Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)CCN
Reactant: CCCC(O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(O)c1ccc(C(=O)NCCC(=O)OCC)cc1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
N,N-dimethylformamide (8.60 mL) was added to a vial containing 4-(1-hydroxybutyl)benzoic acid (250 mg, 1.29 mmol), ethyl 3-aminopropanoate hydrochloride (395 mg, 2.57 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′ tetramethyluronium hexafluorophosphate (979 mg, 2.57 mmol). Diisopropylethylamine (1.12 mL, 6.44 mmol) was then added. The reaction was stirred for 16 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded ethyl 3-(4-(1-hydroxybutyl)benzamido)propanoate (350 mg, 93% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 6.84 (br. s., 1H), 4.74 (t, J=6.5 Hz, 1H), 4.23-4.07 (m, 2H), 3.72 (q, J=5.9 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 1.85-1.72 (m, 1H), 1.72-1.58 (m, 1H), 1.52-1.37 (m, 1H), 1.37-1.30 (m, 1H), 1.28 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (M+1) 294.3.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[C:6]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39].[H-].[Na+].[Br:42][C:43]1[CH:44]=[N:45][C:46](Cl)=[N:47][CH:48]=1.CN(C=O)C>C1COCC1>[Br:42][C:43]1[CH:44]=[N:45][C:46]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[C:6]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH3:39])=[N:47][CH:48]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCO
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCOc1ncc(Br)cn1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
4-i-Propyl-phenyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (60 mg, Example 3) was dissoved in THF (8 ml). Sodium hydride (14 mg, 60% dispersion in mineral oil) was added and stirring continued for 10 min. 5-Bromo-2-chloro-pyrimidine (37 mg) was added and the mixture was heated to 60° C. for 120 min. DMF (0.5 ml) was added and the solution was stirred at r.t. for 48 h. The solvents were evaporated, water (12 ml) and a 10% solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water and purified by chromatography through silica gel with EtOAc/Hex=1:1 to give 4-i-propyl-phenyl sulfamic acid-[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(o-methoxy-phenoxy)-2-(4-pyridyl)pyrimidin-4-yl]-amide (55.4 mg). tR=5.30 min, (LC); [M+H]+=710.35 (ES+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Br:14]Br>C(O)(=O)C>[Br:14][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[F:1])[NH:8][N:7]=[C:6]2[C:11]([OH:13])=[O:12]
Reactant: BrBr
Reactant: O=C(O)c1n[nH]c2cc(F)ccc12
Solvent: CC(=O)O
Product: O=C(O)c1n[nH]c2cc(F)c(Br)cc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
A mixture of 6-fluoro-1H-indazole-3-carboxylic acid (4.95 g, 23.8 mmol) and acetic acid (50 mL) was treated with bromine (2.0 mL, 38 mmol) dropwise at room temperature. The reaction mixture was heated to 90° C. and stirred for 16 hours under an atmosphere of nitrogen. The reaction mixture was then exposed to the atmosphere and stirred at 95° C. for 72 hours. The resulting solids were collected while the reaction mixture was still hot and rinsed with diethyl ether two times. The solids were dried at 50° C. under reduced pressure to give the title compound (2.89 g). 1H NMR (500 MHz, DMSO-d6) δ 8.31 (d, J=6.8 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][CH2:23][CH2:24][CH2:25]I>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:25][CH2:24][CH2:23][Cl:22])[C:6]=2[CH:12]=1
Reactant: O=C1COc2cc([N+](=O)[O-])c(Cl)cc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C1COc2cc([N+](=O)[O-])c(Cl)cc2N1CCCCl
Yield: 40.3 %

Procedure:
Crude 6-Chloro-7-nitro-4H-benzo[1,4]oxazin-3-one (81MF2253a) (2.60 g, 10.0 mmol), Cs2CO3 (4.88 g, 15.0 mmol) and 3-chloro-1-iodopropane (2.25 g, 11.0 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF2253b) (1.23 g, 36%). 1H NMR (CDCl3) δ 7.66 (s, 1H), 7.20 (s, 1H), 4.70 (s, 2H), 4.12 (t, J=7.6 Hz, 2H), 3.67-3.59 (m, 2H), 2.21-2.13 (m, 2H); 13C NMR (CDCl3) δ 163.6, 143.5, 133.3, 133.2, 122.4, 117.2, 115.2, 67.4, 42.1, 39.6, 29.8.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][S:7](=[O:11])(=[O:10])[CH2:6][CH2:5]1.C(N(CC)CC)C.[N+:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29])([O-:21])=[O:20]>C(Cl)Cl>[O:10]=[S:7]1(=[O:11])[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N+:19]([O-:21])=[O:20])(=[O:29])=[O:30])[CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCCN1CCS(=O)(=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
A mixture of 4-(2-aminoethyl)thiomorpholine 1,1-dioxide (2.00 g, 11.2 mmol) and triethylamine (1.42 g, 14.0 mmol) in DCM (100 mL) was cooled in an ice bath and treated slowly with 2-nitrobenzene-1-sulfonyl chloride (2.49 g, 11.2 mmol). The mixture was removed from the ice bath and stirred at rt for 18 h. The resulting mixture was washed with water (2×50 mL) and the combined aqueous washes were extracted with DCM (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a yellow solid. Purification by silica gel chromatography (linear gradient 100% DCM to 100:1 DCM:MeOH) gave the title compound as a pale yellow solid (3.47 g, 85% yield). LCMS: m/z 364 (M+H+), retention time 0.98 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.71 (t, J=5.49 Hz, 2H) 2.96 (br. s., 4H) 3.05 (br. s., 4H) 3.20 (q, J=5.49 Hz, 2H) 5.93 (br. s., 1H) 7.73-7.84 (m, 2H) 7.84-7.93 (m, 1H) 8.11-8.23 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1ccc([N+](=O)[O-])c2ccoc12
Product: CN(C)C=Cc1ccc([N+](=O)[O-])c2ccoc12
Yield: 107.1 %

Procedure:
Add 7-methyl-4-nitrobenzofuran (3.5 g, 19.7 mmol) to tert-butoxybis(dimethylamino)methane (10.3 g, 59.1 mmol), and reflux the mixture under nitrogen for 40 minutes. Concentrate under reduced pressure, dissolve in xylenes (50 mL), concentrate under reduced pressure, and dry under vacuum to obtain 4.9 g (100%) of the title compound as a deep red-brown solid. HRMS (M+H)=233.0928.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[C:24]([NH:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:26])[CH3:25]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:24]([NH:27][C:28]1[CH:33]=[C:32]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:26])[CH3:25]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CC(=O)Nc1cccc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)c1
Temperature: 110 °C
Yield: 35 %

Procedure:
A mixture of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 1.0 equivalent), 3-acetamidophenylboronic acid (2.0 equivalents), and PdCl2(dppf) (0.08 equivalent) in 1:2 saturated NaHCO3/dioxane (0.15 M with respect to 2D) was heated at 110° C. for 15 minutes in the microwave. After cooling to room temperature, the crude mixture was filtered and the filtrate was purified by preparatory LC-MS to give the titled compound (35%) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 2.09 (s, 3H) 5.20 (s, 1H) 6.60 (d, J=2.27 Hz, 1H) 7.52-7.57 (m, 1H) 7.60-7.64 (m, 2H) 7.73-7.77 (m, 1H) 7.84-7.89 (m, 1H) 7.99-8.07 (m, 2H) 8.20 (d, J=2.27 Hz, 1H) 8.28 (t, J=1.77 Hz, 1H) 10.24 (s, 1H) 11.28 (s, 1H). ESI-MS: m/z 430.3 (M+H)+.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[NH:21][CH:22]=[C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH:31]=[C:30]([C:35]2[CH:40]=[CH:39][C:38]([C:41]4[NH:45][C:44]([C@@H:46]5[CH2:50][CH2:49][CH2:48][N:47]5C(OC(C)(C)C)=O)=[N:43][CH:42]=4)=[CH:37][CH:36]=2)[CH:29]=[CH:28]3)[N:24]=1)=O)(C)(C)C>C(Cl)Cl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:47]1[CH2:48][CH2:49][CH2:50][C@H:46]1[C:44]1[NH:45][C:41]([C:38]2[CH:39]=[CH:40][C:35]([C:30]3[CH:29]=[CH:28][C:27]4[C:32](=[CH:33][CH:34]=[C:25]([C:23]5[NH:24][C:20]([C@@H:16]6[CH2:17][CH2:18][CH2:19][NH:15]6)=[N:21][CH:22]=5)[CH:26]=4)[CH:31]=3)=[CH:36][CH:37]=2)=[CH:42][N:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)c[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(-c2cnc([C@@H]3CCCN3)[nH]2)ccc1-c1ccc2cc(-c3cnc([C@@H]4CCCN4)[nH]3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of a TFA salt of (S)-tert-butyl 2-(5-(4-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (50 mg) in DCM (10 mL) was added TFA (2.0 mL, 26 mmol) in one portion. The mixture was agitated at room temperature for 2 h. The reaction was concentrated under vacuum to yield a TFA salt of 2-((S)-pyrrolidin-2-yl)-5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazole (51.5 mg) as orange solid, which was used without further purification. LC-MS retention time 0.978 min; m/z 475.19 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. HPLC-MS (TFA) 78457-087 using a Waters Sunfire C18 column 4 6×50 mm 5u showed the reaction was complete peak found at RT=0.978 min. MH+=475.19. 1H NMR (500 MHz, MeOD) δ ppm 8.34 (s, 1H), 8.20 (s, 1H), 8.03 (dd, J=14.2, 8.7 Hz, 2H), 7.84-7.96 (m, 7H), 7.79-7.84 (m, 1H), 4.99-5.11 (m, 2H), 3.48-3.63 (m, 4H), 2.57-2.70 (m, 2H), 2.41-2.55 (m, 2H), 2.29-2.41 (m, 2H), 2.15-2.29 (m, 2H).
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH:4]2[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>CC(C)=O.O>[C:13]([O:12][C:10]([N:1]1[CH:5]2[CH2:6][N:7]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:8][CH2:9][CH:4]2[CH2:3][CH2:2]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC2CCNCC21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2CCN(CCCCl)CC21
Yield: 75 %

Procedure:
To a solution of tert-butyl octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1.21 g) in acetone (15 mL) was added K2CO3 (3.00 g) and 1-bromo-3-chloropropane (1.6 mL). The reaction mixture was heated to reflux for 7 h, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 for 1 h and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) CH2Cl2/MeOH) to afford the title compound as pale yellow liquid (1.20 g, 75.00%).
Reaction SMILES: [CH2:1]1[CH2:33][O:32][C:3]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:9][C@H:8]([O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:7]2[CH2:24][CH:25]=[O:26])[O:2]1.Br[C:35]([F:49])([F:48])[C:36]#[C:37][CH2:38][CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>C1COCC1.[Zn].[Hg]Cl>[O:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[O:11][C@@H:10]1[CH2:9][C@H:8]([O:18][SiH2:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C@H:7]([CH2:24][CH:25]([OH:26])[C:35]([F:49])([F:48])[C:36]#[C:37][CH2:38][CH2:39][O:40][Si:41]([C:44]([CH3:45])([CH3:46])[CH3:47])([CH3:43])[CH3:42])[C@H:6]1[CH2:5][CH2:4][C:3]1([O:2][CH2:1][CH2:33][O:32]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCC1(CC[C@@H]2[C@H](CC=O)[C@@H](O[SiH2]C(C)(C)C)C[C@H]2OC2CCCCO2)OCCO1
Reactant: CC(C)(C)[Si](C)(C)OCCC#CC(F)(F)Br
Agent: Cl[Hg]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCCCC1(CC[C@@H]2[C@@H](CC(O)C(F)(F)C#CCCO[Si](C)(C)C(C)(C)C)[C@@H](O[SiH2]C(C)(C)C)C[C@H]2OC2CCCCO2)OCCO1

Procedure:
To a solution of 2-[(1S,2R,3R,5S)-2-(3,3-ethylenedioxyoctyl)-3-(tetrahydropyranyloxy)-5-(t-butylsiloxy)cyclopentyl]acetaldehyde (64) (1.00 g) in THF (25 ml) was added activated zinc powder (2.54 g), and while cooling on ice, the solution of 1-bromo-1,1-difluoro-5-(t-butyl-dimethylsilyloxy)-2-pentyne (i) (0.92 g) in THF (5 ml) was added dropwise to the resultant mixture. To the resultant solution was added mercury chloride (0.11 g) and the resultant mixture was stirred under ultrasonic irradiation. The reaction mixture was treated in the conventional manner and the obtained crude product was subjected to silica gel column chromatography to give the title compound (65).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[CH3:27]>CN(C=O)C.[Cu]I>[F:34][C:30]1[CH:29]=[C:28](/[C:26](/[CH3:27])=[CH:25]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1cccc(F)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol) L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by HPLC. Yield: 6 mg as the TFA salt. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.40 (m, 1H), 7.30 (d, 1H), 7.22 (m, 2H), 7.10 (m, 3H), 6.90 (s, 1H), 4.80 (d, 1H), 4.20 (d, 1H), 3.90 (m, 1H), 3.40 (m, 1H), 3.30 (m, 1H), 3.10 (s, 3H), 2.95 (m, 1H), 2.45 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH:4](C(Cl)=O)[CH2:3][CH2:2]1.NC1C=CC=C(C(O)=O)C=1O.C1C2N(CCCC2)C([C:35]2[O:36][C:37]3[C:43]([C:44]([NH2:46])=[O:45])=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=2)CC1>>[CH:9]1([C:35]2[O:36][C:37]3[C:43]([C:44]([NH2:46])=[O:45])=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=2)[CH:10]2[N:5]([CH2:4][CH2:3][CH2:2][CH2:1]2)[CH2:6][CH2:7][CH2:8]1
Reactant: NC(=O)c1cccc2nc(C3CCCC4CCCCN43)oc12
Reactant: O=C(Cl)C1CCCC2CCCCN21
Agent: Nc1cccc(C(=O)O)c1O
Product: NC(=O)c1cccc2nc(C3CCCN4CCCCC34)oc12

Procedure:
Following the experimental procedure as described in Examples 2A to 2B, and substituting benzyl 4-methylbenzoylchlordie with octahydro-1H-quinolizine-4-carbonyl chloride, and replacing 3-hydroxyanthranilic with 3-aminosalicylic acid, the title compound 2-(octahydro-1H-quinolizin-4-yl)benzo[d]oxazole-7-carboxamide is made
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1[NH:6][C:7]([CH3:31])=[C:8]([C:24]([O:26][CH2:27][CH2:28][CH2:29]Cl)=[O:25])[CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]>CS(C)=O>[CH3:4][C:5]1[NH:6][C:7]([CH3:31])=[C:8]([C:24]([O:26][CH2:27][CH2:28][CH2:29][C:1]#[N:2])=[O:25])[CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: [C-]#N
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCl)C1c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCC#N)C1c1ccccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 67.6 %

Procedure:
0.55 g (11 mmol) of sodium cyanide in 15 ml of dimethylsulphoxide are added dropwise at a reaction temperature of 60° C. to a solution of 4.09 g (10 mmol) of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(2-nitrophenyl)-5-(3-chloropropoxy)carbonyl-pyridine in 10 ml of dimethylsulphoxide. The reaction mixture is then stirred for 2.5 hours at 120° C. and is poured into 150 ml of ice water after it has cooled down. The mixture is extracted with 3×50 ml of ethyl acetate. After dehydration and concentration of the organic phases by evaporation under vacuum, 5.7 g of a brown oil are obtained. This oil is chromatographed on silica gel with dichloromethane/methanol (99:1). After concentration by evaporation under vacuum and recrystallisation of the residue from methanol, the main fraction yields 2.7 g (68%) of yellow crystals, melting point 48°-51° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=2)[OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:26]=[C:27]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[C:41](O)=[O:42])[C:28](=[O:34])[C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:32][C:29]([CH3:33])([CH2:30][CH3:31])[C:28](=[O:34])[C:27]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[C:41]([O:10][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=1)[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:42])=[O:26]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)COc1cccc([C@H](O)CCc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O[C@H](CCc1ccccc1)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A solution of alcohol 3 (342 mg, 1.0 mmol) in CH2Cl2 (3 mL) was treated with (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (23, 255 mg, 1.0 mmol, prepared from L-pipecolic acid in 4 steps following literature procedures by Holt et al. J. Amer. Chem. Soc., 1993, 115, 9925-9938), followed by 1,3-dicyclohexylcarbodiimide (DCC, 247 mg, 1.2 mmol), and 4-(dimethylamino)-pyridine (DMAP, 85 mg, 0.70 mmol) under a nitrogen atmosphere. The resulting bright yellow suspension was allowed to stir overnight. The mixture was then filtered through glass wool and chromatographed (silica gel, 20% EtOAc/hexanes) to give (1R)-3-Phenyl-1-(3-(tert-butoxycarbonylmethoxy)phenyl]-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarboxylate (470 mg, 82%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) (single diastereomer, mixture of rotamers) 7.50-6.90 (m, 9H), 5.93 (t, J=6.0 Hz, 1H), 5.46 (d, J=3.4 Hz, 0.83 H, pipercolate a-H of rotamer A), 4.67 (s, 2H), 3.50 (d, J=12.9 Hz, 1H), 3.32 (td, J=12.5, 3.0 Hz, 1H), 2.75 (m, 2H), 2.53 (d, J=13.6 Hz, 1H), 2.41 (m, 1H), 2.22 (m, 1H), 2.97-2.71 (m, 6H), 1.62 (s, 9H), 138 (s, 3H), 1.35 (s, 3H), 1.03 (t, J=7.4 Hz); 13C NMR (CDCl3, 75 MHz) (single diastereomer, mixture of rotamers) 208.3, 175.0, 170.0, 168.0, 167.5, 158.5, 141.7, 141.2, 130.2, 128.9, 128.7, 126.5, 120.2, 114.7, 113.6, 82.8, 66.1, 51.6, 47.1, 44.5, 38.2, 32.9, 32.0, 28.4, 26.8, 25.3, 24.0, 23.4, 21.6, 9.2. HRMS(FAB): (M+Na)+ calcd: 602.3094. found: 602.3090.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:38][N:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>C(#N)C.C(N(CC)CC)C>[CH3:13][C:10]([CH3:11])([CH3:12])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:14]([N:48]1[CH2:47][CH2:46][N:45]([CH:42]2[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]2)[CH2:50][CH2:49]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: CN1CCC(N2CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCC(N2CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)C)CC2)CC1
Yield: 101.4 %

Procedure:
To a solution of Boc-D-tert-leucine (0.46 g) and HOBt (0.46 g) in acetonitrile (20 ml) was added WSC (0.58 g), and the reaction mixture was mixed at room temperature for 15 minutes. Then, 1-(1-methyl-4-piperidyl)piperazine (0.70 g) and triethylamine (0.61 g) were added, and the reaction mixture was mixed at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless oil (0.80 g, quantitative).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].N1C=CC=C(C)C=1.[CH2:26]([NH:28][CH2:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)[CH3:27]>[OH-].[NH4+]>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:32]3[CH2:33][CH2:34][CH:30]([CH2:29][NH:28][CH2:26][CH3:27])[CH2:31]3)[CH:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: CCNCC1CCNC1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1cccnc1
Product: CCNCC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)C1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of 2.70 g (10.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 60 ml of β-picoline and 3.85 g (30.0 mmole) of N-ethyl-3-pyrrolidinemethanamine were refluxed overnight. Reaction mixture was cooled to room temperature, 100 ml concentrated ammonium hydroxide added, and the solvents removed at reduced pressure. A solution of 200 ml dichloromethane/ether (1:3) was added. The resulting precipitate was filtered, washed with ethanol/ether (1:3) and finally with ether until dry to give 1.87 g of 1-ethyl-7-[3-[(ethylamino)-methyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 248°-252° C.