in ether-hexane and cooled for 48 hours. The mixture is separated by partition chromatography. Fraction 3 is triturated in hexane, filtered and the solid is dried. The solid is triturated in hexane and chilled producing crystals. The crystals are collected, washed with hexane and dried. These crystals are heated to solution in 12 ml. of ethanol and cooled. A 12 ml. portion of hexane is added and the tan crystals are collected, washed with hexane and dried giving the desired product, mp. 147°-149° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:18]([C:34]([F:37])([F:36])[F:35])=[CH:17][N:16]=1.C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH3:40])[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:18]([C:34]([F:37])([F:35])[F:36])=[CH:17][N:16]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2C)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C)CC3)cc2C)ncc1C(F)(F)F

Procedure:
Methyl 2-(2-(2-(2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (54) (1.10 g, 2.15 mmol) was dissolved in dry MeOH (20 mL) and formaldehyde solution (37% aq; 348 μL, 4.29 mmol) was added. Sodium triacetoxyborohydride (2.27 g, 10.7 mmol) was added under nitrogen and the resultant mixture was stirred at room temperature for 16 hours. Ethyl acetate (50 mL) was added and the mixture was washed with 10% NaHCO3 solution (20 mL). The organic layer was separated, dried (MgSO4) then the volatiles removed by evaporation under reduced pressure. Chromatography (SiO2, 0-50% MeOH/DCM) gave the title compound (I55) (480 mg, 42%) as a cream solid; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.83-7.73 (m, 1H), 7.35 (s, 1H), 7.32-7.19 (m, 3H), 7.19-7.09 (m, 2H), 7.07-6.97 (m, 1H), 3.76 (s, 2H), 3.70 (s, 3H), 3.23 (d, J=11.5 Hz, 2H), 3.17-3.04 (m, 4H), 2.61-2.51 (m, 1H), 2.50 (s, 3H), 2.35 (s, 3H), 2.33-2.24 (m, 2H), 2.02-1.84 (m, 4H). LCMS Method C: rt 5.25 min; m/z 527.2 [M+1]+.
Reaction SMILES: C([O:8][CH2:9][C:10]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][C:28]=3[Cl:29])[NH:25][CH:24]=[C:23]4[C:30]([O:32][CH3:33])=[O:31])=[CH:16][CH:15]=2)[CH2:13][O:12][CH2:11]1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:29][C:28]1[CH:27]=[C:26]2[C:22]([C:23]([C:30]([O:32][CH3:33])=[O:31])=[CH:24][NH:25]2)=[CH:21][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([C:10]2([CH2:9][OH:8])[CH2:11][O:12][CH2:13]2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(COCc5ccccc5)COC4)cc3)cc12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(CO)COC4)cc3)cc12
Temperature: 25 °C
Yield: 24.8 %

Procedure:
To a 0° C. slurry of methyl 5-[4-(3-Benzyloxymethyl-oxetan-3-yl)-phenyl]-6-chloro-1H-indole-3-carboxylate (200 mg, 0.433 mmol) in DCM (5 mL) was added boron trichloride (1.73 mL, 1.0M in DCM, 1.73 mmol) via syringe, and the mixture was allowed to warm to room temperature over five hours. The reaction mixture was concentrated to dryness, diluted with ethyl acetate (200 mL), washed with water (10 mL) and saturated brine (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford an orange film, which was purified by flash chromatography (12 g silica, 20-100% ethyl acetate/heptane, 38 column volumes). Product fractions were combined and concentrated in vacuo to afford the title compound as a colorless oil (40 mg, 25% yield). MS (ES+) 372 (M+H)+; 1H NMR (500 MHz, CD3OD) δ ppm 8.00-8.04 (m, 2H), 7.60 (s, 1H), 7.44-7.55 (m, 4H), 4.10 (s, 2H), 3.95-4.07 (m, 4H), 3.88 (s, 3H).
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23](Cl)=[O:24])=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[NH:1][CH:2]=[CH:3][C:4]1=2)=[O:24])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: c1cc2c([nH]1)CCCCN2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCCCc2[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (664 mg) in DCM (10 mL) at 0° C. was added oxalyl chloride (4.7 mmol), followed by one drop of DMF. After stirring at rt for 2 hours, the solvent was concentrated to give S)-2-chlorocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester. To a solution of 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine (350 mg, 2.6 mmol) was added TEA (362μL) and (S)-2-chlorocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester (dissolved in 10 mL of DCM). After stirring at rt for overnight, the reaction was diluted with DCM, washed with NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 410 mg of (S)-2-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepine-4-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[NH:14][C:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][C:12]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.[BH3-]C#N.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[NH:14][CH:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH:12]3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1cccc2c3c([nH]c12)CCN(C(=O)OCC)C3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Nc1cccc2c1NC1CCN(C(=O)OCC)CC21
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of ethyl 6-[(ethoxycarbonyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (4.5 g, 13.6 mmol) in CH2Cl2 (40 mL) at 0° C. was added TFA (20 mL) followed by NaCNBH3 (1.8 g, 27 mmol) and stirred at rt for 3 hours before the solvent was removed by the nitrogen stream. To the resulting residue were added CH2Cl2 (40 mL) and 6N HCl (20 mL) and stirred for 0.5 hour. The solution was diluted with water (20 mL), 1N NaOH (30 mL) and extracted with CH2Cl2 (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford ethyl 6-[(ethoxycarbonyl)amino]-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (3.6 g, 80%) as a clear oil. MS [M+H]+ 334. 1H NMR (CDCl3, 300 MHz): δ 6.97 (d, 1H, J=7.3 Hz), 6.85 (d, 1H, J=7.3 Hz), 6.72 (t, 1H, J=7.3 Hz), 4.05 (m, 4H), 3.41 (m, 4H), 1.92 (m, 2H), 1.20–1.24 (m, 6H) ppm.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@H:9]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=3[F:25])[CH2:8]2)[O:4][NH:3]1.Br>>[F:25][C:18]1[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:17]=1[C@@H:9]1[CH2:8][C@@H:7]([C:5]2[O:4][NH:3][C:2](=[O:1])[CH:6]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1c1cc(F)c(F)cc1F
Agent: Br
Product: O=c1cc([C@H]2CCN[C@H](c3cc(F)c(F)cc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
(2S,4S)-Methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylate (203 mg, 0.57 mmol) (from example 63, step 4) was dissolved in hydrogen bromide (33% in acetic acid, 4 mL, 22.84 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4S)-2-(2,4,5-trifluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (138 mg, 81%). 1H NMR (600 MHz, dmso) δ 1.62-1.70 (m, 1H), 1.80 (tt, 1H), 1.90-1.96 (m, 1H), 2.00-2.06 (m, 1H), 2.68 (dt, 1H), 2.85-2.91 (m, 1H), 3.20 (s, br., 1H), 3.90 (d, 1H), 5.86 (d, 1H), 7.43-7.56 (m, 2H). HRMS Calculated for [C14H13F3N2O2+H]+: 299.1007. Found: 299.1023
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[N:4]1[C:10]([C:12]1[S:16][C:15]([CH3:17])=[N:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:11].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34](O)=[O:35])[CH:27]=[CH:26][CH:25]=1>>[CH3:9][CH:5]1[N:4]([C:10]([C:12]2[S:16][C:15]([CH3:17])=[N:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:11])[CH:3]([CH2:2][NH:1][C:34]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:33]=2[N:24]=[CH:25][CH:26]=[CH:27]3)=[O:35])[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: Cc1nc(-c2ccccc2)c(C(=O)N2C(C)CCCC2CN)s1
Product: Cc1nc(-c2ccccc2)c(C(=O)N2C(C)CCCC2CNC(=O)c2cccc3cccnc23)s1

Procedure:
The title compound was prepared by following the general procedure A using rac-(2-(aminomethyl)-6-methylpiperidin-1-yl)(2-methyl-4-phenylthiazol-5-yl)methanone and quinoline-8-carboxylic acid. MS (ESI) 485 (M+H).