Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[Br:1][C:2]1[C:3]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1cc(I)c(Br)cn1
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Clc1cc(-c2ccccc2Cl)c(Br)cn1
Temperature: 90 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
A mixture of 10.8 g (33.9 mmol) 5-bromo-2-chloro-4-iodo-pyridine, 5.84 g (37.3 mmol) 2-chlorophenylboronic acid, 200 ml dimethoxyethane and 50 ml of a 2 M aqueous solution of sodium carbonate was deoxygenated by three freeze-thaw cycles. After addition of 381 mg (1.70 mmol) palladium(II) acetate and 917 mg (3.39 mmol) triphenylphosphine the reaction mixture was stirred at 90° C. for 4 h. Cooling to room temperature was followed by dilution with water and extraction with two portions of tert-butyl methyl ether. The combined organic extracts were washed with brine, dried with magnesium sulfate and concentrated. Column chromatography afforded 7.74 g (75%) of the title compound as a white solid.
Reaction SMILES: I.C[O:3][C:4]1[CH:24]=[CH:23][C:7]2[C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=4)[CH:12]=3)=[N:9][O:10][C:6]=2[CH:5]=1.C(O)(=O)C.C(OC(=O)C)(=O)C>O>[OH:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:8]1[C:7]3[CH:23]=[CH:24][C:4]([OH:3])=[CH:5][C:6]=3[O:10][N:9]=1)[CH:20]=[CH:19]2
Reactant: COc1ccc2cc(-c3noc4cc(OC)ccc34)ccc2c1
Agent: I
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Oc1ccc2cc(-c3noc4cc(O)ccc34)ccc2c1
Temperature: 160 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
Hydriotic acid (57% w/w aq., 10 mL) was added into a mixture of 6-methoxy-3-(6-methoxy-2-naphthyl)-1,2-benzisoxazole (1.0 g, 3.3 mmol), acetic acid (10 mL) and acetic anhydride (5 mL). The reaction mixture was stirred at 160° C. for 2 h, and then cooled to room temperature and poured into water. The precipitated solid was filtered off and dried to give a yellow solid (0.89 g, 91% yield, m.p. 280-282° C.); MS m/e 278 (M+H)+.
Reaction SMILES: [C:1]([CH:3]1[CH:7]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2].C(N(CC)CC)C.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(#N)C>[C:1]([CH:3]1[CH:7]([C:8]2[N:12]=[N:11][N:10]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[N:9]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: CCCCCCCCCCCCBr
Reactant: N#CC1CCCC1c1nnn[nH]1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCn1nnc(C2CCCC2C#N)n1

Procedure:
The tetrazole (b) obtained above (11.0 g; 0.067 moles) was dissolved in acetonitrile (150 mL) containing one equivalent of triethylamine (6.8 g; 0.067 moles). The solution was heated to reflux followed by the addition of 1-bromo dodecane (16.8 g; 0.067 moles). Isolation of the 2-isomer was achieved employing the same conditions described for Example 11.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]([O:23]C)=[O:22].[OH-].[K+].Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1COCC1>[N+:10]([C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:20]([C:21]([OH:23])=[O:22])[O:1][C:2]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: COC(=O)CCl
Reactant: O=Cc1ccc([N+](=O)[O-])cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc([N+](=O)[O-])cc2o1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
5.8 g (34.7 mmol) of 2-hydroxy-4-nitrobenzaldehyde, 1.28 g (3.5 mmol) of tetrabutylammonium iodide and 19.2 g (138.8 mmol) of potassium carbonate are mixed, 7.9 g (72.9 mmol) of methyl chloroacetate are added, and the mixture is heated at 130° C. for 12 h. 100 ml of THF are added and, while cooling in ice, 11.7 g (208.2 mmol) of potassium hydroxide are added. Addition of 100 ml of water is followed by stirring at room temperature for 20 h. The pH is adjusted to pH 1 with conc. hydrochloric acid. The mixture is extracted with ethyl acetate. The organic phase is washed with water and dried over sodium sulfate. Addition of silica gel is followed by concentration and chromatography on silica gel (mobile phase: toluene/methanol/acetic acid). Concentration of the product fractions and drying in vacuo result in 1.31 g (18.2% of theory) of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C(=O)=O.[CH3:11][C:12](C)=[O:13].C([Li])CCC.CCCCCC.[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([OH:35])=[O:34])=[CH:31][CH:32]=1.C1OC1.Cl>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[OH:13][CH2:12][CH2:11][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: O=C(O)c1ccc(CCCO)cc1
Reaction time: 0.33 h
Yield: 27.7 %

Procedure:
To a chilled and stirred solution of diisopropylamine (4.63 ml, 33 mmole) in 20 ml of dry tetrahydrofuran at -78° C. (dry ice-acetone bath) under nitrogen was added dropwise 1.7M n-butyllithium in hexane (19.4 ml, 33 mmole). After 20 minutes, a solution of p-toluic acid (2.042 g, 15 mmole) in 20 ml of dry tetrahydrofuran was added dropwise. After strirring at -78° for another 1.5 hours, HMPA (4 ml) was added and then immediately followed by a solution of dry ethylene oxide (2.99 g, 67.9 mmole) in 10 ml of dry tetrahydrofuran. The resulting solution was stirred at -78° for two hours, acidified with 5% hydrochloric acid, warmed up to room temperature and most of the tetrahydrofuran removed in vacuo. The aqueous solution was saturated with sodium chloride and extracted with ethyl ether (3×100 ml). The combined ether extracts were concentrated to 100 ml and extracted with 0.5N sodium hydroxide solution (2×50 ml). This was acidified with 10% hydrochloric acid and extracted with ethyl ether (3×100 ml). The ether extracts were dried over anhydrous MgSO4 and evaporated in vacuo to give a gum. This was chromatographed on a silica gel (120 g, Baker 60-200 mesh) column, eluting successively with dichloromethane-ethyl acetate (9:1 and 1:1), ethyl acetate and dichloromethane-methanol (9:1) to give 750 mg (27.7% solid) of tlc-homogeneous title acid compound with a consistent H1 -NMR spectrum.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8](O)=[O:9].P(Cl)(Cl)(Cl)(Cl)Cl.[C:31]([O:40][CH2:41][CH3:42])(=[O:39])[C:32]1[C:33](=[CH:35][CH:36]=[CH:37][CH:38]=1)[NH2:34]>ClCCl>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([NH:34][C:33]1[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=1[C:31]([O:40][CH2:41][CH3:42])=[O:39])=[O:9]
Reactant: CCOC(=O)c1ccccc1N
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1NC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Under an ice-cooled condition, 332 mg (1 mmol) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl) pyridine-3-carboxylic acid was suspended in dried dichloromethane. The mixture was stirred with addition of 229 mg (1.1 mmol) of phosphorus pentachloride little by little for one hour. At -30° C., 1650 mg (10 mmol) of ethyl anthranilate was added to the reaction mixture. The reaction mixture was further stirred at room temperature for one hour. After washing with water, the raction mixture was dried over anhydrous sodium sulfate. The thus obtained mixture was chromatographed on a silica gel column for purification, whereby 486 mg (100%) of the captioned compound was obtained as an oily material.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:17]([NH:19][C:20](=O)[CH3:21])[CH:18]=1)[CH2:4][CH2:5][CH3:6].[Cl:38]CC[CH2:41][S:42](Cl)(=[O:44])=[O:43].CCN(C(C)C)C(C)C.[H-].[Na+].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.O.CCOC(C)=O.CCOCC>[ClH:38].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[C:17]([N:19]2[CH2:20][CH2:21][CH2:41][S:42]2(=[O:44])=[O:43])[CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(NC(C)=O)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [H-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(N2CCCS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
To a solution of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenylamine (Example 62, 0.2 mmol, 88 mg) in dry DCM (1.0 mL) was added 3-chloropropanesulfonyl chloride (0.4 mmol, 71 mg), DIEA (0.4 mmol, 70 μL), and DMAP (10 mg). And the mixture was stirred at room temperature for 1 hour then condensed. It was then diluted with water/EtOAc. The solvent was removed in vacuo and dried under vacuum over night. The residue was dissolved in dry THF (1.0 mL) at 0° C., NaH (60% dispersion in mineral oil, 0.8 mmol, 32 mg) was added and the mixture was heated at 50° C. for 4 hours. It was then poured into ice-water and extracted with ethyl acetate. The organic layers combined, condensed and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (35 mg). LCMS: m/z 544 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.70 and 7.81 (1H, s), 7.01-7.12 (3H, m), 5.37-5.56 (1H, m), 4.52-4.58 (1H, m), 3.21-3.69 (8H, m), 3.06-3.13 (2H, m), 2.93 (3H, s), 1.92-2.59 (8H, m), 1.27-1.82 (12H, m), 0.80 (3H, t).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]#[N:13])=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][N:21]=[C:20](Br)[CH:19]=1)[CH3:15].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>C1(C)C=CC=CC=1.[Cu](I)I>[CH2:14]([O:16][C:17](=[O:25])[C:18]1[CH:19]=[CH:20][N:21]=[C:22]([N:10]2[CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]([C:12]#[N:13])=[CH:9]2)[CH:23]=1)[CH3:15]
Reactant: CCOC(=O)c1ccnc(Br)c1
Reactant: N#Cc1c[nH]cc1-c1ccccc1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccnc(-n2cc(C#N)c(-c3ccccc3)c2)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
To a solution of 4-phenyl-1H-pyrrole-3-carbonitrile (0.1 g) in toluene (0.70 mL) were added 2-bromo-isonicotinic acid ethyl ester (0.19 g), potassium phosphate (0.31 g), (1R,2R)-(−)-N,N′-dimethylcyclohexane-1,2-diamine (0.02 g) and copper iodide (0.007 g) at room temperature, and this mixture was stirred at 110° C. for 24 hours. The insoluble material was removed by filtration through Celite, and this filtrate was concentrated. This obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=10/90-66/34) to give the title compound (0.066 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[NH2:25])[CH2:13]2)=[CH:8][CH:7]=1.[C:26](=O)([O:35]N1C(=O)CCC1=O)[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:13]2)=[CH:8][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc(-c3ncco3)cc2)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Product: O=C(N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc(-c3ncco3)cc2)C1)OCc1ccccc1
Yield: 31 %

Procedure:
Benzyl (1R,2R)-2-((S)-1-(4-(oxazol-2-yl)phenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using (1R,2R)—N1-(1-(4-(oxazol-2-yl)phenyl)piperidin-3-yl)cyclohexane-1,2-diamine (from Example 15, step D) (11.58 mg, 0.034 mmol) and benzyl 2,5-dioxopyrrolidin-1-yl carbonate (8.5 mg, 0.034 mmol) according to General Procedure H to give 5 mg (20% yield) of the title compound as a pink solid. Anal. Calcd. for C28H34N4O3 m/z 474.5, found: 475.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.90 (d, J=8.8 Hz, 2H), 7.71 (s, 1H), 7.39 (s, 1H), 7.24-7.08 (m, 5H), 6.98 (d, J=8.7 Hz, 2H), 4.79 (s, 2H), 3.67-3.53 (m, 1H), 3.53-3.42 (m, 2H), 3.42-3.30 (m, 2H), 3.29-3.19 (m, 2H), 2.22 (d, J=10.4 Hz, 1H), 2.14-1.85 (m, 5H), 1.84-1.54 (m, 4H), 1.44-1.19 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:12][C@@H:13]1[C:18]2=[C:19]3[C:28](=[C:29]([O:31][CH3:32])[CH:30]=[C:17]2[O:16][C:15]([CH3:40])([CH3:39])[C@@H:14]1[OH:41])[C:27](=[O:33])[C:26]1[C:21](=[CH:22][CH:23]=[C:24]2[CH:37]=[CH:36][CH:35]=[CH:34][C:25]2=1)[N:20]3[CH3:38]>N1C=CC=CC=1>[C:4]1(/[CH:3]=[CH:2]/[C:1]([O:41][CH:14]2[C:15]([CH3:39])([CH3:40])[O:16][C:17]3[C:18](=[C:19]4[C:28](=[C:29]([O:31][CH3:32])[CH:30]=3)[C:27](=[O:33])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]5[CH:37]=[CH:36][CH:35]=[CH:34][C:25]5=3)[N:20]4[CH3:38])[CH:13]2[OH:12])=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)[C@@H](O)[C@@H](O)C(C)(C)O2
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)C(O)C(OC(=O)/C=C/c1ccccc1)C(C)(C)O2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1.33 mmol of cinnamoyl chloride are added to a previously cooled solution of 0.30 mmol of the compound of Example 4 in 4 ml of pyridine. After stirring at 0° C. for 90 minutes, the reaction mixture is evaporated under reduced pressure. Chromatography over silica gel (cyclohexane, and then cyclohexane/acetone: 94/6 to 90/10) allows the expected product to be isolated.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[S:16]1[CH:20]=[CH:19][N:18]2[CH:21]=[N:22][CH:23]=[C:17]12.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([C:23]2[N:22]=[CH:21][N:18]3[CH:19]=[CH:20][S:16][C:17]=23)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cn2cncc2s1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)c2ncn3ccsc23)cc1
Reaction time: 0.17 h
Yield: 14.1 %

Procedure:
A solution of 23.9 g of p-toluenesulfonyl chloride in 100 ml of dichloromethane was cooled to ice temperature in an argon atmosphere. Aluminum chloride (15.3 g) was added thereto. The mixture was stirred for 10 min. A solution of 3.15 g of imidazo[5,1-b]thiazole in 25 ml of dichloromethane was added dropwise thereto. The mixture was stirred for 22 hr. Dichloromethane (200 ml), 70 ml of water, and 75 g of a sodium carbonate powder were added thereto, followed by extraction. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure to give 995 mg of 7-p-toluenesulfonylimidazo[5,1-b]thiazole.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[CH:15](C(OC)=O)[C:16]([O:18]C)=[O:17])([OH:5])=[O:4]>O.CO.C(OCC)(=O)C>[C:16]([CH2:15][C:7]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=1[C:3]([OH:5])=[O:4])([OH:18])=[O:17]
Reactant: COC(=O)C(C(=O)OC)c1cc([N+](=O)[O-])ccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)Cc1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
A solution of sodium hydroxide (5.0 g, 125 mmol) in water (60 mL) was added to a solution of dimethyl 2-(2-carboxy-5-nitrophenyl)malonate (7.0 g, 21.5 mmol) in methanol (60 mL) at room temperature. After the reaction solution was stirred at room temperature for 3 hours, methanol was distilled off. The resulting residue was acidified using 1N hydrochloric acid (11 mL). The suspension was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. After the crude product was stirred in ethyl acetate (20 mL) at 70 to 80° C. overnight, the temperature was allowed to return to room temperature. The precipitate was collected by filtration, and dried under reduced pressure to give the title compound (1.13 g, 23%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[OH:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>ClCCl>[CH2:25]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@H:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O[C@@H]1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution of oxalyl chloride (6.28 mL, 72.4 mmol) in dichloromethane (75 mL) at −60° C. under nitrogen is added a solution of DMSO (10.7 mL, 151 mmol) in dichloromethane (75 mL) dropwise and stirred at −60° C. for 15 min. (1R,2S)-2-(dibenzylamino)cyclopentanol (17.0 g, 60 mmol) in dichloromethane (75 mL) is added and the reaction is stirred at −60° C. for 30 min. TEA (46 mL, 330 mmol) is added and the reaction is allowed to warm to room temperature and stirred for 1 h. Water is added (100 mL) and the reaction is stirred overnight. The dichloromethane layer is separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as an orange oil (13.96 g, 83%). ES/MS m/z 280 (M+1).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH:16]([CH3:28])[CH2:17][C:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O)=[CH:11][CH:10]=2)[CH:8]=1.O.O.O.O.O.O.[Cl-].[Mg+2].[Cl-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.Cl>C(O)C.O.C(Cl)Cl>[CH3:28][C@H:16]1[CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:13]2[C:12](=[CH:11][CH:10]=[C:9]([N:7]3[CH:8]=[C:4]([CH3:3])[N:5]=[CH:6]3)[CH:14]=2)[NH:15]1
Reactant: Cc1cn(-c2ccc(NC(C)CC(=O)NC(=O)OC(C)(C)C)cc2)cn1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Cc1cn(-c2ccc3c(c2)[C@H](NC(=O)OC(C)(C)C)C[C@H](C)N3)cn1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
Sodium borohydride (29 mg, 0.767 mmol) was added to a solution of 1,1-dimethylethyl (3-{[4-(4-methyl-1H-imidazol-1-yl)phenyl]amino}butanoyl)carbamate (for a preparation see Intermediate 103) (340 mg, 0.949 mmol) in ethanol (6 mL) cooled at −15° C. (cold bath: ethanol/card ice). Magnesium chloride hexahydrate (202 mg, 0.996 mmol) in water (1 mL) was then slowly added keeping the temperature below 10° C.). The mixture was then stirred at 0° C. for 45 min and at room temperature for 45 min before being poured onto a stirred mixture of citric acid (456 mg, 2.371 mmol), HCl (1M in water, 10 mL) and DCM (5 mL). The resulting mixture was stirred for 30 min at room temperature then the layers were separated. The aqueous phase was basified with solid K2CO3 and extracted twice with AcOEt (25 mL). The combined organic phases were washed with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 4 to 8% MeOH in DCM) gave 1,1-dimethylethyl [(cis)-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (273 mg, 0.797 mmol, 84%) as a white solid.
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[NH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2.Cl>ClCCl.C(OCC)(=O)C>[CH3:14][C:15]1[NH:16][C:17]2[C:22]([C:23]=1[C:2](=[O:3])[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: Cc1cc2ccccc2[nH]1
Reactant: COC(=O)CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1c(C)[nH]c2ccccc12
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3-(chloroformyl)propionate (3 ml) and aluminum chloride [6.50 g) in dichloromethane (40 ml) was stirred at 20° C. for 1 hour. A solution of 2-methylindole (3 g) in dichloromethane (20 ml) was added to the mixture at 20° C. and the resulting mixture was stirred at 20° C. for 1 hour. The reaction mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the residue was purified by column chromatography on silica gel (100 g) eluting with chloroform and with recrystallization from a mixture of ethyl acetate and hexane to give methyl 4-(2-methylindol-3-yl)-4-oxobutyrate (908 mg) as pale brown crystals.
Reaction SMILES: [OH-].[C:2]([C:5]1[CH:36]=[CH:35][C:8]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:31]=[CH:30][C:17]3[C:18](=[O:29])[CH2:19][C:20]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])([CH3:22])[O:21][C:16]=3[C:15]=2[CH2:32][CH2:33][CH3:34])=[C:7]([CH2:37][CH2:38][CH3:39])[C:6]=1[OH:40])(=[O:4])[CH3:3]>O.O1CCCC1.CO>[C:2]([C:5]1[CH:36]=[CH:35][C:8]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:31]=[CH:30][C:17]3[C:18](=[O:29])[CH2:19][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])([CH3:22])[O:21][C:16]=3[C:15]=2[CH2:32][CH2:33][CH3:34])=[C:7]([CH2:37][CH2:38][CH3:39])[C:6]=1[OH:40])(=[O:4])[CH3:3]
Reactant: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C)(CCC(=O)OC)CC3=O)ccc(C(C)=O)c1O
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C)(CCC(=O)O)CC3=O)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
A solution of 0.5 g (19.5 mmole) of liythium hydroxide in 10 ml of water was added to a solution of 2.2 g (3.9 mmole) of the title compound of Example 6 in 25 ml of tetrahydrofuran and 20 ml of methanol. After the reaction mixture was stirred for 3 hours at room temperature, the solvent was evaporated and water was added to the residue. After extracting with a small amount of diethyl ether, the aqueous layer was acidified with dilute hydrochloric acid and allowed to stand in the cold overnight. The solid was filtered, washed with water and recrystallized from ethyl acetate/hexane to yield 1.83 g of the title compound, mp. 80°-83°. Structure assignment was confirmed by nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([CH3:15])([OH:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[OH:14][C:12]([CH3:15])([CH3:13])[CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(O)CCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)COc1ccc(C=O)cc1
Temperature: 25 °C

Procedure:
5.00 g (40.94 mmol) of 4-hydroxybenzaldehyde, 4.44 g (40.94 mmol) of 1-chloro-2-methyl-2-propanol and 6.08 g (57.32 mmol) of sodium carbonate are initially charged in 50 ml of dry DMF and stirred under reflux for 24 h. After cooling to RT, 20 ml of ethyl acetate and 20 ml of sat. aqueous sodium bicarbonate solution are added. The phases are separated, and the organic phase is dried over magnesium sulfate. After removal of the solvent, the residue is purified by column chromatography on silica gel 60 (mobile phase gradient: cyclohexane/ethyl acetate 5:1→1:1). This gives a reddish solid which is used without further purification for the subsequent step.