Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.[Cl:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:20])=[CH:8][C:9]=3[S:16]([CH3:19])(=[O:18])=[O:17])=[O:13])[CH2:30][CH2:29]2)=[O:27])=[CH:34][CH:35]=1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Product: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Yield: 33.5 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (138 mg) described in Preparation Example 22 and 4-(4-chlorobenzoyl)piperidine (97 mg) and by the reaction and treatment in the same manner as in Example 87, [4-(4-chlorobenzoyl)piperidin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylphenyl]methanone (76 mg) was obtained. Using the obtained [4-(4-chlorobenzoyl)piperidin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylphenyl]methanone (76 mg) and methylboronic acid (37 mg) and by the reaction and treatment in the same manner as in Example 115, the title compound (37 mg) was obtained.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH2:18]O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)(Cl)[Cl:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH2:18][Cl:21])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cc(-c2ccccc2)c2ccc(O)cc2c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Oc1ccc2c(-c3ccccc3)cc(CCl)cc2c1

Procedure:
To a solution of the alcohol from Step 1 (1.46 g, 5.8 mmoL) in CH2Cl2 (50 mL) was added CCl4 (5.7 mL, 58 mmoL, 10 eq.) followed by Ph3P (3 g, 11.7 mmoL, 2 eq.). The resulting mixture was refluxed for 2 hr. The solvent was evaporated and a purification by flash chromatography on silica gel (hexanes: EtOAc; 8:2) gave the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][C:25]2[N:26]=[C:27]3[CH:33]=[CH:32][N:31]([S:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)(=[O:36])=[O:35])[C:28]3=[N:29][CH:30]=2)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.[Br:43]C(Cl)(Cl)C(Br)(Cl)Cl>O1CCCC1>[Br:43][C:32]1[N:31]([S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:28]2=[N:29][CH:30]=[C:25]([CH2:24][CH2:23][C:17]3[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:15]([O:14][CH3:13])[CH:16]=3)[N:26]=[C:27]2[CH:33]=1
Reactant: COc1cc(CCc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a stirred solution of N,N-diisopropylamine (0.610 mL, 4.25 mmol) in tetrahydrofuran (2.0 mL) at −78° C., n-butyllithium (2.5 M in hexanes, 1.70 mL, 4.25 mmol) was added dropwise. After the white precipitate formed, the mixture was warmed up to 0° C. for 10 minutes. The resulting resulted solution was added to a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (1.30 g, 3.07 mmol) in tetrahydrofuran (10 mL) at 78° C. After 30 min, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (1.10 g, 3.38 mmol) in tetrahydrofuran (6 mL) was added dropwise. After another 1 hour, the reaction mixture was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, and then concentrated. The residue was purified on silica gel (eluting with 0 to 50% EtOAc in hexanes) to give the desired product (1.30 g, 84%). LCMS calculated for C22H21BrN3O4S (M+H)+: m/z=502.0. Found: 502.0; 1H NMR (400 MHz, CDCl3): δ 8.15-8.12 (m, 3H), 7.68-7.58 (m, 1H), 7.51-7.47 (m, 2H), 6.88 (s, 1H), 6.31 (d, J=2.0 Hz, 2H), 6.28 (t, J=2.5 Hz, 1H), 3.72 (s, 6H), 3.16-3.12 (m, 2H), 2.99-2.96 (m, 2H) ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[N:15]1.[I-].[K+].[OH-].[Na+].[CH3:23][S:24]([OH:27])(=[O:26])=[O:25].C(OCC)(=O)C.C(OC(C)C)(C)C>O.C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH3:23][S:24]([OH:27])(=[O:26])=[O:25].[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:14]2[CH:18]=[CH:17][N:16]=[N:15]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCCl)cc1
Reactant: c1c[nH]nn1
Agent: CS(=O)(=O)O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: COc1ccc(CCCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
1-(4-Chlorobutyl)-4-methoxybenzene (950 mg, 4.78 mmol), 1H-1,2,3-triazole (660 mg, 9.55 mmol) and potassium iodide (793 mg, 4.78 mmol) were added to t-butanol (5 ml). Sodium hydroxide (382 mg, 9.55 mmol) was added and the mixture was refluxed under heating for 11 hours. After cooling to room temperature, toluene and water were added and the mixture was partitioned. The organic layer was washed successively with water, 20% citric acid, saturated aqueous sodium hydrogen carbonate and water, and was concentrated under reduced pressure. To the residue were added ethyl acetate (6 ml) and isopropyl ether (3 ml). Methanesulfonic acid (402 mg, 4.18 mmol) was added at room temperature. Ethyl acetate/isopropyl ether=2/1 (2 ml) was added and the mixture was stirred at room temperature for 30 min. The precipitated crystals were collected by filtration and dried under reduced pressure to give 1-[4-(4-methoxyphenyl)-butan-1-yl]-1H-1,2,3-triazole methanesulfonate (1.14 g, yield 73%).
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]1=[O:9])[CH3:2].[NH:10]=[N+:11]=[N-:12].C1(=O)NC(=O)C=C1>C1(C)C=CC=CC=1>[N:10]([CH:5]1[CH2:6][C:7](=[O:8])[N:3]([CH2:1][CH3:2])[C:4]1=[O:9])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=N
Reactant: CCN1C(=O)C=CC1=O
Agent: O=C1C=CC(=O)N1
Solvent: Cc1ccccc1
Product: CCN1C(=O)CC(N=[N+]=[N-])C1=O
Temperature: -30 °C
Yield: 93 %

Procedure:
A solution in toluene of N-ethylmaleimide, HN3 (excess relative to the maleimide), and the (salen)AlN3 catalyst depicted above (10 mol % relative to the maleimide) was maintained at −30° C. for 18 h. After a standard quench and work-up of the reaction mixture, the crude material was purified to yield 2-azido-N-ethylsuccinimide (93%, 93% ee).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH3:70])[CH2:12][CH2:13][C@@H:14]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:34](=[O:62])[C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][CH:44]([C@H:47]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=4[C:55]4[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=4)[OH:48])[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)(=[O:32])=[O:31])=[CH:26][C:25]=1[S:63]([C:66]([F:69])([F:68])[F:67])(=[O:65])=[O:64])[CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(C(C)(C)C)(C)C.Cl>O1CCOCC1.CO>[Cl:61][C:58]1[CH:59]=[CH:60][C:55]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[C@H:47]([OH:48])[CH:44]2[CH2:43][CH2:42][N:41]([C:38]3[CH:39]=[CH:40][C:35]([C:34]([NH:33][S:30]([C:27]4[CH:28]=[CH:29][C:24]([NH:23][C@H:14]([CH2:13][CH2:12][N:11]([CH2:10][CH2:9][OH:8])[CH3:70])[CH2:15][S:16][C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[C:25]([S:63]([C:66]([F:67])([F:68])[F:69])(=[O:64])=[O:65])[CH:26]=4)(=[O:31])=[O:32])=[O:62])=[CH:36][CH:37]=3)[CH2:46][CH2:45]2)=[CH:56][CH:57]=1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN(CCO)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 80.1 %

Procedure:
To a solution of N-(4-((R)-4-((2-(tert-butyldimethylsilyloxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)-4-(4-((R)-(4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzamide (INTERMEDIATE 34, 2.96 g, 2.51 mmol) in dioxane (5.03 ml) and methanol (5.03 ml) was added slowly HCl (4M in dioxane, 15.08 ml, 60.33 mmol). Approximately half way through addition, a slight exotherm was noted, and the reaction was cooled to 0° C. Addition of hydrochloric acid in dioxane (4M) continued, and once complete, the ice bath was removed. The resulting yellow solution was allowed to warm to r.t. and stirred for 3 min before being concentrated under reduced pressure to half volume and diluted with ethyl acetate. The resulting mixture was washed with sodium bicarbonate (saturated, aqueous) and sodium chloride (saturated, aqueous) before being dried over sodium sulfate, filtered, and concentrated. Upon concentration, a thick oily residue precipitated out of solution and this material was redissolved in acetone before being reconcentrated to a beige film. This film was dissolved in 10% methanol in ethyl acetate and purified by column chromatography (ISCO, 330 g SiO2, isocratic 15% methanol in ethyl acetate for 30 min) to afford the title compound (1.90 g, yield: 80%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23].N1C2C(=CC=CC=2)[C:26]2([C:36]3=CC4OCOC=4[CH:43]=[C:35]3[O:34][CH2:33]2)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[O:34]1[CH2:33][CH2:26][CH2:36][C@@H:35]1[CH2:43][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc3c(cc12)OCCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 1′-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one was obtained (80%) as a colorless solid: mp 134-138° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.29 (dd, J=7.8, 7.8 Hz, 1H), 7.14-7.01 (m, 3H), 6.58 (s, 1H), 6.36 (s, 1H), 4.91 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.31-4.18 (m, 2H), 4.12-4.04 (m, 2H), 4.01-3.68 (m, 5H), 2.21-1.85 (m, 5H), 1.77-1.66 (m, 1H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.0, 177.8, 156.8, 153.0, 146.3, 143.0, 142.9, 132.3, 132.2, 128.94, 128.90, 123.9, 123.8, 123.4, 123.34, 123.28, 116.14, 116.10, 109.8, 109.6, 103.5, 80.58, 77.1, 76.9, 70.9, 68.4, 68.3, 58.04, 58.02, 44.7, 32.3, 29.4, 29.1, 25.9, 25.7; MS (ES+) m/z 394.1 (M+1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[C:8]([F:10])[CH:9]=1.I[CH2:18][CH:19]([CH3:24])[O:20][CH2:21][CH2:22]I>C1COCC1>[CH2:15]([O:14][C:12]([C:11]1([C:6]2[CH:5]=[C:4]([F:3])[CH:9]=[C:8]([F:10])[CH:7]=2)[CH2:22][CH2:21][O:20][CH:19]([CH3:24])[CH2:18]1)=[O:13])[CH3:16]
Reactant: CC(CI)OCCI
Reactant: CCOC(=O)Cc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2cc(F)cc(F)c2)CCOC(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
Sodium hydride (60% w/w dispersion in mineral oil, 9.17 g) was added portionwise to a solution of ethyl 3,5-difluorophenylacetate (17 g) in THF (400 ml) and the mixture was stirred at ambient temperature for 1 hour. A solution of 1,5-diiodo-2-methyl-3-oxapentane (30.3 g) in THF (20 ml) was added dropwise and the mixture was stirred at ambient temperature for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using a 19:1 v/v mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate as eluent. There was thus obtained, as a mixture of diastereoisomers, 4-ethoxycarbonyl-4-(3,5-difluorophenyl)-2-methyltetrahydropyran (16.5 g). The mixture of diastereoisomers was separated by further chromatography using a 10:1 v/v mixture of petroleum ether (b.p 40°-60° C.) and ethyl acetate as eluent. There was thus obtained:
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].Cl>CO.O1CCOCC1>[C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)(=[O:5])[CH3:4]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of NaOH (1.7 g/12 ml) was added to methyl 4-acetylbenzoate (5.04 g, 28.3 mmol) in MeOH-dioxane (2:1, 60 ml). After stirring at room temperature for 12 hr, the mixture was acidified with 5N HCl, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4. Evaporation of solvent gave 4-acetylbenzoic acid as a white solid.
Reaction SMILES: C[N:2]([CH3:5])C=O.[CH2:6]([O:8][CH:9]([O:13][CH2:14][CH3:15])[CH2:10]CCl)[CH3:7]>C(O)C.[Pd]>[CH2:6]([O:8][CH:9]([O:13][CH2:14][CH3:15])[CH2:10][CH2:5][NH2:2])[CH3:7]
Reactant: CN(C)C=O
Reactant: CCOC(CCCl)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(CCN)OCC
Temperature: 60 °C
Reaction time: 96 h
Yield: 63 %

Procedure:
To 500 mL of dimethylformamide (DMF) containing Nan3 (26.0 g, 400 mmol) was added 3-chloropropionaldehyde diethyl acetal (33.3 g, 200 mmol). The solution was warmed to 60° C., and the reaction was monitored by GC (50° C., 1 min to 250° C. at 15° C./min, DB5-15m). (Retention time (tR) of starting material 5.1 min, product 6.5 min). The reaction mixture was diluted with 1 L of ice water and extracted with ether (3×500 mL). The combined ether extracts were washed with water (2×500 mL) and then dried over MgSO4. Removal of solvent afforded a crude product, which was dissolved in 500 mL of ethanol containing Pd/C (10%, 2.03 g, 2 mmol). The suspension was degassed, saturated with H2, and stirred under an H2 balloon for four days at which time GC analysis of the product amine (tR 5.4 min) indicated a complete reaction. The solution was degassed and filtered through Celite 545, and the solvent was removed under reduced pressure. The residue was diluted with 25 mL of 12 N KOH and extracted with ether (2×50 mL). The ether layer was filtered through glass wool/Na2CO3 and dried over Na The solvent was removed under water aspirator vacuum, and the residue was distilled to yield 3-aminopropanal diethylacetal (18.6 g 126 mmol, 63%): bp17 80°-81.5° C. (bp20 68°-70° C. agreed with b.p. in Becke, F. German Patent 845,348, 1952, Chem. Abstr. 47 (1952) 542); 1H-NMR (200 MHz CDCl3) δ 1.21 (t, 6 H, CH3), 1.58 (s, 2 H, NH2), 1.78 (q. 2 H CH2). 2.81 (t, 2 H, NCH2), 3.53 and 3.66 (m, 4 H, OCH2), 4.62 (t, 1 H, CH). Anal. Calcd for C7H17NO2 : C, 57.1; H, 11.6. Found: C, 57.1; H, 11.5.
Reaction SMILES: [I:1]I.[CH2:3]([O:5][C:6](=[O:22])[C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[NH:8][CH:9]=[O:10])[CH3:4]>C(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[CH2:3]([O:5][C:6](=[O:22])[C@H:7]([CH2:11][C:12]1[C:17]([I:1])=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[NH:8][CH:9]=[O:10])[CH3:4]
Reactant: II
Reactant: CCOC(=O)[C@H](Cc1ccc(OC)c(OC)c1)NC=O
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cc(OC)c(OC)cc1I)NC=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.3 %

Procedure:
Iodine (2.1 g, 8.3 mmol) was added to a solution of dimethoxy derivative 2 (2.1 g, 7.5 mmol) and silver trifluoroacetate (2.0 g, 9.1 mmol) in methylene chloride (110 mL) and the reaction mixture was stirred at room temperature for 48 h. The yellow precipitate that formed was filtered and washed with methylene chloride. The combined filtrates were washed with 1M Na2S2O5 (2×75 mL), water (2×75 mL), dried and concentrated under reduced pressure to give a solid residue. Recrystallization of this residue from ethyl acetate and petroleum ether gave a white solid 3 (2.3 g, 75%); m.p. 151°-152° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.[C:21]1(=O)[CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:21]1([N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)[CH2:5][CH2:6]2)[CH2:24][CH2:23][CH2:22]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CCNCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC2CCN(C3CCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-(4-piperidinylmethyl)-1-piperidinecarboxylate (may be prepared as described in Description 2) (4.8 g), cyclobutanone (3.81 ml) and triethylamine (4.7 ml) were stirred in DCM (200 ml) at room temperature. After 10 min sodium triacetoxyborohydride (7.2 g) was added and the reaction was stirred at room temperature overnight. The reaction mixture was evaporated and redissolved in dichloromethane (50 ml). After washing with saturated potassium carbonate solution (2×50 ml), saturated sodium hydrogen carbonate solution (2×50 ml) and saturated brine (50 ml) the organic phase was dried (MgSO4) and evaporated to give the title compound (D5) as a colourless solid (5.72 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([N+:11]([O-])=O)=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:3]=1.[H][H]>O1CCCC1.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[C:5]([NH2:11])=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:3]=1
Reactant: CC(C)c1cc(Cl)nc(C(C)C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)c1cc(Cl)nc(C(C)C)c1N

Procedure:
30.0 g of 6-chloro-2,4-diisopropyl-3-nitropyridine are dissolved in 450 ml of tetrahydrofuran and, after the addition of 30.0 g of Raney nickel (suspended in ethanol), hydrogenated under a hydrogen pressure of 20 bar at from +30° C. to +35° C. The reaction mixture is filtered over diatomaceous earth and the filtrate is concentrated. The residue is purified by column chromatography on silica gel (eluant: ethyl acetate/hexane 3). 6-Chloro-2,4-diisopropyl-3-aminopyridine is obtained in the form of a clear crystalline powder, m.p. 53°-56° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C@H:10]([C:22]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=[CH:31]3)[CH2:27][CH2:26][CH2:25][N:24]4[CH:23]=2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.CCN(C(C)C)C(C)C.[CH:50]([S:53](Cl)(=[O:55])=[O:54])([CH3:52])[CH3:51]>C(Cl)Cl>[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([C@@H:11]2[CH2:12][N:8]([S:53]([CH:50]([CH3:52])[CH3:51])(=[O:55])=[O:54])[CH2:9][C@H:10]2[C:22]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=[CH:31]3)[CH2:27][CH2:26][CH2:25][N:24]4[CH:23]=2)=[CH:14]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41787.4 %

Procedure:
To a solution of (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 450 μmol) in DCM (5 mL) under a nitrogen atmosphere was added 4M HCl in dioxane (1.7 mL, 6.8 mmol). The mixture was stirred at room temperature for 2 h. The solvent was then removed under vacuum and the residue dissolved in DCM (5 mL). DIPEA (320 μL, 1.8 mmol) and isopropylsulfonyl chloride (77 mg, 0.54 μmol) were added and the mixture stirred at room temperature for 16 h. The solvent was removed under vacuum and the residue dissolved in DCM, washed with saturated sodium carbonate solution and water and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/hexanes) to yield 1-[(3R,4R)-4-(1H-indol-3-yl)-1-(propane-2-sulfonyl)-pyrrolidin-3-yl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline as a white solid (101 mg, 50%). M.p.=100-115° C.; 1H NMR (400 MHz, DMSO-d6) δ: 10.85 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.23 (s, 1H), 7.03 (t, J=7.2 Hz, 1H), 6.94 (t, J=7.2 Hz, 1H), 6.86 (t, J=7.6 Hz, 1H), 6.78 (d, J=7.2 Hz, 1H), 4.07-3.95 (m, 6H), 3.55-3.46 (m, 3H), 2.84 (t, J=6.0 Hz, 2H), 2.05 (t, J=5.6 Hz, 2H), 1.32 (m, 6H). LCMS: m/e 448.13 [M+H].
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][C:18]([OH:32])([C:21](=[O:31])[NH:22][CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[NH2:14][CH:15]1[CH2:20][CH2:19][C:18]([OH:32])([C:21]([NH:22][CH:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:24])=[O:31])[CH2:17][CH2:16]1
Reactant: CC(NC(=O)C1(O)CCC(NC(=O)OC(C)(C)C)CC1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)C1(O)CCC(N)CC1)c1ccccc1

Procedure:
Trifluoroacetic acid (1.5 ml) was added to a solution of crude [4-hydroxy-4-(1-phenyl-ethylcarbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (320 mg) in dichloromethane (6.0 ml). The reaction was judged to be complete by LCMS in less than 90 minutes. The reaction was diluted with dichloromethane and quenched to pH 12 using 5N sodium hydroxide. The crude product was extracted with two volumes of dichloromethane, dried over sodium sulfate, filtered and concentrated to 4-amino-1-hydroxy-cyclohexanecarboxylic acid (1-phenyl-ethyl)-amide (210 mg). LCMS M+H=263.2.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]([N:33]3[CH2:34][CH2:35][N:30]([C:28]4[S:27][N:26]=[C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[N:29]=4)[CH2:31][CH2:32]3)=[O:18])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(Nc1ccc2ncsc2c1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccc2ncsc2c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 20.3 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl 1,3-benzothiazol-6-ylcarbamate (240 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 63.2 mg (20.3%) of the desired product as a solid.