Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:5][C:6]1[N:7]([CH2:15][CH2:16][C:17]([O-:19])=[O:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:3][CH3:4].[NH2+]1CCCCC1.[CH2:26]([O:33][CH2:34][CH:35]=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][CH2:34][CH:35]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:6]=2[CH2:5][N:2]([CH3:1])[N:3]1[CH3:4])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=CCOCc1ccccc1
Reactant: CNN(C)Cc1cc2ccccc2n1CCC(=O)[O-]
Agent: C1CC[NH2+]CC1
Product: CN1Cc2c(c3ccccc3n2CCC(=O)O)C(COCc2ccccc2)N1C

Procedure:
Compound 4 was reacted with benzyloxyacetaldehyde, which was chosen as a model small molecule aldehyde for its UV absorption and aqueous solubility properties, to produce the azacarboline product (Compound 5). To a solution of Compound 4 (16.2 mg, 46.8 mmol) in aqueous acetonitrile (1:3 water:acetonitrile, 800 μL) was added benzyloxyacetaldehyde (7.23 μL, 51.5 μmol, 1.10 equiv). After 1 h, the solution was purified by C18 silica gel chromatography (0-100% acetonitrile in water with 0.1% acetic acid). Toluene was added to the eluent to aid in removal of residual acetic acid, and the product was isolated as a pale brown oil (16.2 mg, 41.2 μmol, 88%). 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=7.8 Hz, 1H), 7.38-7.34 (m, 2H), 7.34-7.30 (m, 3H), 7.18-7.15 (m, 2H), 7.08-7.05 (m, 1H), 4.65 (d, J=12.4 Hz, 1H), 4.58 (d, J=12.4 Hz, 1H), 4.28-4.18 (m, 2H), 4.10 (m, 1H), 3.91 (t, J=9.0 Hz, 1H), 3.81 (s, 1H), 3.76-3.64 (m, 2H), 2.69 (t, J=6.8 Hz, 2H), 2.63 (s, 3H), 2.39 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 175.08, 138.74, 136.27, 131.75, 128.42, 127.92, 127.60, 126.61, 121.43, 119.61, 118.74, 109.33, 105.41, 73.46, 71.94, 61.61, 44.16, 41.33, 39.19, 34.98, 31.17. HRMS (ESI) calcd for C23H28N3O3 [M+H]+: 394.2131. found: 394.2120.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH3:24])[C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29]>>[CH2:1]([O:8][C:9]1[C:10]([C:33]2[CH:34]=[CH:35][C:30]([CH:28]=[O:29])=[CH:31][CH:32]=2)=[CH:11][C:12]([CH2:13][N:14]([CH3:24])[C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:25][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCC(=O)N(C)Cc1ccc(OCc2ccccc2)c(Br)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: CCCCCCCC(=O)N(C)Cc1ccc(OCc2ccccc2)c(-c2ccc(C=O)cc2)c1
Yield: 81.1 %

Procedure:
In a manner similar to that of Example 1(e), by reacting 13.6 g (31 mmol) of N-(4-benzyloxy-3-bromo benzyl)-N-methyloctanamide and 6.1 g (40 mmol) of 4-formylbenzene boronic acid, 11.5 g (69%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [NH2:1][CH:2]([CH2:14][O:15][CH:16]([F:18])[F:17])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[CH:26](=[O:28])[CH3:27]>C1COCC1.C(OCC)(=O)C>[C:26]([NH:1][CH:2]([CH2:14][O:15][CH:16]([F:18])[F:17])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])(=[O:28])[CH3:27]
Reactant: CC=O
Reactant: NC(COC(F)F)C(=O)NCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NC(COC(F)F)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
To a solution of 2-amino-3-difluoromethoxy-N-(4-fluorobenzyl)propionamide (200 mg, 0.762 mmol) and triethylamine (293 mg, 2.9 mmol) in THF (5 mL), acetic hydride (93 mg, 0.915 mmol) was added. The reaction mixture was stirred at room temperature for three hours, diluted with ethyl acetate, and washed with water. The organic layer was concentrated with silica gel and purified by column chromatography with 50-100% ethyl acetate in hexanes. The product was triturated with diethyl ether to give 2-(acetylamino)-N-benzyl-3-(difluoromethoxy)propanamide (140 mg, 60.3%) as a white solid, MP: 130.8° C. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.24 (dd, 2H), 7.03 (t, 2H), 6.73 (w, 1H), 6.41 (d, 1H), 6.24 (wt, 1H), 4.71 (m, 1H), 4.44 (d, 2H), 4.24 (dd, 1H), 4.01 (dd, 1H) and 2.05 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[I-].[CH3:4][N+:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:14]=3[CH:15]=2)=[CH:7][CH:6]=1>O.CO>[CH3:4][N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:14]=3[CH:15]=2)[CH2:9][CH2:10]1
Reactant: C[n+]1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC=C(c2cc3cc(Cl)ccc3o2)CC1

Procedure:
A solution of 70 g of sodium borohydride in 150 ml of water is added dropwise, with stirring and external cooling, to a solution of 70 g of 1-methyl-4-(5-chloro-2-benzofuranyl)-pyridinium-iodide in 500 ml of methanol, the manner of addition being such that the reaction temperature does not exceed 35°. The solution is subsequently stirred for 20 hours at room temperature. The methanol is thereupon evaporated off in vacuo; the aqueous phase remaining behind is extracted twice with 500 ml of chloroform each time, the chloroform solution dried over sodium sulphate, filtered, and concentrated by evaporation. The 1-methyl-4-(5-chloro-2-benzofuranyl)-1,2,3,6-tetrahydropyridine obtained is recrystallised from hexane, and then melts at 108°-118°. The hydrochloride prepared therefrom with a solution of hydrogen chloride in ethyl acetate melts, after recrystallisation from ethyl acetate, at 266°.
Reaction SMILES: CN(C=O)C.[NH:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:7]([C:15]([OH:17])=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[CH2:33]([NH2:37])[CH:34]([CH3:36])[CH3:35]>C(N(CC)CC)C>[NH:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:7]([C:15]([NH:37][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)CN
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
In a DMF solution containing a mixed anhydride prepared from 2.0 g of Boc-Phe-OH, 1.15 ml of triethylamine and 1.08 ml of isobutyl chloroformate, 1.50 ml of isobutylamine was added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 51 (Process 1) to give 1.91 g of the title compound.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[N:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][CH2:78][O:79][CH3:80])[CH2:73][CH2:72]5)=[CH:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[N:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH2:77][CH2:78][O:79][CH3:80])[CH2:75][CH2:76]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: COCCN1CCN(c2ccc(-c3cnc4c(c3)c(-c3cnn(Cc5cccc(F)c5)c3)cn4S(=O)(=O)c3ccc(C)cc3)cn2)CC1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCCN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Yield: 37.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (70 mg, 0.105 mmol) was hydrolyzed by lithium hydroxide (25 mg, 0.63 mmol), THF/methanol/water (3/2/1 ml) to yield 20 mg (37.7% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.55-8.51 (m, 3H), 8.23 (s, 1H), 8.12-8.09 (dd, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 7.40-7.30 (m, 1H), 7.15-7.10 (m, 2H), 7.06-7.00 (m, 2H), 5.45 (s, 2H), 3.79-3.76 (t, 2H), 3.60-2.90 (m, 8H). MS: m/z=512.15 (M+1), HPLC: 95.27% in method A.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:36]1[C:44]2[C:39](=[C:40](B3OC(C)(C)C(C)(C)O3)[C:41]([F:45])=[CH:42][CH:43]=2)[CH:38]=[CH:37]1)(C(C)(C)C)(C)C>>[F:45][C:41]1[C:40]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([CH:19]5[CH2:22][O:21][CH2:20]5)[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:39]2[C:44](=[CH:43][CH:42]=1)[NH:36][CH:37]=[CH:38]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CCC(C4COC4)CC3)ccc2n1
Product: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2nc(CN3CCC(C4COC4)CC3)ccc2n1

Procedure:
4-(2-chloro-6-((4-(oxetan-3-yl)piperidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (0.11 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 59.8 mg of 130 following reverse phase HPLC purification.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[CH:31][NH:32]3)[O:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)(=[O:3])[NH2:2].Cl.O1CCOCC1>C(Cl)Cl.CO>[NH:32]1[C:33]2[C:29](=[C:28]([C:6]3[O:7][C:8]([C:9]4[CH:10]=[CH:11][C:12]([N:15]5[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]5)=[CH:13][CH:14]=4)=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4cccc5[nH]ccc45)nc3C(N)=O)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)c1nc(-c2cccc3[nH]ccc23)oc1-c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To a suspension of tert-butyl 4-(4-(4-carbamoyl-2-(1H-indol-4-yl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.027 g, 0.06 mmol) in DCM (1 ml) was added 4M HCl in dioxane (0.5 ml, 2.0 mmol) and the reaction stirred at room temperature for 2 hours. The mixture was then diluted with MeOH and purified by SPE using a MP-TsOH cartridge (500 mg) to afford 2-(1H-indol-4-yl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide (0.0078 g, 0.02 mmol, 36%). 1H NMR (DMSO) δ 2.86 (4H, br. t), 3.22 (4H, br. t), 7.06 (2H, d), 7.21 (1H, t), 7.35 (1H, br. t), 7.56-7.60 (2H, m), 7.62 (1H, d), 7.79 (1H, br. s), 7.86 (1H, dd), 8.30 (2H, d), 11.51 (1H, br. s). LCMS (2) Rt: 2.36 min; m/z (ES+) 388.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][OH:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][O:12][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)c(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 394A (1.8 g, 10.5 mmol) in CH2Cl2 (10 ml) was added dihydropyran (1.94 ml, 21.2 mmol) and PPTS (150 mg, 0.60 mmol). The reaction was stirred at rt overnight, washed with brine, concentrated, purified by silica gel flash column chromatography to give 394B (1.88 g, 70%) (100% CH2Cl2).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:60]#[N:61])[C:52]([O:58][CH3:59])=[CH:53][CH:54]=4)[O:49][C:48]=3[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:60]#[N:61])[C:52]([O:58][CH3:59])=[CH:53][CH:54]=4)[O:49][C:48]=3[C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1C#N
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1ccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2c1C#N
Yield: 42.9 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(8-cyano-7-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (15 mg, 0.0287 mmol) was reacted to give the title compound (5.2 mg, 43%). LCMS (Method E): RT=3.47 min, M+H+=423. 1H NMR (400 MHz, CDCl3): δ 8.43 (d, J=9.3 Hz, 1H), 7.49-7.44 (m, 2H), 7.41-7.33 (m, 3H), 7.29 (d, J=7.4 Hz, 2H), 7.20 (d, J=7.4 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H), 4.11 (s, 3H), 2.61-2.51 (m, 2H), 2.23-2.02 (m, 3H), 1.83-1.64 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[C:4]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:5][CH2:6][CH:7]=1>CO>[CH3:13][C:4]12[CH2:8][CH:9]3[C:10]([CH3:12])([CH3:11])[C:2]([CH3:1])([C:3]1=[O:14])[CH:7]3[CH2:6][CH2:5]2
Reactant: CC(C)=CCC1(C)CCC=C(C)C1=O
Solvent: CO
Product: CC12CCC3C(C1)C(C)(C)C3(C)C2=O
Yield: 49.9 %

Procedure:
A solution of 2,6-dimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-enone (10.0 g, 52.1 mmol) in methanol (250 ml) was irradiated using a Hg-lamp during 3 h. The solvent was evaporated in vacuo and the residue distilled in a Kugelrohr oven to yield 5.0 g of a colorless oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.C[O:29][C:30](=O)[CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:29])[CH2:31][C@H:32]5[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Reactant: COC(=O)C[C@H]1CC[C@H](O)CC1
Agent: Cl
Product: O=C(C[C@H]1CC[C@H](O)CC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1

Procedure:
The title compound, white solid (159 mg, quant.), MS (ISP) m/z=469.3 [(M+H)+], was prepared in analogy to example 2 from trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate A) (150 mg, 0.34 mmol) and trans-(4-hydroxy-cyclohexyl)-acetic acid methyl ester [CAS-Nr. 1124174-16-8, WO 2010/031735] (71 mg, 0.41 mmol). The purification was performed by precipitation from Et2O.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[C:21]3[O:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].[H][H]>O1CCOCC1.[Pd]>[CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]3[O:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:18][CH:19]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(C=C2OC(=O)NC2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(CC2OC(=O)NC2=O)cc1
Yield: 89.5 %

Procedure:
A solution of 5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]oxazolidine-2,4-dione (100 mg) (obtained from example 26) in 1,4-dioxane (10 ml) was reduced with hydrogen in the presence of 10% palladium on charcoal (20 mg) at 50 psi for 24. The mixture was filtered through a bed of celite. The filtrate was evaporated to dryness under reduced pressure, purified by column chromatography (2:1 EtOAc/petroleum ether as eluent) to afford the title compound (90 mg, 90%).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].ON1C2C=CC=CC=2N=N1.[Cl:25][C:26]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>C(Cl)(Cl)Cl>[Cl:25][C:26]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:29]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 3.0 g of tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, 3.2 g of 1-(3-dimethyl-aminopropyl) -3-ethylcarbodiimide hydrochloride, 2.6 g of 1-hydroxybenzotriazole, 2.9 g of 2,3-dichlorobenzoic acid and 60 ml of chloroform was stirred at room temperature for 17 hours and then diluted with chloroform. An insoluble matter was filtered off using Celite and the resulting mixture was washed with water with saturated brine. The resulting organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated in vacuo and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=9/1 to 1/1) to give the title compound.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[BH4-].[Na+].Cl>CCO.O>[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][CH:2]([C:1]#[N:5])[C:3]#[N:4])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: N#CCC#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(C#N)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of malononitrile (3.15 mL, 50.0 mmol) in 50 mL of 95% EtOH, 4-fluorobenzaldehyde (5.28 mL, 50 mmol) was added and the mixture was stirred at room temperature overnight. The white solid precipitated out and this suspension was diluted with 25 mL of EtOH then treated with sodium borohydride (0.946 g, 25.00 mmol) in one portion. This mixture was stirred at ambient temperature for 2 hours until reaction was complete. Water and 1N HCl solution was added carefully to quench sodium borohydride. The precipitate was then filtered, washed with copious amount of water, air-dried to give 5.92 g of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.43 (m, 2H) 7.06-7.17 (m, 2H) 3.90 (t, J=6.78 Hz, 1H) 3.27 (d, J=6.72 Hz, 2H). MS (ESI) m/z 173.1 (M−H)−.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:23])[C:12]1[C:17]([O:18]C)=[CH:16][CH:15]=[C:14]([Br:20])[C:13]=1[O:21][CH3:22])[CH2:2][CH3:3].[ClH:24].CC(C)=O>CO>[ClH:24].[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:23])[C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([Br:20])[C:13]=1[O:21][CH3:22])[CH2:2][CH3:3]
Reactant: CCCN1CCCC1CNC(=O)c1c(OC)ccc(Br)c1OC
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Product: CCCN1CCCC1CNC(=O)c1c(O)ccc(Br)c1OC
Yield: 55 %

Procedure:
The title compound was prepared from (-)-N-n-propyl-2-(3-bromo-2,6-dimethoxybenzamidomethyl)pyrrolidine by dealkylation in the same manner as described in Example 2. Yield 55%. M.p. (HCl) 137°-138° C. (acetone). [α]D25 =-68° C. (c=0.12; MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[CH:28][C:29](O)=[O:30])[CH:22]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O>[O:30]=[C:29]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])/[CH:28]=[CH:27]/[C:23]1[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cccnc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
To a stirring solution of 2.82 g (9.7 mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, in 25 mL of dimethyl formamide (DMF) cooled in an ice bath was added 1.54 g (9.7 mmol) of 3-(3-pyridyl)acrylic acid. To the heterogenous mixture was added 1.74 mL (10 mmol) of N,N-diisopropylethylamine and 1.92 g (10 mmol) of N,N-dimethylaminopropylethylcarbodiimide hydrochloride. The reaction was stirred over night at ambient temperature. To the reaction was added 100 mL of ethyl acetate (EtOAc) and 100 mL of a saturated solution of KHCO3. The resulting layers were separated, and the organic layer was washed three times with saturated KHCO3 and two times with water. The organic layer was then dried over Na2SO4 anhydrous and filtered. The solvent was removed under vacuum, and the resultant solid was chromatographed. The yield of isolated product was 2.16 g (53%). Analysis calculated for C22H17N4O3Cl (M.W. 420.86): C, 62.79; H, 4.07; N, 13.31; Cl, 8.42. Found: C, 62.72; H, 4.27; N, 12.78; Cl 8.21.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[F:18])=[CH:8][C:7]([CH2:19]O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:23])=O>C(Cl)Cl>[Cl:23][CH2:19][C:7]1[CH:8]=[C:9]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[F:18])[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(-c2cc(CO)ccc2C2CC2)c1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2cc(CCl)ccc2C2CC2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50.8 %

Procedure:
To a dry, round bottom flask containing 13.4 (0.24 g, 0.88 mmol) under an argon atmosphere was added dry DCM (5 mL). The resulting homogeneous solution was cooled to 0° C. After 15 minutes, thionyl chloride (0.20 mL, 2.74 mmol) was added dropwise at 0° C. Upon complete addition of thionyl chloride, the mixture was allowed to warm to room temperature and for 16 hours. After 19 hours, the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (SiO2 gel 60, eluted with 0 to 15% EtOAc in hexanes) to yield a colorless oil 13.5 (0.13 g, 49% yield.) 1H NMR (400 MHz, CDCl3) δ ppm 7.36 (2H, dd, J=8.2, 2.0 Hz), 7.13 (1H, m), 6.98 (1H, d, J=8.2 Hz), 6.93 (2H, m), 4.62 (2H, s), 3.84 (3H, s), 1.87 (1H, m), 0.91 (2H, m), 0.7 (2H, m).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](OCC)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>CCCCCC>[Si:1]([O:8][C@@H:9]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:10]=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)O[C@H](C=O)c1ccccc1

Procedure:
Following a procedure similar to that described in Preparation 25, but using 8.8 g of ethyl (S)-α-(t-butyldimethylsilyloxy)-α-phenylacetate (prepared as described in Preparation 24), 300 ml of dry hexane and 30 ml of a 1M solution of diisobutylaluminum hydride in hexane, and then purifying the reaction product by column chromatography through silica gel, using a 1:60 by volume mixture of ethyl acetate and hexane as the eluent, the title compound was obtained having an Rf=0.29 (thin layer chromatography over silica gel, using a 1:80 by volume mixture of ethyl acetate and hexane as the developing solvent).