Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:2]1.[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][CH2:29][C:30](O)=[O:31])[CH:24]=[C:25]([F:27])[CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][CH2:29][C:30]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]3[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]4[NH:17][CH:18]=[CH:19][C:9]=34)[CH2:2]2)=[O:31])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: NC(=O)c1cnc2[nH]ccc2c1NC1CCCNC1
Reactant: O=C(O)CNc1cc(F)cc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cnc2[nH]ccc2c1NC1CCCN(C(=O)CNc2cc(F)cc(Cl)c2)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a solution of 4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (132 mg, 0.51 mmol, 1.0 eq) and 2-((3-chloro-5-fluorophenyl)amino)acetic acid (124 mg, 0.61 mmol, 1.2 eq) in DMF (3 mL) was added HBTU (387 mg, 1.02 mmol, 2.0 eq) and DIPEA (1 mL). The resulting mixture was stirred at 80° C. for 16 h and the solvent was concentrated in vacuo to afford a residue which was purified by prep-HPLC (MeOH/H2O with 0.05% TFA as mobile phase) to give afford the title compound as a light brown solid (110 mg, yield: 50%). 1H NMR (400 MHz, CD3OD) δ: 8.23 (s, 1H), 7.09-7.02 (m, 1H), 6.66-6.61 (m, 1H), 6.42-5.94 (m, 3H), 4.35-4.10 (m, 1H), 4.08-3.91 (m, 2H), 3.79-3.74 (m, 1H), 3.65-3.53 (m, 2H), 3.43-3.40 (m, 2H), 2.06-2.04 (m, 1H), 1.82-1.73 (m, 2H), 1.62-1.59 (m, 1H). ESI-MS (M+H)+: 445.15.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[N:7]=1)[CH3:2].O.[OH-].[Li+].Cl[CH2:58][C:59]1[O:60][C:61](=[O:65])[O:62]C=1C>>[CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:5]([C:12]([O:14][CH2:15][C:16]2[O:65][C:61](=[O:62])[O:60][C:59]=2[CH3:58])=[O:13])=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(CC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1oc(=O)oc1CCl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 48.8 %

Procedure:
Following a procedure similar to that described in Example 78(a), but using 2.25 g of ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazole-5-yl)-phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 68 (a)] and using 203 mg of lithium hydroxide monohydrate for hydrolysis and 0.95 g of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (74% purity) for esterification, 1.23 g of the title compound was obtained as crystals, melting at 145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9]([O:15][CH2:16][CH2:17][CH2:18][NH2:19])=[C:8]3[NH:20][C:21]4[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][C:26]=4[C:7]3=[CH:6][C:5]2=1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[CH:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH2:37][NH:19][CH2:18][CH2:17][CH2:16][O:15][C:9]2[C:8]3[NH:20][C:21]4[C:26](=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[C:7]=3[CH:6]=[C:5]3[C:4]4[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:12]=4[NH:11][C:10]=23)=[CH:29]1
Reactant: NCCCOc1c2[nH]c3ccc(Cl)cc3c2cc2c1[nH]c1ccc(Cl)cc12
Reactant: O=Cc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Clc1ccc2[nH]c3c(OCCCNCc4c[nH]c5ccccc45)c4[nH]c5ccc(Cl)cc5c4cc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 3-(2,10-dichloro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)propan-1-amine (1 equiv) in 1,2-dichloroethane (10 mL/mmol), under an atmosphere of argon, was added 1H-indole-3-carbaldehyde (1 equiv), NaBH(OAc)3 (2 equiv), and then HOAc (2-3 equiv). The resulting mixture was stirred at RT overnight, and then partitioned between dichloromethane and 2 M Na2CO3. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was subjected to chromatography on silica gel, eluting with CH2Cl2/MeOH (10% cNH3.H2O) to the expected product in 50-80% yield. 1H NMR (400 MHz, CD3CN) δ 11.0 (br s, 2H), 9.25 (br s, 1H), 8.31 (s, 1H), 7.99 (d, J=2.4 Hz, 2H), 7.64 (d, J=7.6 Hz, 1H), 7.44 (dt, J=8.4, 0.8 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.19-7.10 (m, 3H), 7.00 (ddd, J=7.2, 6.8, 0.8 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 4.29 (t, J=5.6 Hz, 2H), 4.09 (s, 2H), 3.07 (t, J=6.0 Hz, 2H), 2.00 (pentalet, J=5.8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24](O)=[O:25])[CH2:19][CH2:18]3)=[O:16])[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[C:29]([O:33][C:34]([NH:36][CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:35])[NH:36][CH:37]1[CH2:41][CH2:40][N:39]([C:24](=[O:25])[CH2:23][N:20]2[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][C:12]3[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=4)[S:10][CH:11]=3)[CH2:18][CH2:19]2)[CH2:38]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)CN2CCN(C(=O)Cc3csc(NC(=O)c4ccc(Cl)cc4)n3)CC2)C1

Procedure:
In analogy to example 22.3, (4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetic acid (example 22.2) was coupled with 3-(tert-butyloxycarbonylamino)pyrrolidine, using general method C, to give {1-[2-(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester. Off-white solid. MS 591.3 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][N:26]([C:29]2[CH:37]=[C:36]3[C:32](C4CCNCC=4[N:35]3[CH3:38])=[CH:31][CH:30]=2)[C:25](=[O:43])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O.CCOC(C)=O>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]3[C:24]4[CH2:25][N:26]([CH2:13][C@@H:9]5[CH2:10][CH2:11][CH2:12][N:8]5[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:27][CH2:28][C:23]=4[N:35]([CH3:38])[C:36]=3[CH:37]=2)[C:25](=[O:43])[CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCNC2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C[C@@H]1CCCN1C(=O)OC(C)(C)C)CC2
Temperature: 60 °C
Yield: 7.9 %

Procedure:
A solution of (S)-tert-butyl-2-(bromomethyl)pyrrolidine-1-carboxylate (0.45 g, 1.7 mmol) in DMSO (1.5 mL) was added to a solution of 4-(benzyloxy)-1-(9-methyl-2,3,4,9,-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-one (0.33 g, 0.85 mmol), and Cs2CO3 (1.10 g, 3.4 mmol) in DMSO (2.8 mL), and the resulting solution was heated at 60° C. for 18 h. The reaction mixture was diluted with H2O and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were washed with brine (2×25 mL), dried over Na2SO4 and concentrated to dryness under reduced pressure. Purification by flash column chromatography (40 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 hold 5 column volumes, increased to 0:100:0 over 20 column volumes) provided a clear film. The film was diluted with EtOAc and washed with brine (4×10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (19 mg, 3%) as a clear film: ESI MS m/z 569 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]=[C:23]([NH2:28])[C:22]3[N:29]=[C:30]([CH2:35][O:36][CH3:37])[N:31]([CH2:32][CH2:33][CH3:34])[C:21]=3[C:20]=2[CH:19]=1.CN(C=O)C>O>[CH3:37][O:36][CH2:35][C:30]1[N:31]([CH2:32][CH2:33][CH3:34])[C:21]2[C:20]3[CH:19]=[C:18]([O:17][CH2:16][CH2:15][CH2:14][N:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)[CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:28])[C:22]=2[N:29]=1
Reactant: C1COCCN1
Reactant: CCCn1c(COC)nc2c(N)nc3ccc(OCCCCl)cc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(COC)nc2c(N)nc3ccc(OCCCN4CCOCC4)cc3c21
Temperature: 50 °C
Reaction time: 3 h
Yield: 9.1 %

Procedure:
Potassium carbonate (530 mg, 3.84 mmol), morpholine (92 mg, 1.06 mmol), and 8-(3-chloropropoxy)-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (350 mg, 0.96 mmol) were added to 15 mL of DMF and heated to 50° C. for 18 hours. Analysis by LC/MS indicated the presence of two peaks and the reaction mixture was cooled and poured into 500 mL of deionized water. After three hours, no precipitation was observed. Sodium chloride (250 g) was added to the mixture and the mixture was stirred vigorously overnight. The precipitate was collected by filtration, dissolved in dichloromethane, and purified by chromatography on a HORIZON HPFC system (eluting with a gradient of methanol/dichloromethane (20:80) in dichloromethane from 0:100 to 40:60). The resulting material was concentrated under reduced pressure, crystallized from acetonitrile, and dried under high vacuum to yield 36 mg of 2-methoxymethyl-8-(3-morpholin-4-ylpropoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as tan crystals, mp 193-196° C.
Reaction SMILES: C[C@@H]1C2NC=CC=2C(=O)N1.C(O[C:16]([NH:18][C@H:19]([CH2:23][O:24][CH3:25])[C:20](O)=O)=[O:17])(C)(C)C.C[C@@H]1C2[NH:32][C:33]([B:35]3[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:43])([CH3:42])[O:36]3)=[CH:34][C:30]=2C(=O)N1>>[CH3:25][O:24][CH2:23][CH:19]1[C:20]2[NH:32][C:33]([B:35]3[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:43])([CH3:42])[O:36]3)=[CH:34][C:30]=2[C:16](=[O:17])[NH:18]1
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: C[C@H]1NC(=O)c2cc[nH]c21
Product: COCC1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21

Procedure:
6-(Methoxymethyl)-5,6-dihydropyrrolo[3,4-b]pyrrolo-4(1H)-one (485a) was prepared in a manner similar to that described for Intermediate 702, starting from (R)-2-((tert-butoxycarbonyl)amino)-3-methoxypropanoic acid (prepared according to the procedure in WO 2012/051551). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.32 (br. s., 1H), 7.58 (s, 1H), 6.83 (d, J=2.74 Hz, 1H), 6.09 (d, J=2.74 Hz, 1H), 4.50 (ddd, J=6.75, 5.58, 1.37 Hz, 1H), 3.37-3.49 (m, 2H), 3.30 (s, 3H). m/z (ES, +ve) 167.0 (M+H)+. 6-(Methoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (485b) was prepared in a manner similar to that described for Intermediate 705, using 6-(methoxymethyl)-5,6-dihydropyrrolo[3,4-b]pyrrolo-4(1H)-one (485a) as the starting material. 1H NMR (400 MHz, CDCl3) δ ppm 6.93 (d, J=1.76 Hz, 1H), 5.85 (s, 1H), 4.56-4.65 (m, 1H), 3.55 (dd, J=8.61, 7.04 Hz, 1H), 3.40-3.47 (m, 4H), 1.30-1.36 (m, 12H). m/z (ES, +ve) 293.1 (M+H)+.
Reaction SMILES: CC(C[AlH]CC(C)C)C.CO[C:12](=O)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[Br:22].[NH2:24][CH2:25][CH2:26][NH:27][S:28]([C:31]1[C:32]2[CH:33]=[CH:34][N:35]=[CH:36][C:37]=2[CH:38]=[CH:39][CH:40]=1)(=[O:30])=[O:29]>>[Br:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH2:12][NH:24][CH2:25][CH2:26][NH:27][S:28]([C:31]1[C:32]2[CH:33]=[CH:34][N:35]=[CH:36][C:37]=2[CH:38]=[CH:39][CH:40]=1)(=[O:30])=[O:29]
Reactant: COC(=O)COc1ccc(F)cc1Br
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Agent: CC(C)C[AlH]CC(C)C
Product: O=S(=O)(NCCNCCOc1ccc(F)cc1Br)c1cccc2cnccc12

Procedure:
By following a similar procedure as described in Example 1, DIBAL-H reduction of (2-bromo-4-fluoro-phenoxy)-acetic acid methyl ester, and subsequent reductive amination with isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide gives the free amine of the title compound as a white foam. ESIMS: m/z 468 [(M+H)+, 79Br], 470 [(M+H)+, 81Br].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:33][CH2:34]CS([O-])(=O)=O)[CH2:15][CH2:14][N:13]([C:16](=[O:32])[C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[C:20]([O:26][CH2:27][CH3:28])=[C:19]([O:29][CH2:30][CH3:31])[CH:18]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[C:41]1([C:47]2([C:53]([NH2:55])=[O:54])[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:33][CH2:34][N:50]3[CH2:49][CH2:48][C:47]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([C:53]([NH2:55])=[O:54])[CH2:52][CH2:51]3)[CH2:15][CH2:14][N:13]([C:16](=[O:32])[C:17]3[CH:18]=[C:19]([O:29][CH2:30][CH3:31])[C:20]([O:26][CH2:27][CH3:28])=[C:21]([O:23][CH2:24][CH3:25])[CH:22]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(OC)c(OC)c3)C2)cc(OCC)c1OCC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: CCOc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(OC)c(OC)c3)C2)cc(OCC)c1OCC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]1[CH2:16][CH2:15][CH:14]([C:17]2[C:24]([F:25])=[CH:23][C:20]([C:21]#N)=[C:19]([F:26])[CH:18]=2)[CH2:13]1.[OH2:27].S(=O)(=O)(O)[OH:29]>>[NH2:3][CH:12]1[CH2:16][CH2:15][CH:14]([C:17]2[C:24]([F:25])=[CH:23][C:20]([C:21]([OH:29])=[O:27])=[C:19]([F:26])[CH:18]=2)[CH2:13]1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(F)c(C2CCC(N3C(=O)c4ccccc4C3=O)C2)cc1F
Reactant: O
Product: NC1CCC(c2cc(F)c(C(=O)O)cc2F)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 35.2 g (0.1 mol) of 4-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)cyclopentyl]-2,5-difluorobenzonitrile in 150 ml of 98% sulfuric acid was heated at 100° for 6 hours. The reaction mixture was poured onto 1.2 L of ice and water and stirred for 2 hours until the granular precipitate dispersed. The solid was removed by filtration, washed with water and the wet filter cake suspended in 200 ml of concentrated hydrochloric acid. The suspension was heated at reflux for 8 hours and evaporated to dryness in vacuo. The residue was triturated with 250 ml of ethanol/ether (1:1); the solid was removed by filtration, washed with ethanol/ether (1:1), ether, and dried in vacuo to give 20.1 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[NH3:1].[CH2:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])[CH:3]=2)[CH2:9][CH2:10]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCN1CCC(c2cccc(N)c2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCN1CCC(c2cccc(NS(C)(=O)=O)c2)CC1
Product: N
Yield: 130.3 %

Procedure:
To a solution of 4-(3-aminophenyl)-N-hexylpiperidine (Preparation 50, 178 mg, 0.68 mmol) in pyridine (5 ml) at room temperature under an atmosphere of nitrogen was added methanesulfonyl chloride (79 ml, 1.03 mmol) over 10 min. The resultant mixture was stirred overnight, poured onto water (10 ml) and extracted with ethyl acetate (3×10 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo at 80° C. to give the crude product which was purified by silica column chromatography, eluting with ethyl acetate:hexane:0.880 ammonia (90:9:1) to give the title compound as a pale brown oil (150 mg, 65%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[C:8]([NH:11][CH2:12][CH:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21](F)=[C:20]([F:25])[CH:19]=2)[CH2:14]1)(=[O:10])[CH3:9]>CN(C)C=O.C(OCC)(=O)C>[F:25][C:20]1[CH:19]=[C:18]([C:15]2[CH2:14][CH:13]([CH2:12][NH:11][C:8](=[O:10])[CH3:9])[O:17][N:16]=2)[CH:23]=[CH:22][C:21]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)NCC1CC(c2ccc(F)c(F)c2)=NO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NCC1CC(c2ccc(-n3ccnc3)c(F)c2)=NO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 28.2 %

Procedure:
Imidazole (225 mg) is dissolved in 5 ml dimethylformamide in a 25 ml one neck round bottom flask under nitrogen. The solution is cooled to 0° C., is treated with 60% sodium hydride (132 mg), and the mixture is stirred 20 minutes at room temperature. The solution is treated with (-)-5-(acetamidomethyl)-3-(3,4-difluorophenyl)-isoxazoline (Step 1, Example 11) (763 mg), and the reaction is stirred 6 hours at 65° C. The reaction is cooled, is diluted with 25 ml ethyl acetate, and is washed with 4×25 ml 50% saturated 1:1 sodium chloride/sodium bicarbonate. The organics are dried over anhydrous magnesium sulfate and are concentrated in vacuo to a white solid. The crude material is chromatographed over 25 g silica gel (230-400 mesh), eluting with 4% methanol/dichloromethane while collecting 5 ml fractions. Fractions 33-69 are combined and concentrated to give 256 mg of a white solid which is washed with ethyl acetate to afford 227 mg (25%) of the title compound as a white solid, mp 155-156° C, [α]25D -76° (c 0.30).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.F[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C(N(CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)c1cccc(Br)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cccc(Br)c1
Reaction time: 18 h
Yield: 73.7 %

Procedure:
A mixture of 1-(3-bromophenyl)ethanamine (1.0 g, 5.0 mmol), 2,4-difluoro-1-nitrobenzene (0.8 g, 5.0 mmol), N,N-diisopropylethylamine (1.7 mL, 10.0 mmol) and acetonitrile (20 mL) was stirred for 18 h and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo to yield the title compounds as a yellow oil (1.25 g, 74%). 1H NMR (400 MHz, CDCl3): δ 8.51 (d, 1 H), 8.25 (m, 1 H), 7.48 (s, 1 H), 7.41 (m, 1 H), 7.25 (m, 2 H), 6.36 (m, 1 H), 6.24 (m, 1 H), 4.55 (m, 1 H), 1.63 (d, 3 H). MS (ESI) m/z: Calculated: 338; Observed: 339 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]O)=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:16]2[N:17]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=3)[C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Reactant: OCc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 23 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzoimidazole-2-carbonyl)-piperidine (1.50 g, 4.57 mmol), 4-fluorobenzyl alcohol (0.50 mL, 4.58 mmol) and triphenylphosphine (1.44 g, 5.50 mmol) in tetrahydrofuran (15 mL). Add diethylazodicarboxylate (0.87 mL, 5.50 mmol) dropwise at room temperature. After 23 hours, evaporate the reaction mixture in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 25% ethyl acetate/hexane to give 1-(t-butoxycarbonyl)-4-(1-(4-fluoro-benzyl)-1H-benzoimidazole-2-carbonyl)-piperidine.
Reaction SMILES: [CH3:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH2:3]1.[CH3:14][C:15]([CH3:21])([CH2:19]C)[CH2:16][CH2:17]O.C(N=C=NC(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:14][C:15]([CH3:21])([CH3:19])[CH2:16][CH2:17][O:12][C:11]([C:2]1([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][C:4](=[O:10])[CH2:3]1)=[O:13]
Reactant: CC1(C)CC(=O)CC(C)(C(=O)O)C1
Reactant: CCC(C)(C)CCO
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)CCOC(=O)C1(C)CC(=O)CC(C)(C)C1
Yield: 56.7 %

Procedure:
1,5,5-trimethyl-3-oxo-1-cyclohexylcarboxylic acid (3.0 g) (M. S. Ziegler and R. M. Herbst, J. Org. Chem. 1951, 16, 920) was treated with 3,3-dimethylpentanol (1.84 g), DMAP (2.21 g) and 1,3-diisopropylcarbodiimide (2.17 g) in CH2Cl2 (80 mL) under standard coupling conditions to give 2.41 g (55% yield) of 3-(3,3-dimethylbutoxycarbonyl)-3,5,5-trimethylcyclohexanone. Mass spectrum (EI) indicated parent ion at m/e 268.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:9][C:10](=[O:31])[N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:27]([F:30])([F:29])[F:28])=[N:18][C:19]([C:20]([N:22]3[CH2:26][CH2:25][S:24][CH2:23]3)=[O:21])=[C:13]2[CH2:12]1)(C)(C)C.[ClH:43]>C(OCC)(=O)C>[ClH:43].[NH2:7][C@H:8]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:9][C:10]([N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:27]([F:28])([F:30])[F:29])=[N:18][C:19]([C:20]([N:22]3[CH2:26][CH2:25][S:24][CH2:23]3)=[O:21])=[C:13]2[CH2:12]1)=[O:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCSC3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCSC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 75 %

Procedure:
(R)-[3-oxo-3-[1-(thiazolidine-3-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 20a (0.15 g, 0.24 mmol) was added to a solution of 2.2 N hydrochloric acid in 5 mL of ethyl acetate. The reaction mixture was reacted at room temperature for 4 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-3-amino-1-[1-(thiazolidine-3-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 20 (100 mg, yield 75%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH2:32]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([N:37]1[CH2:38][CH2:39][CH:40]([NH:43][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:30])[F:29])[C:9]=4[CH:17]=3)[CH:19]=2)[CH2:41][CH2:42]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: CCOC(=O)N1CCC(NC(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-aminopiperidine-1-carboxylic acid ethyl ester as in General Procedure 10 to give the title compound. LCMS: m/z=601.99 (M+H+); retention time=0.86 minutes.