Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3=[CH:17][C:18]4[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=4[CH:24]=[C:15]3[N:14]([CH3:29])[C:13]3[CH:30]=[CH:31][C:32](Br)=[CH:33][C:12]=3[N:11]=2)=[CH:6][CH:5]=1.[CH:36]([O:38]CCCC)=[CH2:37].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3=[CH:17][C:18]4[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=4[CH:24]=[C:15]3[N:14]([CH3:29])[C:13]3[CH:30]=[CH:31][C:32]([C:36](=[O:38])[CH3:37])=[CH:33][C:12]=3[N:11]=2)=[CH:6][CH:5]=1
Reactant: C=COCCCC
Reactant: COC(=O)c1ccc(C2=Nc3cc(Br)ccc3N(C)c3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2=Nc3cc(C(C)=O)ccc3N(C)c3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-(2-bromo-5,7,7,10,10-pentamethyl-7,8,9,10-tetrahydro-5H-5,13-diazabenzo[4,5]cyclohepta[1,2-b]naphthalen-12-yl)benzoic acid methyl ester (16, R5=CH3, Z=H, 1.9 mmol), butyl vinyl ether (4.8 mmol), Pd(OAc)2 (0.058 mmol), DPPP (0.11 mmol), K2CO3 (2.3 mmol), and H2O (0.3 mL) in DMF (5 mL) is stirred at 120° C. for 1.5 h under nitrogen atmosphere. After cooling to room temperature, the mixture is poured into 1N HCl and extracted twice with EtOAc. The combined extracts are washed with H2O, brine, dried over MgSO4 and evaporated in vacuo. The residue is purified by flash column chromatography (SiO2; hexane: EtOAc=9:1 to 3:1) to give the ester (19) (R4=CH3, Z=H, R5=CH3) as yellow solid.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[N:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:9]1([N:6]2[C:5]3[CH:15]=[CH:16][C:2]([C:20]4[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1ccc2c(c1)ncn2-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: c1ccc(-n2cnc3cc(-c4ccncc4)ccc32)cc1
Yield: 66.2 %

Procedure:
5-Bromo-1-phenyl-1H-benzoimidazole (11) (13.4 g, 49.1 mmol), 4-pyridylboronic acid (6.63 g, 54.0 mmol), palladium(II) acetate (551 mg, 2.45 mmol) and triphenylphosphine (1.93 g, 7.36 mmol) were stirred in 80 mL of n-PrOH in a flask equipped with a reflux condenser, under Ar. Sodium carbonate (6.24 g, 58.9 mmol) was dissolved in 30 mL of water and the resulting solution was added to the nPrOH mixture. The resulting mixture was degassed three times by alternating vacuum and argon atmoshphere. The reaction was then heated to reflux. After 18 h the reaction as cooled, diluted with water and extracted three times with EtOAc. The combined extracts were washed with sat. NaCl (aq), dried over sodium sulfate, filtered and concentrated. Purification by flash column chromatography (95:5 CH2Cl2/MeOH) afforded 8.82 g of 1-phenyl-5-pyridin4-yl-1H-benzoimidazole (66% yield). 1H NMR (CDCl3) δ8.68 (d, J=6.0 Hz, 2H), 8.18 (s, 1H), 8.17 (s, 1H), 7.63-7.59 (m, 6H), 7.56-7.51 (m, 3H). Mass Spectrometry (for C18H13N3): [M+H]+ 272.1182, theoretical 272.1182.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:30])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c5) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: C1(C)C=CC=CC=1.C(OC([NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][CH:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][CH2:19]2)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][CH:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][CH2:19]2
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)OC(C)(C)C)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CCc2cc(N)ccc2O1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
Into the ethyl 2-(6-(tert-butyloxycarbonylamino)chroman-2-yl)acetate toluene solution of Example 3 (7 L) was added 1480 g of trifluoroacetic acid. The solution was warmed to 60° C. for 2 h. After distilling-off about 2 L of toluene under reduced pressure (T≦60° C.), the mixture was cooled to room temperature. About 10 L of 10% (w/w) of aqueous sodium bicarbonate was added slowly to the well-stirred mixture until the pH was above 7. The mixture was stirred for 20 min and the aqueous fraction separated. The aqueous fraction was extracted with 3×1 L of toluene. The combined organic fractions were washed with 3 L of brine, dried over 200 g of anhydrous sodium sulfate, and filtered. The volume of solvent was reduced to 6 L by distillation under reduced pressure (T≦60° C.) to provide a toluene solution of ethyl 2-(6-aminochroman-2-yl)acetate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:23][CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:40]>C(Cl)Cl.O1CCOCC1>[ClH:40].[ClH:40].[CH:34]1([C:18]2[N:17]=[N:16][C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:20][C:19]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:23][CH:22]=2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCCCC3)nn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1cc(-c2cc(OC3CCNCC3)nnc2C2CCCCC2)ccc1OC1CCCCC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.40 mmol, 0.08 g) in THF (0.45 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (0.54 mmol, 0.022 g) and continued stirring for 10 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 6-chloro-3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-pyridazine (0.27 mmol, 0.10 g) in THF (0.45 mL). After completion of addition, the reaction mixture was warmed to 65° C. and stirred for 2 hours. After cooling the reaction to room temperature, the reaction was quenched with water (1 mL) and extracted with ethyl acetate (1×2 mL). The ethyl acetate layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 4 g SiO2 cartridge eluting with an ethyl acetate/hexanes gradient to give 4-[6-cyclohexyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 81%). To a solution of 4-[6-cyclohexyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.22 mmol, 0.12 g) in DCM (1.5 mL) was added 4 N HCl in dioxane (0.5 mL) and the reaction was stirred for 30 min. The solvents were removed under reduced pressure and the residue was triturated with anhydrous ethyl ether (50 mL) and filtered to give 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.095 g).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.FC(F)(F)C(O)=O.[NH:20]1[CH2:24][CH2:23][CH:22]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)(=[O:36])=[O:35])[CH2:21]1>>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([N:20]3[CH2:24][CH2:23][CH:22]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[NH:33][S:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)(=[O:35])=[O:36])[CH2:21]3)[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2sc(Cl)nc12
Reactant: O=S(=O)(Nc1ccccc1OCC1CCNC1)c1ccccn1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2sc(N3CCC(COc4ccccc4NS(=O)(=O)c4ccccn4)C3)nc12

Procedure:
Compound 32 is prepared using synthesis method 3 using intermediates 2c and 6b (yield: 51%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C[Al](C)C.CO[C:12]([C:14]1[CH:19]=[C:18]([NH2:20])[N:17]2[N:21]=[C:22]([C:24]3[O:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[N:23]=[C:16]2[CH:15]=1)=[O:13].Cl>O1CCOCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:12]([C:14]1[CH:19]=[C:18]([NH2:20])[N:17]2[N:21]=[C:22]([C:24]3[O:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[N:23]=[C:16]2[CH:15]=1)=[O:13])[CH3:2]
Reactant: COC(=O)c1cc(N)n2nc(-c3ccc(C)o3)nc2c1
Reactant: CCNCC
Agent: C[Al](C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)C(=O)c1cc(N)n2nc(-c3ccc(C)o3)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 35 mg (0.44 mmol) diethylamine in 0.5 ml dioxane was added 0.5 ml methylaluminoxane (10% in toluene) (in a variant trimethylaluminium was used instead of methylaluminoxane which proofed to give comparable results) and stirred for 1 h at room temperature. 31 mg (0.11 mmol) 5-Amino-2-(5-methyl-furan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid methyl ester in 1 ml dioxane was added and the mixture was heated to 80° C. for 72 h. After addition of 0.4 ml 1N HCl the mixture was evaporated to dryness and the residue was taken up in 1.5 ml DMSO, filtered, and the title compound was isolated by reversed phase HPLC eluting with a water/acetonitrile gradient to yield 8.6 mg (25%).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:3]1=2.C(N(CC)CC)C.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>C(Cl)Cl>[O:1]=[S:2]1(=[O:16])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:24]([CH:25]([CH3:27])[CH3:26])=[O:28])[CH:13]=[CH:14][C:3]1=2
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccc2c(c1)-c1ccccc1S2(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)Nc1ccc2c(c1)-c1ccccc1S2(=O)=O
Yield: 46.1 %

Procedure:
5,5-Dioxo-2-aminodibenzothiophene (J Med Chem, (1994), 37 (13), 2085-9; 231 mg, 1.0 mmol) was suspended in a solution of DCM (10 ml) and triethylamine (111 mg, 1.1 mmol). iso-Butyrylchloride (106.5 mg, 1.0 mmol) was added dropwise and the resultant mixture was stirred for 16 hours at ambient temperature. The mixture was evaporated in vacuo and the residue was purified by chromatography (Bond Elut column) eluting with 0-2.5% methanol in DCM to give the product as a colourless solid (139 mg). NMR: 10.38 (brs, 1H), 8.37 (s, 1H), 7.85-8.00 (m, 3H), 7.80 (d, 1H), 7.74 (d, 1H), 7.63 (t, 1H), 2.66 (m, 1H), 1.13 (d, 6H); m/z 302.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[C:6]([C:8](=O)[CH2:9]Cl)[CH:7]=1.[OH-].[Na+].[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:12]([CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[CH:9]=[CH:8]2
Reactant: CN1CCC(Nc2ccc(Br)cc2C(=O)CCl)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(n2ccc3cc(Br)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 59.2 %

Procedure:
To an ice cold solution of compound 79 (583 mg, 1.526 mmol) in 95% ethanol (25 mL) was added 1M sodium hydroxide (1.526 mL, 1.526 mmol) followed by sodium borohydride (28.9 mg, 0.763 mmol) and the mixture stirred under ice cooling for 45 minutes. The reaction was quenched with ice cold H2O (25 mL), diluted with CH2Cl2, transferred to a separatory funnel and the organic layer separated. The aqueous layer was further extracted with CH2Cl2 (twice) and the combined organic layers washed with brine, dried over sodium sulfate and concentrated to residue. The residue was taken up in anhydrous dioxane (25 mL) and heated to reflux for 3 hours. After cooling to room temperature the reaction was treated with ice-cold 2N potassium carbonate, diluted with CH2Cl2, transferred to a separatory funnel and the organic layer separated. The aqueous layer was further extracted with CH2Cl2 (twice) and the combined organic layers washed with water (twice), brine, dried over sodium sulfate concentrated under reduced pressure and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2 2.5:97.5 to 5:95) to yield an off white solid, 80 (265 mg, 59.3%). 1H NMR (DMSO-d6) δ 1.83-1.93 (m, 2H), 1.95-2.04 (m, 2H), 2.13 (dt, 2H, J=11.5, 2.2 Hz), 2.23 (s, 3H), 2.89 (d, 2H, J=11.4 Hz), 4.28-4.35 (m, 1H), 6.44 (d, 1H, J=3.1 Hz), 7.22 (dd, 1H, J=8.7, 1.8 Hz), 7.51-7.56 (m, 2H), 7.72 (d, 1H, J=1.9 Hz); ESI-MS (m/z, %): 293/295 (MH+, 100%).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:42])[CH2:21][N:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:23]2=[O:41])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.O1CCOCC1>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:42])[CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:23]2=[O:41])[CH2:16][CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)C(=O)C1c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(CN1CCNC(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
The compound from Example 101D (0.24 g, 0.42 mmol) was dissolved in methanol and treated with 4 N HCl in dioxane at ambient temperature for 2 hours. The reaction mixture was concentrated and then partitioned in 1 N NaOH/methylene chloride. The organic layer was dried over MgSO4, concentrated in vacuo and chromatographed, eluting with 5% MeOH/methylene chloride to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.15-7.48 (m, 15H), 4.30-4.44 (m, 3H), 3.91-4.27 (m, 2H), 3.33-3.55 (m, 4H), 2.80-3.07 (m, 4H), 2.23-2.34 (m, 4H); MS (ESI+) m/z 469 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[C:12]([OH:14])=[O:13].[C:15]([S:23][CH:24]([CH3:28])[C:25](Cl)=[O:26])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[C:15]([S:23][CH:24]([CH3:28])[C:25]([N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[C:12]([OH:14])=[O:13])=[O:26])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C1CCc2ccccc2N1
Reactant: CC(SC(=O)c1ccccc1)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(SC(=O)c1ccccc1)C(=O)N1c2ccccc2CCC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-1,2,3,4-Tetrahydro-2-quinolinecarboxylic acid hydrochloride (43 g) in pyridine (300 ml) was treated dropwise with 2-benzoylthiopropanoyl chloride (46 g) with vigorous stirring. After stirring at room temperature overnight, the mixture was poured onto ice (300 g) and acidified with concentrated hydrochloric acid. The product was extracted with ether and the ether extracts combined, dried over sodium sulfate, and concentrated to dryness in vacuo. The residue, (±)-1-(2-benzoylthio-1-oxopropyl)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid, was crystallized from acetonitrile (100 ml); yield 7 g, m.p. 157°-159°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][C:22]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:17]=4[C:15]=3[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][C:22]4[CH2:21][CH2:20][NH:19][CH2:18][C:17]=4[C:15]=3[CH:16]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4ccc(Cl)cc4)cc3c2C1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccc2oc3c(c2c1)CNCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 160.1 %

Procedure:
The product of step A (118 mg, 0.26 mmol) was Boc-deprotected by treating with 4N HCl in dioxane (2 mL). After stirring for 2 h at ambient temperature the reaction mixture was quenched with 10% sodium bicarbonate solution (20 mL) and extracted with dichloromethane. The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 95:5 chloroform/methanol) to give 8-(4-chlorophenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine hydrochloride (80 mg, 87%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.02 (d, J=1.8 Hz, 1H), 7.91-7.84 (m, 2H), 7.78 (dd, J=8.7, 2.1 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.48-7.41 (m, 2H), 3.99 (t, J=2.1 Hz, 2H), 3.24 (t, J=5.7 Hz, 2H), 2.85-2.76 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]([CH3:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[N:5]1.[N:15]([O-])=[O:16].[Na+].O>C(O)(=O)C>[OH:1][C@H:2]([CH3:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[C:11]=2[N:15]=[O:16])[CH:6]=[N:5]1
Reactant: O=N[O-]
Reactant: C[C@@H](O)Cn1ncc2ccc(O)cc21
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](O)Cn1ncc2ccc(O)c(N=O)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 465.1 %

Procedure:
To a solution of 1-[(R)-2-hydroxypropyl]-1H-indazol-6-ol (2.0 g, 1.04 mmol) in acetic acid (20 mL) was added sodium nitrite (0.72 g, 10.4 mol) and the mixture was stirred at room temperature for 1 hour. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2×200 mL). The combined extracts were washed with water (200 mL), and a saturated aqueous solution of sodium bicarbonate (200 mL), dried over magnesium sulfate, filtered and evaporated to a residue which was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give a red solid (1.07 g, 47%): LC/MS m/z 222.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([N+:15]([O-:17])=[O:16])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]1CCN2C(=NCCC2)CC1.CI>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([N+:15]([O-:17])=[O:16])[N:9]=1)[CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c([N+](=O)[O-])n1
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)c1ccc(Br)c([N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 35.4 %

Procedure:
To a solution of (5-bromo-6-nitro-pyridin-2-yl)-carbamic acid tert-butyl ester (11) (4.2 g, 13.2 mmol) in dry DMF (21 mL), DBU (5.02 g, 33.0 mmol)! was added at 0° C. Methyl iodide (3.75 g, 26.4 mmol) was added slowly at 0° C. After stirring for 3 hours at 0° C. the reaction mixture was quenched and the product was precipitated upon addition of aqueous NaHSO4(1M). The crude product was isolated by filtration and purified by recrystallisation from a mixture of MeCN and water to afford (5-bromo-6-nitro-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester 12 (1.55 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16](=[O:33])[CH2:17][CH2:18][C:19]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)=[O:20])[CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12].[BH4-].[Na+]>CO.O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]([OH:33])[CH2:17][CH2:18][CH:19]([C:21]2[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=2)[OH:20])[CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCOc1c(OC)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCOc1c(OC)cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a solution of 1-(3-methoxy-4-propoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-butane-1,4-dione (11.53 g, 25 mmole) in 350 mL of methanol and 250 mL of tetrahydrofuran was added dropwise a solution of sodium borohydride (3.076 g, 81.34 mmol) in 140 mL of water. After the addition was completed, the mixture was stirred at room temperature for 3 hours, quenched with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and evaporated to provide a foam (11.53 g, 99.24%). 1H NMR (CDCl3): 1.05 (t, 3H), 1.80-1.95 (m, 6H), 3.80-3.98 (m, 12H), 4.1 (t, 2H), 4.72 (m, 2H), 6.6 (s, 2H), 7.15 (s, 1H), 7.35 (s, 1H).
Reaction SMILES: O.Cl.C(OC([NH:10][C@@:11]1([C:35]([O:37]C(C)(C)C)=[O:36])[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C@@H:15]([OH:27])[C@@H:14]2[C@H:12]1[C@H:13]2[C:28]([O:30]C(C)(C)C)=[O:29])=O)(C)(C)C>O1CCOCC1>[ClH:25].[NH2:10][C@@:11]1([C:35]([OH:37])=[O:36])[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C@@H:15]([OH:27])[C@@H:14]2[C@H:12]1[C@H:13]2[C:28]([OH:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 186.3 %

Procedure:
A mixture of water (430 mL) and 37% HCl in water (299.9 mL, 3.65 mol) is added to a suspension of di-tert-butyl (1S,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (215 g, 365.3 mmol) in 1,4-dioxane (73.1 mL). The resulting slurry is stirred at 100° C. for 4.5 hours, cooled to 25° C. and concentrated in vacuo to provide a white solid. Triturate sequentially with methyl tert-butyl ether (2 L) and hexanes (2 L) and then filter to collect the solids. Dry under vacuum for 16 hours. The solid is washed again with methyl tert-butyl ether (2×1 L) and hexane (1 L), then dried under vacuum at 50° C. overnight to yield the title compound as a white solid (140.4 g, 93% yield). MS (m/z): 376/378 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:6]2=O.C1COCC1.[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]2[CH2:4][C:5]([CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:6][C:7]=2[CH:8]=[C:9]2[C:13]=1[CH2:12][CH2:11][CH2:10]2
Reactant: O=C1c2cc3c(c(Br)c2CC1CC1CCCCC1)CCC3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Brc1c2c(cc3c1CCC3)C=C(CC1CCCCC1)C2
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of 39.5 g (0.114 mol) of 4-bromo-2-(cyclohexylmethyl)-3,5,6,7-tetrahydro-s-indacen-1(2H)-one in 170 ml of THF 15.2 g (0.398 mol) of NaBH4 was added. Further on, 340 ml of methanol was added dropwise by vigorous stirring for 2 h. The resulting mixture was stirred for 12 h at room temperature, evaporated to a volume of ca. 300 ml, and then 100 ml of 3.0 M HCl was added. The product was extracted with 3×200 ml of dichloromethane. The organic extract was dried over Na2SO4 and then evaporated to dryness. A solution of the residue and 1.4 g of TsOH in 800 ml of toluene was refluxed for 30 min with Dean-Stark head. The obtained solution was passed through short layer (50 mm) of silica gel 60 (40-63 um), the filtrate was evaporated to dryness. This procedure gave 34.7 g (93%) of the title product which was further used without an additional purification.