Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:13]2[NH:12][N:11]=[N:10][C:9]=2[C:8]2[CH2:7][C:6]34[CH2:24][CH:16]([C:17](=[O:23])[C:18]([C:19]([F:22])([F:21])[F:20])=[C:5]3[C:4]=2[CH:3]=1)[CH2:15][CH2:14]4>CN(C=O)C.ClCCl.[OH-].[OH-].[Pd+2].[Pd]>[F:21][C:19]([F:20])([F:22])[C:18]1[C:17](=[O:23])[CH:16]2[CH2:24][C:6]3([CH2:7][C:8]4[C:9]5[N:10]=[N:11][NH:12][C:13]=5[CH:2]=[CH:3][C:4]=4[C:5]=13)[CH2:14][CH2:15]2
Reactant: O=C1C(C(F)(F)F)=C2c3cc(Cl)c4[nH]nnc4c3CC23CCC1C3
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1C(C(F)(F)F)=C2c3ccc4[nH]nnc4c3CC23CCC1C3
Reaction time: 29 h

Procedure:
To a solution of 4-chloro-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta-[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one (2.3 g, crude product from the preceding step, ˜6.1 mmol) in DMF (230 mL) were added 20% Pd(OH)2 on carbon (1 g) and 5% palladium on calcium carbonate (1 g) and the mixture was hydrogenated at atmospheric pressure. After 29 hours, additional 20% Pd(OH)2 on carbon (175 mg) and 5% palladium on calcium carbonate (175 mg) were added. After 24 hours more, the mixture was filtered through a pad of Celite®, washing thoroughly with EtOAc. The filtrate was partitioned between EtOAc and water which had been acidified with a small amount of 1N hydrochloric acid. The aqueous layer was thoroughly extracted with EtOAc and the combined organic layers were washed with 1N hydrochloric acid, water and brine. After drying over MgSO4, the solvent was removed under reduced pressure to give an oily solid which was dissolved in dichloromethane and evaporated to give a solid. Chromatography on silica gel (elution with 1:1 EtOAc/hexanes+0.1% HOAc followed by 99:99:2 EtOAc/hexanes/methanol+0.1% HOAc) gave 6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta-[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:28])[C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=[O:23])=[CH:14][CH:13]=2)=[C:6]([CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[C:31](C1C=CC(N(CC2C=CC(C(O)C3C=C(C=CC=3)C#N)=CC=2)C)=C(C)C=1O)(=O)C>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([OH:28])[C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=[O:23])=[CH:16][CH:17]=2)[CH3:31])=[C:6]([CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N(C)Cc2ccc(C(O)c3cccc(C#N)c3)cc2)c(C)c1O
Reactant: CC(=O)c1ccc(NCc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)c(C)c1O
Product: CC(=O)c1ccc(N(C)Cc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)c(C)c1O

Procedure:
The title compound is prepared essentially as described for 3-({4-[(4-acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-phenyl}-hydroxy-methyl)-benzoic acid employing 3-[(4-{[(4-acetyl-3-hydroxy-2-methyl-phenyl)-methyl-amino]-methyl}-phenyl)-hydroxy-methyl]-benzonitrile. LC-MS (m/e): 420 (M+1). 1H NMR (DMSO-d6) δ 12.87 (1H, s), 7.91 (1H, m), 7.73 (1H, m), 7.63 (1H, d), 7.57 (1H, m), 7.37 (1H, dd), 7.29 (2H, d), 7.19 (2H, d), 6.55 (1H, d), 5.71 (1H, s), 4.17 (2H, s), 2.62 (3H, s), 2.50 (s, 3H), 2.08 (3H, s).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([O:16]C2C=CC=CC=2)=O)=[CH:6][CH:5]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([C:34]#[N:35])[CH:27]=1>>[C:34]([C:28]1[C:29]([C:32]#[N:33])=[CH:30][N:31]=[C:26]([NH:25][C:14]([N:11]2[C:12]3[C:7](=[CH:6][CH:5]=[C:4]([CH:3]([O:2][CH3:1])[O:23][CH3:24])[N:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:16])[CH:27]=1)#[N:35]
Reactant: N#Cc1cnc(N)cc1C#N
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Oc1ccccc1)CCC2
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(C#N)c(C#N)cn1)CCC2

Procedure:
From intermediate 3 and 6-aminopyridine-3,4-dicarbonitrile, reacted in an analogous manner to the preparation of intermediate 2. (UPLC-MS 1) tR 1.15 min, ESI-MS 379.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11](=O)[CH3:12])=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:9](=[O:14])[CH:10]=[C:11]2[CH3:12]
Reactant: CC(=O)CC(=O)Nc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: Cc1cc(=O)[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 50.0 g (195 mmol) of N-(4-bromophenyl)-3-oxobutyramide in 217 mL of concentrated sulfuric acid was heated to 120° C. for 1 hour. After cooling to RT, the reaction solution was added to 1.5 L of ice water, stirred for 30 minutes, and the precipitate formed was filtered and washed with 4 L of water. Subsequently it was dried at 35° C. in the circulating air dryer until a constant weight was achieved. Yield: 24.0 g (52% of theoretical); C10H8BrNO (M=238.081); calc.: molpeak (M+H)+: 238/240 (Br); found: molpeak (M+H)+: 238/240 (Br); HPLC-MS: 4.8 minutes (method B).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH:21][CH2:22][C:23]1([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.CC(C)([O-])C.[K+]>O1CCCC1.C(=O)(O)[O-].[Na+]>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:5]2[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:3]([CH2:2][O:21][CH2:22][C:23]3([C:36]4[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=4)[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[CH2:27][CH2:28]3)[CH:4]=2)=[CH:14][CH:15]=1)#[N:20]
Reactant: N#Cc1ccc(-c2cc(CBr)cc(C(F)(F)F)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccncc2)CC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A flask was charged with 3′-(bromomethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (157 mg, 0.462 mmol) and tert-butyl 4-(hydroxymethyl)-4-(pyridin-4-yl)piperidine-1-carboxylate (90 mg, 0.308 mmol) in tetrahydrofuran (10 mL) at 0° C. The reaction was treated with potassium tert-butoxide (34.6 mg, 0.308 mmol), stirred at 0° C. for 20 min, and treated with another aliquot of potassium tert-butoxide (34.6 mg, 0.308 mmol). The reaction was allowed to warm to room temperature for 30 min, then diluted with 10% sodium bicarbonate, and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (1×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (0%→65% ethyl acetate/hexanes) gave 50 mg (29%). Mass spec.: 552.18 (MH)+ LC tr=2.54 min (HPLC Method 1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[C@H:19]([C:20]3[C:30]4=[C:31]5[C:26](=[CH:27][CH:28]=[CH:29]4)[CH2:25][CH2:24][CH2:23][N:22]5[CH:21]=3)[C:18](=[O:32])[NH:17][C:16]2=[O:33])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd]>[C:20]1([C@H:19]2[C@H:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:16](=[O:33])[NH:17][C:18]2=[O:32])[C:30]2=[C:31]3[C:26](=[CH:27][CH:28]=[CH:29]2)[CH2:25][CH2:24][CH2:23][N:22]3[CH:21]=1
Reactant: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccc(O)cc1
Yield: 44.1 %

Procedure:
A mixture of (±)-trans-3-[4-(benzyloxy)phenyl]-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrrolidine-2,5-dione (0.2 g) and Pd/C (10% w/w, 0.076 g) was stirred under 1 atmosphere of hydrogen gas overnight. The catalyst was filtered off through a pad of celite and concentrated. The residue was purified by column chromatography on silica gel eluting with 30-40% ethyl acetate in hexane to provide (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(4-hydroxyphenyl)pyrrolidine-2,5-dione 0.07 g as a light yellow solid. Mp 105-107° C.; 1H NMR (acetone-d6) 400 MHz δ: 10.27 (s. 1 H), 8.34 (s, 1 H), 7.17-7.21 (m, 4 H), 6.80-6.91 (m, 4 H), 4.39 (d, J=7.0 Hz, 1 H), 4.22 (d, J=7.0 Hz, 1 H), 4.13 (d, J=5.6 Hz, 2 H), 2.92 (d, J=5.2 Hz, 2 H), 2.15-2.19 (m, 2 H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][N:14]=3)[CH:11]=2)[N:6]([C:27](=[O:29])[CH3:28])[C@@H:5]([CH3:30])[CH2:4]1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C(#N)C.C(=O)(O)[O-].[NH4+].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]>[CH3:30][C@H:5]1[CH2:4][C@@H:3]([NH:2][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][N:14]=3)[CH:11]=2)[N:6]1[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](N)C[C@@H]1C
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC#N
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Temperature: 130 °C
Yield: 38 %

Procedure:
1-((2S,4R)-4-amino-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone hydrochloride (for a preparation see Intermediate 65) (100 mg, 0.232 mmol), 2-bromopyridine (0.044 mL, 0.464 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (18.3 mg, 0.046 mmol), tris(dibenzylideneacetone)dipalladium(0) (21.3 mg, 0.023 mmol) and sodium tert-butoxide (66.9 mg, 0.696 mmol) were combined in 1,4-dioxane (2 mL) and the mixture degassed over a period of 15 mins, before being heated under microwave irradiation to 130° C. for 25 mins. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (50 mL) and DCM (3×50 mL). The organics were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue which was dissolved in acetonitrile (20 mL) and 0.1M aq. ammonium bicarbonate (20 mL). The mixture was filtered, and the filtrate concentrated in vacuo to give a residue which was purified by MDAP (HpH) to give 1-((2S,4R)-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone (41 mg, 0.087 mmol, 38% yield). LCMS: (Formate, 2 min), Rt=0.55 mins, MH+472
Reaction SMILES: [ClH:1].C(OC([NH:9][C@H:10]([C:18]([O:20][CH2:21][CH2:22][SiH3:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[SiH3:23][CH2:22][CH2:21][O:20][C:18](=[O:19])[C@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH2:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OCC[SiH3]
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)OCC[SiH3]
Reaction time: 1.5 h

Procedure:
30 mL of a 4.0 M solution of HCl in dioxane was added to the Boc-PheOSET from the previous step. The mixture was stirred for 90 minutes. The solvents were evaporated, giving a waxy solid, phenylalanine silylethyl ester hydrochloride (HCl.PheOSET).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[F:30][C:31]1([F:41])[CH2:34][N:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:41][C:31]1([F:30])[CH2:34][N:33]([CH:35]2[CH2:36][CH2:37][N:38]([CH2:18][C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)[CH2:39][CH2:40]2)[CH2:32]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: FC1(F)CN(C2CCNCC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N4CC(F)(F)C4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.139 g, 0.36 mmol), 4-(3,3-difluoroazetidin-1-yl)piperidine (0.075 g, 0.43 mmol) and 4 Å molecular sieves (0.4 g) in DCE (5 mL). The reaction mixture was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.15 g, 0.71 mmol) was added and the reaction mixture was stirred for 72 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 12:88) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 576 as an off-white solid (0.104 g, 53%). LCMS (Method I): RT=2.61 min, [M+H]+ 552.2 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.99 (m, 1 H), 7.65-7.61 (m, 1 H), 7.27-7.20 (m, 2 H), 4.60-3.95 (s, 4 H), 3.81 (s, 3 H), 3.80-3.74 (m, 6 H), 3.52 (t, J=12.3 Hz, 4 H), 3.27 (q, J=7.4 Hz, 2 H), 2.79-2.70 (m, 2 H), 2.20-2.10 (m, 3 H), 1.68-1.59 (m, 2 H), 1.34 (t, J=7.4 Hz, 3 H), 1.30-1.17 (m, 2 H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10]([NH2:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.O>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10]([NH:12][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N)C1
Reactant: Clc1nc2ccccc2s1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Temperature: 110 °C

Procedure:
A mixture of tert-butyl(cis-3-aminocyclobutyl)carbamate (1.26 g, 6.77 mmol), 2-chlorobenzothiazole (0.965 mL, 6.77 mmol) and N,N-diisopropylethylamine (2.354 mL, 13.53 mmol) in DMSO (5 mL) was heated to 110° C. in a sealed microwave vial for 4 h, cooled to room temperature, diluted with water and extracted with EtOAc. EtOAc extract was concentrated and crude material purified with ISCO using silica gel column eluting with 0-80% EtOAc/hexane to give the desired product tert-butyl(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)carbamate (1.5 g, 4.70 mmol, 69.4% yield). m/z: 320.1 (M+1).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C@@H:8]1[CH2:12][NH:11][CH2:10][C@H:9]1[CH2:13][N:14]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16])(C)(C)C.CC#N.O.CC#N>O>[OH:6][CH2:7][C@@H:8]1[CH2:12][NH:11][CH2:10][C@H:9]1[CH2:13][N:14]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16]
Reactant: CC(C)CN(C[C@@H]1CNC[C@H]1C(C)(C)O[SiH2]C(C)(C)C)S(=O)(=O)c1ccccc1
Solvent: O
Solvent: CC#N
Product: CC(C)CN(C[C@@H]1CNC[C@H]1CO)S(=O)(=O)c1ccccc1

Procedure:
The title compound is prepared as described above for Example 9/step H (Scheme 5) from N-[(3S*,4S*)-4-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-3-ylmethyl]-N-isobutyl-benzenesulfonamide. MS (LC-MS): 327.1 [M-Boc+H]+; tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 4.17 min.
Reaction SMILES: CC(C)=CCC/C(/C)=C/CC/C(/C)=C/CN1C(=O)C2C=CC=C(O)C=2N[C:19]2[C:18]([OH:30])=[CH:17][C:16]([OH:31])=CC1=2.C([O:38][C:39](=[O:41])[CH3:40])(=O)C.CCOC(C)=O.O>N1C=CC=CC=1>[CH3:19][C:18]([CH2:17][C:16]([CH2:40][C:39]([OH:38])=[O:41])=[O:31])=[O:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CN1C(=O)c2cccc(O)c2Nc2c(O)cc(O)cc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)CC(=O)CC(=O)O
Reaction time: 1 h

Procedure:
BU-4664L (20 rag) was stirred with acetic anhydride (1.0 ml) in anhydrous pyridine (1.5 ml) for 18 hours at room temperature. To the reaction mixture, EtOAc and water (20 ml each) were added and stirred for one hour. After washing with water (20 ml portions) twice, the organic layer was concentrated to give a yellow solid. The residue was purified by preparative TLC (SiO2, CH2Cl2 -MeOH 20:1) followed by Sephadex LH-20 chromatography using CH2Cl2 -MeOH (4:6) as a developing solvent to give triacetate BU-4664L (2, 13 mg), m.p. >200° C. (dec.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[OH:13].[Br:14][CH2:15][CH:16](OC)OC.C1COCC1.OS(O)(=O)=O>O.CCOC(C)=O>[Br:14][CH2:15][CH:16]1[O:13][C:4]2[CH:5]=[C:6]([S:9]([CH3:12])(=[O:10])=[O:11])[CH:7]=[CH:8][C:3]=2[CH2:2][O:1]1
Reactant: CS(=O)(=O)c1ccc(CO)c(O)c1
Reactant: COC(CBr)OC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Yield: 179.8 %

Procedure:
2-(hydroxymethyl)-5-(methylsulfonyl)phenol (3.3 g, 16.3 mmol), 2-bromo-1,1-dimethoxyethane (19.0 ml, 163 mmol), dry THF (30 ml) and concentrated H2SO4 (5 ml) were heated at 55° C. for 1 h. The reaction mixture was brought to ambient temperature and EtOAc and water were added. The phases were separated and the aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness to give an oil (9.0 g). The oil was crystallizing upon cooling. The product was washed with EtOAc, EtOH and DEE and afforded the pure title compound (4.0 g, 80%). MS m/z (rel. intensity, 70 eV) 308 (M+, 11), 306 (M+, 10), 213 (45), 184 (bp), 77 (35).
Reaction SMILES: C([O:5][C:6](=[O:44])[C@@H:7]([NH:29][C:30]([O:32][CH2:33][C:34]12[CH2:43][CH:38]3[CH2:39][CH:40]([CH2:42][CH:36]([CH2:37]3)[CH2:35]1)[CH2:41]2)=[O:31])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH:17]2[CH2:19][CH:18]2[C:20](=[O:28])[NH:21][C:22]2[NH:23][CH2:24][CH2:25][CH2:26][N:27]=2)=[CH:15][CH:16]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:34]12([CH2:33][O:32][C:30]([NH:29][C@@H:7]([CH2:8][NH:9][C:10]([C:12]3[S:13][C:14]([CH:17]4[CH2:19][CH:18]4[C:20](=[O:28])[NH:21][C:22]4[NH:23][CH2:24][CH2:25][CH2:26][N:27]=4)=[CH:15][CH:16]=3)=[O:11])[C:6]([OH:44])=[O:5])=[O:31])[CH2:43][CH:38]3[CH2:39][CH:40]([CH2:42][CH:36]([CH2:37]3)[CH2:35]1)[CH2:41]2
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(C2CC2C(=O)NC2=NCCCN2)s1)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H](CNC(=O)c1ccc(C2CC2C(=O)NC2=NCCCN2)s1)C(=O)O)OCC12CC3CC(CC(C3)C1)C2

Procedure:
48 mg of the product obtained in step c) were dissolved in 2 ml of dichloromethane and stirred for 3 hours with 1 ml of trifluoroacetic acid under an inert gas atmosphere at room temperature. The solvents were removed in vacuo, the residue was dissolved in acetic acid and the solution was again evaporated to dryness. This procedure was repeated once. The resinous residue was triturated with diethyl ether. After filtration 30 mg of the title compound were obtained as a colourless amorphous powder.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[C:8]([C:11]1[CH:38]=[CH:37][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([NH:21][CH2:22][C@H:23]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:24]([OH:26])=[O:25])=[O:20])=[CH:13][CH:12]=1)(=[NH:10])[NH2:9].[CH2:39]([O:46][C:47](ON1C(=O)CCC1=O)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>CN(C=O)C>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[C:31]1([S:28]([NH:27][C@@H:23]([CH2:22][NH:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][O:15][C:14]2[CH:37]=[CH:38][C:11]([C:8](=[NH:9])[NH:10][C:47]([O:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:48])=[CH:12][CH:13]=2)[C:24]([OH:26])=[O:25])(=[O:30])=[O:29])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: N=C(N)c1ccc(OCCCC(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N=C(NC(=O)OCc1ccccc1)c1ccc(OCCCC(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of the compound (51 mg) obtained in the above (1) in DMF (2 ml) are added N-(benzyloxycarbonyloxy)succinimide (25 mg) and triethylamine (14 μl), and the mixture is allowed to stand at room temperature for one day. The reaction mixture is concentrated under reduced pressure, and the residue is purified by HPLC, and the fractions containing the title compound are concentrated under reduced pressure. To the residue is added a mixture of 1N hydrochloric acid (2 ml) and acetic acid (2 ml), and the mixture is stirred at 50° C. for 13 hours. The reaction mixture is concentrated under reduced pressure, and the resultant is purified by HPLC to give the title compound (3 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:7]2.C(=O)([O-])[O-].[K+].[K+].O.[C:34](Cl)(=[O:36])[CH3:35]>C(OCC)(=O)C>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:34](=[O:36])[CH3:35])[CH2:5]2
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN)C2
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCNC(C)=O)C2
Reaction time: 0.25 h

Procedure:
To a mixture of 8-(4,5,6,7-tetramethoxyindan-2-yl)octylamine (878 mg), potassiumcarbonate (2.54 g),water (16 ml), and ethyl acetate (16 ml) was dropwise added acetyl chloride (0.341 ml) with cooling with ice. After being stirred for 15 min, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate) and then with recrystallization (hexane-ethyl acetate) to give the entitled compound (0.830 g) as crystals.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].C[N+]1C=CN([C:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:27])C=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: C[n+]1ccn(C(=O)N2CCCCC2)c1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCCCC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(piperidine-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was recrystallized (ethanol) (45%). HPLC-MS m/z=367.02 (M+1), Rt: 4.9 min.
Reaction SMILES: N1C=CC=C(C=C[N:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])C=1>CO.C1COCC1.[Pd]>[N:9]1[CH:18]=[CH:17][CH:16]=[C:11]([CH2:12][CH2:13][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:19])[NH:9][CH:18]=2)[CH:10]=1
Reactant: O=c1c2ccccc2ccn1C=Cc1cccnc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=c1[nH]cc(CCc2cccnc2)c2ccccc12

Procedure:
80 g (322 mmol) of an (E/Z) mixture of 4-[2-(pyridin-3-yl)-vinyl-2H-isoquinolin-1-one in 3100 ml of methanol/THF 1:1 are hydrogenated in the presence of 15.2 g of Pd/C (10%). Filtration and concentration by evaporation yield the crude product. Recrystallisation by dissolving in 650 ml of boiling ethanol, hot filtration, cooling and addition of 1 l of diethylether and 0.2 l of hexane yield colourless 4-[2-(pyridin-3-yl)-ethyl]-2H-isochinolin-1-one; m.p. 187-188° C.