Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[N:11]1([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3ccccc3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2nc(N3CCNCC3)ccc2c1

Procedure:
Prepared in analogy to example 1.6(d) from 4-quinolin-2-yl-piperazine-1-carboxylic acid tert.-butyl ester and dioxane saturated with gaseous hydrochloric acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:27])[NH:20][C:21]([CH3:26])=[CH:22][C:23]=2[CH2:24][CH3:25])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:28][C:29]1([CH3:46])[CH2:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([CH3:45])([CH3:44])[NH:30]1.O1CCOCC1.O.C([O-])([O-])=O.[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:24]([C:23]1[CH:22]=[C:21]([CH3:26])[NH:20][C:19](=[O:27])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:33]2[CH2:32][C:31]([CH3:45])([CH3:44])[NH:30][C:29]([CH3:46])([CH3:28])[CH:34]=2)[CH:3]=1)=[O:15])[CH3:25]
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Reactant: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)nc2c1cnn2C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C2=CC(C)(C)NC(C)(C)C2)nc2c1cnn2C(C)C
Temperature: 100 °C
Yield: 38 %

Procedure:
To a stirred solution of 6-bromo-N-((4-ethyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.37 g, 0.85 mmol) and 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.2 equiv.) in dioxane/water mixture (3 mL+1 mL for 1 mmol), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.05 equiv.) was added and argon was purged again for 10 min Reaction mass was heated at 100° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the desired compound. (38% yield). LCMS: 491.25 (M+1)+; HPLC: 95.01% (@ 254 nm) (Rt;5.463); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.87 (s, 1H), 8.26 (s, 1H), 7.79 (s, 1H), 6.80 (s, 1H), 5.91 (s, 1H), 5.22-5.19 (m, 1H), 4.39 (d, 2H, J=4.0 Hz), 2.42-2.40 (m, 4H), 2.24 (s, 3H), 1.49 (d, 6H, J=6 Hz), 1.24 (s, 6H), 1.14 (s, 6H), 1.11 (m, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1(=[O:17])=[O:16].[CH3:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][CH:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:25]2.[I-].[Na+].NC1C2C(=CC=CC=2)CCC1>CN(C)C=O.C(N(CC)CC)C>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][CH:27]([N:30]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[S:7]1(=[O:17])=[O:16])[CH2:31][CH2:32][CH3:33])[CH2:26][CH2:25]2
Reactant: CCCNC1CCc2cccc(OC)c2C1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Agent: NC1CCCc2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN(CCCCN1C(=O)c2ccccc2S1(=O)=O)C1CCc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.6 %

Procedure:
1.9 g (6.0 mmol) of 2-(4-bromobutyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide were added dropwise to the solution of the 1.3 g (6.0 mmol) of 8-methoxy-2-propylamino-1,2,3,4-tetrahydronaphthalene and 1.3 g (12 mmol) of triethylamine in 15 ml of dimethylformamide. After stirring for 15 hours at room temperature, a spatula tip of sodium iodide was added, and the mixture was heated to 60° C. After 4 hours at this temperature, 0.4 g of the above aminotetralin and 0.3 g of triethylamine were added. Chromatography on silica gel (toluene/ethyl acetate gradients) of the crude product, obtained after removal of the solvent in vacuo, yielded 0.70 g (25%) of the title compound as a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].F[C:12]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].CCCCCC.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:12]1[CH:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: Nc1ccccc1S
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1ccc(C(F)(F)F)cc1Sc1ccccc1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
2-Aminothiophenol (8.17 g, 65 mmol) was added to a mixture of sodium hydride (2.35 g of 80% dispersion, 1.2 eq) in dimethylformamide (DMF, 100 ml) at 0° C. under a nitrogen atmosphere. After stirring for 30 mins 2-fluoro-4-trifluoromethylbenzonitrile (11.68 g, 0.95 eq) was added and the reaction mixture stirred at 0° C. for 1 hr then kept at 10° C. overnight. The solvent was evaporated in vaccuo and the residue taken up in ether (100 ml) and washed with sodium bicarbonate solution (1M, 100 ml). The organic layer was separated and dried (sodium sulphate, Na2SO4), and evaporated to give a yellow solid. The title compound (12.5 g, m.p. 102°-104° C., Rf 0.67, hexane/EtOAc 2:1) was obtained in pure form by chromatography on silica eluting first with hexane/ethyl acetate (6:1) then (4:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].CCN=C=NCCCN(C)C.CN1CCOCC1.Cl.[CH3:33][O:34][NH:35][CH3:36]>Cl.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([N:35]([O:34][CH3:33])[CH3:36])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
To a solution of CH2Cl2 (1L) was added 3-fluoro-4-nitrobenzoic acid (100 g, 540 mmol) and EDCI (155.3 g, 810 mmol) followed by NMM (178 mL, 1.62 mol) and N-methoxymethanamine hydrochloride (79.0 g, 810 mmol). The solution was allowed to stir under N2 at rt for 17 h. The reaction mixture was then diluted with 1N HCl (1 L), transferred to separatory funnel, and separated. The organic phase was washed with 1N NaOH (2×500 mL) and water (250 ML). All aqueous layers were back extracted with EtOAc (2×500 mL). The organic layers were combined, dried (MgSO4), filtered, and concentrated in vacuo. to afford 102.3 g of the above compound as a yellow solid (448 mmol, yield 83%). 1H-NMR (DMSO-d6) δ 8.22 to 8.18 (t, J=8.0 Hz, 1H), 7.79 to 7.76 (d, J=11.5 Hz, 1H), 7.60 to 7.58 (d, J=8.3 Hz, 1H), 3.56 (s, 3H), 3.28 (s, 3H); MS [M+H]+=229. 1; LCMS RT=2.27 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Br)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B2OCCCO2)=[C:17]([F:27])[C:16]=1[O:28][CH3:29].[F-].[K+]>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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([O:28][CH3:29])[C:17]=2[F:27])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: COC(=O)c1cc(N)c(F)c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Product: COC(=O)c1cc(N)c(F)c(-c2ccc(Cl)c(OC)c2F)n1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A 50 mL round bottom flask equipped with a reflux condenser was charged with solid methyl 4-amino-6-bromo-5-fluoropicolinate (1.0 g, 4.02 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (1.227 g, 5.02 mmol), bis(triphenylphosphine)-palladium(II) dichloride (Pd(PPh3)2Cl2; 0.141 g, 0.201 mmol), and KF (0.467 g, 8.03 mmol). The reaction mixture was flushed with nitrogen, and then solvent (3:1 acetonitrile-water, 24 mL) was added. The reaction mixture was heated to reflux under nitrogen for 2 h. Upon cooling to room temperature, the product was filtered, washed with acetonitrile followed by water, and dried in a vacuum oven overnight to give the product (0.89 g) as an off-white solid: mp 204-206° C. An additional 0.29 g of product was isolated from the filtrate for a combined yield of 89%. 1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J=6.6 Hz, 1H), 7.46 (dd, J=8.5, 1.4 Hz, 1H), 7.30 (dd, J=8.4, 7.2 Hz, 1H), 6.71 (s, 2H), 3.93 (s, 3H), 3.83 (s, 3H), 3.31 (s, 4H); 13C NMR (101 MHz, DMSO-d6) δ 164.82 (s), 153.17 (d, J=249.5 Hz), 146.87 (d, J=254.3 Hz), 143.83 (dd, J=13.4, 3.8 Hz), 143.69 (d, J=4.3 Hz), 139.05 (d, J=10.6 Hz), 128.20 (d, J=3.2 Hz), 125.96 (d, J=3.4 Hz), 125.42 (d, J=3.6 Hz), 123.83 (dd, J=14.3, 3.1 Hz), 112.54 (s), 61.56 (s), 52.25 (s); 19F NMR (376 MHz, DMSO-d6) δ −129.37 (d, J=26.0 Hz), −142.56 (d, J=26.3 Hz).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[O:16][CH:15]([CH3:18])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=2[S:10][CH:9]=1.[C:26](OCC)(=[O:28])C.Cl>>[CH3:26][O:28][C:5]1[CH:4]=[C:3]([C:8]2[C:17]3[O:16][CH:15]([CH3:18])[CH2:14][NH:13][CH2:12][C:11]=3[S:10][CH:9]=2)[CH:2]=[CH:7][CH:6]=1
Reactant: CCOC(C)=O
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(-c3ccccc3F)c2O1
Agent: Cl
Product: COc1cccc(-c2csc3c2OC(C)CNC3)c1
Yield: 95 %

Procedure:
tert-Butyl 8-(2-fluorophenyl)-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (168 mg) was stirred in 4 N hydrogen chloride-ethyl acetate solution (5 mL) for 30 min. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give 8-(2-fluorophenyl)-2-methyl-2,3,4,5-tetrahydrothieno[2,3-f][1,4]oxazepine 1 hydrochloride (132 mg, 95%) as colorless crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12]([NH:14][O:15][CH:16]([CH3:22])[C:17](OCC)=[O:18])=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[OH:18][CH2:17][CH:16]([O:15][NH:14][C:12](=[O:13])[O:11][C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:22]
Reactant: CCOC(=O)C(C)ONC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)ONC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 74.3 %

Procedure:
A solution of LiAlH4 (213 mg, 5.62 mmol) in anhydrous THF (8 mL) was added slowly to a solution of ethyl 2-(t-butoxycarbonylaminooxy)propanoate (820 mg, 3.52 mmol) in THF (15 mL) at 0° C. The mixture was stirred at 0° C. for 5 h and then at rt overnight. The solution was quenched with a mixture of Na2SO4 and water, and stirred for an additional 1.5 h. The mixture was filtered and concentrated. The crude was dissolved in EtOAc, washed with water and brine, and then dried over Na2SO4. Solvent was evaporated to afford the title compound as a clear oil (500 mg, 74.4%). 1H-NMR (400 MHz, CDCl3) δ ppm 7.09 (s, 1H), 3.95 (m, 1H), 3.69 (dd, 1H), 3.47 (m, 1H), 1.51 (s, 9H), 1.21 (d, 3H).
Reaction SMILES: [Cl-].[NH4+:2].[OH-].[NH4+].Cl[O-].[Na+].[NH:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[C:9]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Na+].NCl>CC(OC)(C)C.CN(C=O)C>[NH2:2][N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[C:9]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c[nH]c(C(=O)OCC)c1
Reactant: [NH4+]
Agent: NCl
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(N)c1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a flask was added MTBE (2 L) and ammonium chloride (60 g, 1.13 mol). The reaction was cooled to −20° C. Then concentrated aq ammonium hydroxide (160 mL) was added to the reaction followed by slow addition of commercial-grade sodium hypochlorite solution (149 g, 1.5 L). After addition, the reaction was stirred at −20° C. for additional 30 minutes. The MTBE layer was separated and washed with brine and dried over Na2SO4. In a separate flask under nitrogen was added diethyl 1H-pyrrole-2,4-dicarboxylate (40 g, 190 mmol) and dry DMF (400 mL). The reaction was cooled to 0° C. whereupon sodium hydroxide (190 mmol) was added portionwise to the reaction. The reaction was stirred at 0° C. for additional 1 hour before it was cooled to −20° C. At this time, the previously prepared MTBE solution of chloramine was added slowly to the reaction and the reaction was stirred at −20° C. for 1 hour. The reaction was quenched with saturated sodium thiosulfate solution. The organic layer of the reaction was separated and washed with water and brine, dried over sodium sulfate, filtered and concentrated to yield 40 g (95%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm: 7.48 (1H, d, J=1.6 Hz), 7.24 (1H, d, J=1.6 Hz), 5.65 (2H, s), 4.32-4.23 (4H, merging quartets), 1.367-1.32 (6H, merging triplets). LCMS (condition A) m/z=227.2 +ve.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[S:14]([Cl:13])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cc(OC)cc(OC)c1
Product: COc1cc(OC)c(S(=O)(=O)Cl)c(OC)c1
Reaction time: 2 h

Procedure:
16.8 g (0.1 mole) 1,3,5 -trimethoxybenzene were added in portions to 33 ml chlorosulphonic acid, giving a clear pale-yellow solution. The solution was allowed to stand at about 20° C. for 2 hours and was then poured onto ice. The crystals formed were collected, washed with water, taken up in CHCl3, washed with water, and dried with sodium sulphate. The solvent was removed in vacuum, giving 15 g of the crude title compound. The crude product was dissolved in a minimum of hot CHCl3 and di-isopropylether was added. After cooling, white crystals of title compound (9 g) were collected; m.p. 134°-136° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([O:27][C:28]([F:31])([F:30])[F:29])[CH:21]=2)[C:11]1=[O:32])[CH2:7][CH2:8][CH3:9])C.[OH-].[Li+].Cl>O1CCOCC1.O>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:33])=[O:3])[C:11]2=[O:32])=[CH:21][C:22]=1[O:27][C:28]([F:30])([F:31])[F:29]
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2ccc(N)c(OC(F)(F)F)c2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2ccc(N)c(OC(F)(F)F)c2)c2ccccc21
Temperature: 25 °C
Yield: 100 %

Procedure:
3-[3-(4-Amino-3-tri fluoromethoxy-benzyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester—20 mg (0.04 mmol) is dissolved in 1.5 mL of dioxane/water (1:1) and then lithium hydroxide (4.1 mg, 0.17 mmol) is added. The reaction is stirred at room temperature and monitord by LC/MS. Upon completion the reaction is acidified by the addition of 1N HCl. The solvent is evaporated and the residue partitioned between ethyl acetate (2 mL) and water (2 mL). The organic layer is dried over anhydrous sodium sulfate. The solvent is evaporated and the resulting solid is purified by Combi flash chromatography, eluting with 0-20% methanol/dichloromethane to give the title compound (18 mg, 0.04 mmol 95%). LCMS (ESMS): m/z 438.4 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16]Br.Cl>CS(C)=O.O.CCOCC>[C:3]1([C:9]2([C:10]#[N:11])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCCBr
Reactant: N#CCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: N#CC1(c2ccccc2)CCCC1
Yield: 86.7 %

Procedure:
To a suspension of NaH (11.3 g, 281.7 mmol, 60%) in DMSO (75 ml) were added dropwise a mixture of phenyl-acetonitrile (15 g, 128.0 mmol) and 1,4-dibromo-butane (18 ml, 128.0 mmol) dissolved in DMSO:Ether (150 ml, 1:1) at 0° C. and the reaction mixture was stirred at room temperature (RT) for 2 to 3 h. After completion of the reaction, water and 10% HCl solution were added to the crude mass. It was extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (10% EtOAc-hexane) to get 1-phenyl-cyclopentanecarbonitrile (2) (19 g, 86.64%) as a yellow solid. MS: m/z=171 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[O:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([O:31]C)=[O:30])[CH:25]=[CH:26][CH:27]=2)[N:19]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[O:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:26][CH:27]=2)[N:19]=1
Reactant: COC(=O)Cc1cccc(OCc2coc(CCc3nc(-c4ccccc4)oc3C)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCc1nc(COc2cccc(CC(=O)O)c2)co1
Temperature: 50 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a mixture of methyl 2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-oxazolyl]methoxy]phenyl]acetate (0.34 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added a 1N aqueous sodium hydroxide solution (2 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.26 g, 79%) of 2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-oxazolyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]=1[NH2:15].[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C)C=O>[N:16]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]=1[NH2:15])=[N+:17]=[N-:18]
Reactant: Nc1c(OCCCl)cc(Cl)cc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOc1cc(Cl)cc([N+](=O)[O-])c1N
Temperature: 60 °C

Procedure:
A solution of 2-(2-chloro-ethoxy)-4-chloro-6-nitro-phenylamine (3.07 g, 12.2 mmol), sodium azide (1.59 g, 24.4 mmol) in anhydrous N,N-dimethylformamide (30 ml) was allowed to heat at 60° C. for 18 hours. The reaction was poured into water (150 ml) and extracted with ethyl ether (2×100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum to afford an orange solid. The solid was washed with ethyl ether (5 ml) to afford an orange crystalline solid: mp 113-114° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:16]3[CH2:17][CH2:18][N:19]4[C:24]([C:15]=3[NH:14][C:11]2=[CH:12][CH:13]=1)=[C:23]([CH2:25][CH3:26])[CH2:22][CH2:21][C:20]4=[O:27]>C(O)C.[Pd]>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:16]3[CH2:17][CH2:18][N:19]4[CH:24]([C:15]=3[NH:14][C:11]2=[CH:12][CH:13]=1)[CH:23]([CH2:25][CH3:26])[CH2:22][CH2:21][C:20]4=[O:27]
Reactant: CCC1=C2c3[nH]c4ccc(OC)cc4c3CCN2C(=O)CC1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCC1CCC(=O)N2CCc3c([nH]c4ccc(OC)cc34)C12
Reaction time: 8 h

Procedure:
Sodium bicarbonate (500 mg) and palladium-on-charcoal are successively added to a solution of 9-methoxy-1-ethyl-2,3,4,6,7,12-hexahydroindolo[2,3-a]quinolizin-4-one (500 mg) in ethanol. and the mixture is stirred overnight under a hydrogen atmosphere. After filtration and evaporation of the solvent, the crude product is recrystallized from ethyl acetate. 9-Methoxy-I-ethyl-1,2,3 ,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-4-one is thus recovered (76%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[NH:24][C:23]([O:25][C@@H:26]3[CH2:30][O:29][C@@H:28]4[C@@:31]([OH:36])([CH:34]=[O:35])[CH2:32][O:33][C@H:27]34)=[N:22][C:7]2=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>CO>[Cl:3][C:4]1[CH:5]=[C:6]2[NH:24][C:23]([O:25][C@@H:26]3[CH2:30][O:29][C@@H:28]4[C@:31]([CH2:34][OH:35])([OH:36])[CH2:32][O:33][C@H:27]34)=[N:22][C:7]2=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1
Reactant: O=C[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Sodium borohydride (1.3 mg, 0.034 mmol) was added to a stirred solution of (3R,3aR,6R,6aS)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-6-hydroxy-3,3a,5,6a-tetrahydro-2H-furo[3,2-b]furan-6-carbaldehyde (5.4 mg, 0.011 mmol) in methanol (0.5 ml) that had been cooled to 0° C. in an ice bath. After 1.5 hours, additional sodium borohydride (3.0 mg, 0.079 mmol) was added to the reaction mixture. After an additional 1.5 hours, additional sodium borohydride (2.8 mg, 0.074 mmol) was added to the reaction mixture. After another hour, the reaction mixture was placed in the refrigerator overnight. In the morning, the reaction mixture was removed from the refrigerator and placed in an ice bath. Additional sodium borohydride (3.2 mg, 0.085 mmol) was added to the reaction mixture. After 1.5 hours, the reaction mixture was removed from the ice bath and allowed to warm to room temperature. The reaction mixture was directly purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water+0.05% TFA gradient followed by a 80% acetonitrile/water+0.05% TFA flush. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C25H22ClN3O5 479.12 observed m/e: 480.18 (M+H)+ (Rt 1.16/2 min); 1H NMR δ (ppm) (CD3OD): 7.86 (s, 1H), 7.73-7.77 (m, 4H), 7.71 (d, J=7.8 Hz, 2H), 7.48 (t, J=7.6 Hz, 2H), 7.38 (t, J=6.8 Hz, 1H), 5.56 (qt, J=5.4 Hz, 1H), 4.98 (t, J=5.3 Hz, 1H), 4.30 (d, J=5.0 Hz, 1H), 4.20 (dd, J=5.6 Hz, J=10.3 Hz, 1H), 4.15 (dd, J=5.1 Hz, J=10.0 Hz, 1H), 3.80 (d, J=8.7 Hz, 1H), 3.67 (d, J=8.8 Hz, 1H), 3.52-3.58 (m, 2H).
Reaction SMILES: OS(O)(=O)=O.[C:6]1([CH:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:21]([O-])([OH:23])=[O:22]>>[N+:21]([C:9]1[CH:8]=[CH:7][C:6]([CH:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)([O-:23])=[O:22]
Reactant: O=C(O)CC(CC(=O)O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)CC(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A flask charged with concentrated H2SO4 (400 mL) was cooled to 0° C. and treated with 50.0 g (240 mmol) of 3-phenyl-pentanedioic acid portionwise over 20 min and with fuming HNO3 (10 mL) dropwise over 20 min. The mixture was stirred at RT for 3 h, poured over ice (amount equivalent to 1000 mL), and the precipitate was filtered, washed with cold water, air-dried, and dried in a vacuum dessicator. The solid was triturated with a minimum amount of CH3CN, filtered, and air-dried. The filtrate was concentrated and triturated again with a minimum amount of CH3CN, filtered, and air-dried to afford a second batch. The two batches were combined to afford 56.9 g (94%) of the title compound as an off-white solid: 1H-NMR (DMSO-d6; 400 MHz): δ 8.15 (d, 2H, J=8.8 Hz), 7.58 (d, 2H, J=8.8 Hz), 3.62-3.50 (m, 1H), 2.79-2.57 (m, 4H).