Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH2:10][N:11]([CH2:20][CH2:21][CH:22]=[CH2:23])[C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C>[Br-].[Zn+2].[Br-]>[CH3:23][C@H:22]1[CH2:21][CH2:20][N:11]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C@H:10]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:24]
Reactant: C=CCCN(CC(=O)OCc1ccccc1)[C@H](C)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Product: CC(c1ccccc1)N1CC[C@H](C)[C@@H]1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
The title compound was prepared from (R)-[but-3-enyl-(1-phenyl-ethyl)-amino]-acetic acid benzyl ester essentially according to the cyclization protocol described in Karoyan, P.; Chassaing, G. Tetrahedron: Asymm. 1997, 8, 2025–2032 with the following modifications: LDA was added at −40° C., then the solution was warmed to 0° C. for 10 min, then re-cooled to −40° C. for the zinc bromide addition. The transmetallation step was omitted and the anion was quenched directly with 2:1 saturated NH4Cl:ammonium hydroxide. Extractive workup (Et2O) afforded an orange oil which was purified by silica gel chromatography (5–10% EtOAc-hexanes) to give the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH:7]=[CH2:8])[CH3:2].[Cl:10][C:11]([Cl:16])(Cl)[C:12](Cl)=[O:13]>C(OCC)C.COCCOC.[Cu].[Zn]>[Cl:10][C:11]1([Cl:16])[C:12](=[O:13])[CH2:8][CH:7]1[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9]
Reactant: C=CCCC(=O)OCC
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Solvent: COCCOC
Product: CCOC(=O)CCC1CC(=O)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.5 %

Procedure:
A mixture of 4-pentenoic acid ethyl ester (7.07 g, 55.2 mmol) and zinc-copper couple (10.2 g, 140 mmol) in diethyl ether (170 mL) and 1,2-dimethoxyethane (25 mL) was treated dropwise with trichloroacetyl chloride (25 g, 140 mmol). The mixture was stirred at room temperature for 3 days. The reddish heterogeneous reaction mixture was filtered through a pad of celite and the pad was washed with 300 mL Et2O. The filtrate was concentrated to about one half the original volume and the organic phase was washed with two 150 mL portions of H2O and one 150 mL portion of sat NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated to yield a brown liquid. The material was purified by vacuum distillation (90-100° C. @0.044 torr) to yield the title compound (10.49 g, 80%) as a light yellow liquid: GC purity 95.8% (ret. time, 4.92 min).
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:19]=[CH:18][C:10]2[C:11]([C:14]([F:17])([F:16])[F:15])=[N:12][O:13][C:9]=2[C:8]=1[CH2:20][CH2:21][CH3:22].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.CCOCC>[CH2:20]([C:8]1[C:9]2[O:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]=2[CH:18]=[CH:19][C:7]=1[O:6][CH2:27][CH2:26][CH2:25][CH2:24][Br:23])[CH2:21][CH3:22]
Reactant: BrCCCCBr
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCc1c(OCCCCBr)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a DMF solution (50 mL) of 6-hydroxy-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole as prepared in Example 4 step 2 (6.5 gram, 26.5 mmol) was added 1,4-dibromobutane (16 mL, 133 mmol), followed by cesium carbonate (9.1 grams, 27.8 mmol). The mixture was stirred at room temperature overnight. After aqueous/ether work-up and silica gel chromatography (hexanes: 2.5% ethyl acetate), the title compound was obtained.
Reaction SMILES: [N:1]1[C:13]2[C:12](=[O:14])[N:11]3[C:6](=[N:7][CH2:8][CH2:9][CH2:10]3)[C:5]=2[N:4]=[CH:3][CH:2]=1.O.[NH2:16][NH2:17]>C(O)C>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:6]1[C:5]2[N:4]=[CH:3][CH:2]=[N:1][C:13]=2[C:12](=[O:14])[NH:17][N:16]=1
Reactant: NN
Reactant: O=C1c2nccnc2C2=NCCCN12
Solvent: O
Solvent: CCO
Product: NCCCNc1n[nH]c(=O)c2nccnc12

Procedure:
7,8-Dihydro-6H-1,4,5,8a-tetraaza-fluoren-9-one (0.53 mmol) was treated with hydrazine hydrate (3.0 mmol) in ethanol (3 mL) for 20 h at RT. Ethanol was removed under vacuum and the crude produce was purified by flash chromatography (MeOH/DCM/Et3N) to yield 8-(3-amino-propylamino)-6H-pyrazino[2,3-d]pyridazin-5-one.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[C:18]([NH2:20])[CH:19]=1>>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:20][C:18]3[CH:19]=[C:14]([CH3:13])[CH:15]=[CH:16][C:17]=3[S:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (267 mg, 1.56 mmol) was reacted with the product from Example 47b (358 mg, 1.56 mmol) for 48 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (347 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.22 (s, 3H) 2.37 (s, 3H) 2.77 (s, 3H) 6.27 (d, J=7.35 Hz, 1H) 7.04 (d, J=7.72 Hz, 2H) 7.14 (m, 2H) 7.29 (m, 3H) 7.79 (d, J=8.82 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 8.95 (d, J=8.46 Hz, 1H) 11.25 (br. s., 1H) 14.39 (br. s., 1H); MS (ESI+) m/z 372 (M+H)+.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][O:7][CH:8](Cl)Cl.C[O:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][CH:19]2[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[CH:15][CH:14]=1.[OH-].[NH4+]>C(Cl)Cl.O>[NH:26]1[CH:27]=[C:23]([CH2:22][CH:19]2[C:20]3[C:16](=[CH:15][C:14]([CH:13]=[O:12])=[C:8]([O:7][CH3:6])[CH:21]=3)[CH2:17][CH2:18]2)[N:24]=[CH:25]1
Reactant: COC(Cl)Cl
Reactant: COc1ccc2c(c1)C(Cc1c[nH]cn1)CC2
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1C=O)CCC2Cc1c[nH]cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Tin(IV)chloride (1.60 g) is added dropwise to a stirred solution of dichloromethyl methyl ether (0.68 g) in methylene chloride (12 ml) with ice cooling under a nitrogen atmosphere. The solution is stirred at 0° C. for one hour before adding a solution of 4-(6-methoxyindan-1-ylmethyl)-1H-imidazole (0.60 g) in methylene chloride (4 ml). The resulting mixture is allowed to warm to ambient temperature while being stirred for 4 hours. The mixture is then poured into cold water and is made basic with ammonium hydroxide solution. The product is extracted into methylene chloride which is washed with water, dried with sodium sulfate and evaporated to dryness. The crude product is purified by flash chromatography using methylene chloride-methanol as eluent.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:10]2[CH:6]([CH2:7][N:8]([C:11](=[O:22])[C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[CH3:13])[CH2:9]2)[C:5](=[O:23])[CH2:4][CH2:3]1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Mg]Br>>[CH3:24][C:2]1([CH3:1])[C@H:10]2[C@H:6]([CH2:7][N:8]([C:11](=[O:22])[C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[CH3:13])[CH2:9]2)[C@:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])([OH:23])[CH2:4][CH2:3]1
Reactant: COc1ccccc1[C@H](C)C(=O)N1CC2C(=O)CCC(C)(C)C2C1
Reactant: COc1ccccc1[Mg]Br
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2[C@H](C1)[C@@](O)(c1ccccc1OC)CCC2(C)C
Yield: 26.1 %

Procedure:
By working according to the experimental procedure of Example 9, from 0.78 g of 7,7-dimethyl-2-[2-(S)-(2-methoxyphenyl)propionyl]-4-perhydroisoindolone (mixture of (3aR,7aR) and (3aS,7aS) diastereoisomers) and 1.5 g of 2-methoxyphenylmagnesium bromide, and after purification on a column of silica gel (particle size 0.04-0.06 mm, diameter 2.8 cm, height 21 cm), 0.27 g of (3aR*,4R*,7aR*)-7,7-dimethyl-4-(2-methoxyphenyl)-2-[2-(S)-(2-methoxyphenyl)propionyl]-4-perhydroisoindolol is obtained, in the form of a white foam.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=[N:2]1.[CH:17]1(B(O)O)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].N1C=CC=CC=1C1C=CC=CN=1>ClC(Cl)C.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:17]1([N:2]2[CH:3]=[C:4]3[CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8][C:9]3=[N:1]2)[CH2:19][CH2:18]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]ncc2C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2nn(C3CC3)cc2C1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
tert-Butyl 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (4.0 g, 18 mmol) and cyclopropylboronic acid (3.08 g, 35.8 mmol) were combined in dichloroethane (200 mL). After sequential addition of sodium carbonate (3.80 g, 35.8 mmol), copper(II) acetate (3.58 g, 17.9 mmol) and 2,2′-bipyridine (2.80 g, 17.9 mmol), the reaction mixture was stirred at 60° C. for 18 hours while open to the atmosphere. The reaction mixture was then diluted with ethyl acetate (500 mL) and filtered through diatomaceous earth; the filtrate was washed with saturated ammonium chloride solution and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) was followed by supercritical fluid chromatography (Column: Chiral Technologies, Chiralpak AD-H, 5 μm; Eluent: 85:15 carbon dioxide/methanol) to obtain the major regioisomer, which was the first-eluting peak. The indicated regiochemistry was assigned on the basis of NOE studies carried out on C46. Yield: 1.7 g, 6.5 mmol, 36%. LCMS m/z 264.5 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.43 (br s, 1H), 4.42 (br s, 2H), 3.65-3.70 (m, 2H), 3.52-3.58 (m, 1H), 2.64-2.69 (m, 2H), 1.47 (s, 9H), 0.98-1.03 (m, 4H).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)=O.CO.Cl>O1CCCC1>[CH3:1][NH:2][CH2:3][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[S:22][CH:23]=2)[CH3:15])=[CH:11][CH:12]=1
Reactant: CNC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNCCOc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Temperature: 25 °C

Procedure:
1.2 ml of borane/dimethyl sulfide complex are added to a solution of 0.38 g of N-[2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine in 20 ml of absolute tetrahydrofuran, and the mixture is heated to reflux for three hours. The 4 ml of methanol are cautiously added dropwise to the reaction mixture, and the mixture is heated to reflux for one hour. After cooling to room temperature, ethereal hydrochloric acid is added. The resulting solution is evaporated, the resulting residue is taken up in 15 ml of water, and the solution is made alkaline with concentrated ammonia and extracted several times with methylene chloride. The combined extracts are dried with sodium sulphate, evaporated and purified on a silica gel column using methylene chloride/methanol=8:2 as eluant.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][C:14]=1[C:28]([F:31])([F:30])[F:29])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[NH2:32][C:33]1[C:34]([C:42]#[N:43])=[N:35][C:36](Cl)=[CH:37][C:38]=1[NH:39][CH3:40].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C(OCC)(=O)C.O>[NH2:32][C:33]1[C:38]([NH:39][CH3:40])=[CH:37][C:36]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:8])[CH3:7])=[C:14]([C:28]([F:29])([F:30])[F:31])[CH:15]=2)=[N:35][C:34]=1[C:42]#[N:43]
Reactant: CN(CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F)C(=O)OC(C)(C)C
Reactant: CNc1cc(Cl)nc(C#N)c1N
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CNc1cc(-c2ccc(OCCN(C)C(=O)OC(C)(C)C)c(C(F)(F)F)c2)nc(C#N)c1N

Procedure:
tert-Butyl methyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)ethyl)carbamate (22.46 mmol, 10 g), 3-amino-6-chloro-4-(methylamino)picolinonitrile (22.46 mmol, 4.10 g), potassium phosphate (67.4 mmol, 14.30 g), tricyclohexylphosphine (2.69 mmol, 0.756 g), and tris(dibenzylacetone)-dipalladium (0) (1.123 mmol, 1.028 g) were dissolved in Dioxane (20 ml) and Water (10.00 ml) and stirred under nitrogen at 100° C. for 2 hrs. The mixture was diluted with ethyl acetate and filtered through celite. Organic layer was washed with water and separated from the aqueous layer, the organic layer was concentrated in vacuo. This was purified by silica chromatography, eluting with heptane—50/50 heptane/EtOAc to afford tert-butyl 2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoro-methyl)phenoxy)ethyl(methyl)carbamate. (2.11 g)
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].Cl[C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:17][O:18][C:19]=2[N:20]=1.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:4][CH:3]([O:5][C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:17][O:18][C:19]=2[N:20]=1)[CH:2]([CH3:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Reactant: CC(C)C(C)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C(C)Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To a solution of 3-methylbutan-2-ol (0.19 mL) in toluene (4 mL) was added sodium hydride (0.14 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.50 g), BINAP (0.033 g), Pd2(dba)3 (0.024 g) and toluene (4 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-(1,2-dimethylpropoxy)-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.36 g, 61%) as a yellow oil.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C(N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>O1CCCC1>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1Cc2ccccc2C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
43.70 g (258 mol) 2-aminoindane hydrochloride and 53.43 g (528 mmol) triethylamine were mixed with 250 ml of tetrahydrofuran, 42.89 g (270 mmol) 4-fluorobenzoylchloride were added, and the mixture was stirred for 2 h at RT.
Reaction SMILES: C([O:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]3=[O:34])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][C:10]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]3=[O:34])=[CH:22][CH:23]=2)[CH2:16][CH2:17]1)=[O:11]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)COCc4ccccc4)CC3)cc2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)CO)CC3)cc2)C(=O)O1
Reaction time: 20 h

Procedure:
A mixture of (S)-(-)-N-[[3-[4-[1-[(benzyloxy)acetyl]-4-piperidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 18, 207 mg) and 10% palladium-on-carbon (100 mg) in methanol (9 mL) is shaken on a Parr apparatus under a hydrogen atmosphere at 40 psi for 20 hours, the catalyst is removed by filtration through Celite and the filtrate is concentrated under reduced pressure to give the crude product 25 which is chromatographed on silica gel (230-400 mesh, 20 g), eluting with a gradient of methanol/methylene chloride (5/95-10/90). Pooling and concentration of those fractions with an Rf =0.26 by TLC (methanol/chloroform, 10/90) and recrystallization from methylene chloride/diethyl ether gives the title compound, mp 155-157° C.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[C:7]([CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[F:17])#[N:8].O.[OH-].[Na+]>C(OCC)C.S(=O)(=O)(O)O>[NH2:8][CH2:7][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[F:17]
Reactant: N#CCc1ccc(N)cc1F
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: NCCc1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.1 %

Procedure:
To a suspension of aluminum lithium hydride (76 mg) in diethyl ether (5 ml), conc. sulfuric acid (0.053 ml) was added under ice cooling and stirred at room temperature for 1 h. Subsequently, a solution of the compound (100 mg) obtained in Example 251 in diethyl ether (15 ml) was added dropwise at room temperature and heated under reflux for 18 h. To the reaction mixture, water (1 ml) and 2 N aqueous sodium hydroxide solution (10 ml) were added under ice cooling and the mixture was extracted with diethyl ether; the organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 110 mg of the titled compound quantitatively.
Reaction SMILES: [CH2:1]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]2[C:18]3[C:23]([CH:24]=[C:9]2[C:8]1=O)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[OH-].[Na+]>O>[CH2:1]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]2[C:18]3[C:23]([CH:24]=[C:9]2[CH2:8]1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1C(=O)c2cc3ccccc3n2Cc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN1Cc2cc3ccccc3n2Cc2ccccc21
Temperature: 0 °C

Procedure:
To a mixture of 8 g of 11-hexyl-6H-indolo[2,1-c][1,4]benzodiazepin-12(11H)-one, the product of Example 12, 1.5 g of lithium aluminum hydride and 100 ml of THF were added and the mixture was heated to reflux for 4 hours. The reaction mixture was cooled to 0° C. and then 1.5 ml of water, 1.5 ml of 15% NaOH solution and 4.5 ml of water were sequentially added. The resultant white solid was filtered off and the solvent was stripped off to give the titled compound. Recrystallization from i-PrOH gave a colorless solid, mp 45° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:22](B(O)O)=[CH:21][N:20]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:19]=2)=[CH:14][CH:13]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:22]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[CH:7]=3)=[CH:21][N:20]([C:26]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][CH:17]=1
Reactant: Brc1ccc2nccn2c1
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3nccn3c2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
2.2 g 6-bromoimidazo[1,2-a]pyridine, 6 g 3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 25), and 647 mg tetrakistriphenyl phosphine palladium were heated in a solution mixture of 30 mL ethanol, 30 mL toluene and 17 mL of 2 N aqueous sodium carbonate at 80° C. for 2 hours in a stream of nitrogen. The reaction solution was cooled to room temperature, ethyl acetate was added thereto, and the organic layer was dried over magnesium sulfate. After filtration, the organic solvent was evaporated, and the residue was dissolved in dichloromethane and purified by NH silica gel (hexane/ethylacetate). The resulting solid was recrystallized from ethyl acetate/hexane, to give 4.65 g of the title compound as colorless crystals.
Reaction SMILES: C([Li])(CC)C.[CH3:6][O:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11].CN(C)CCN(C)C.[CH:29](=[O:32])[CH2:30]C>O1CCCC1.C(OCC)C>[OH:32][CH:29]([C:17]1[C:9]([C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11])=[C:8]([O:7][CH3:6])[CH:20]=[CH:19][CH:18]=1)[CH3:30]
Reactant: CCN(CC)C(=O)c1ccccc1OC
Reactant: CCC=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1c(OC)cccc1C(C)O
Temperature: -78 °C

Procedure:
13.7 ml of sec-butyllithium (1.4M in cyclohexane/isopentane) are added dropwise to a solution of 5.2 g of 2-methoxy-N,N-diethyl-benzamide and 2.91 g of tetramethylethylenediamine in 50 ml of absolute tetrahydrofuran in such a manner that the temperature does not exceed -68° C. When the addition is complete, the reaction mixture is stirred at -78° C. for a further hour and then 2.5 ml of propionaldehyde are added. The reaction mixture is allowed to warm slowly to room temperature, is subsequently stirred for one hour and is diluted with 300 ml of diethyl ether. The organic phase is washed with 2N hydrochloric acid and then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated by evaporation to yield 6-(1-hydroxyethyl)-2-methoxy-N,N-diethyl-benzamide in the form of a crude product.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([CH3:19])[N:13]=1.Cl>C(OCCO)C>[CH3:19][C:14]1[N:13]=[C:12]([NH2:11])[N:17]=[C:16]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:15]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Solvent: CCOCCO
Product: Cc1cc(Nc2ccc([N+](=O)[O-])cc2)nc(N)n1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
4-Nitroaniline (B1) [9.22 g, 0.07 mol] and 2-amino-4-chloro-6-methyl pyrimidine (E1) (9.30 g, 0.07 mol) were dissolved in 2-ethoxyethanol (330 mL). To the resulting solution were added a few drops of c.HCl, and the resulting mixture was refluxed for 30 min, and then allowed to cool to room temperature overnight. After this time, the reaction mixture was filtered, and the resulting solid was basified by addition of aqueous ammonia solution, and then crystallized from H2O:EtOH to afford amine E2 as an amorphous bright-yellow solid (7.33 g). Concentration of the filtrate, followed by basification and reprecipitation as before, afforded a further quantity (0.78 g, overall yield 51%). 1H NMR [(CD3)2SO]: 2.14 [s, 3H, ArCH3], 6.00 [s, 1H, ArNHAr], 6.37 [s, 2H, ArNH2], 8.00 [ddd, J=10.24, 5.05, 2.96 Hz, 2H, ArH], 8.12 [ddd, J=10.24, 4.95, 2.90 Hz, 2H, ArH], 9.75 [s, 1H, ArH]. LCMS (APCl+): 246 (100%).