Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)#[N:2].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].[Cl-].[Li+]>CN(C=O)C>[NH:22]1[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:2][N:24]=[N:23]1
Reactant: N#CCCCCc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1cncc(-c2[nH]c3ccccc3c2CCCCc2nnn[nH]2)c1

Procedure:
A mixture of 540 mg of 3-(4-cyanobutyl)-2-(3-pyridyl)indole, 173 mg of sodium azide, 142 mg of ammonium chloride and 5 mg of lithium chloride in 2 ml of DMF is heated at 120° overnight. After cooling the mixture is filtered and the filtrate diluted with ca. 25 ml of water. After the pH is adjusted to 10-11 with 3N NaOH, the solution is washed with ether to remove unreacted nitrile. The aqueous phase is adjusted to pH 5-6 with 2N HCl and extracted with ether. The ether extract is washed with water, dried over MgSO4 and concentrated in vacuo. The residue is purified to give 3-[4-(5-tetrazolyl)-butyl]-2-(3-pyridyl)indole.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH:42](O)[CH3:43])=[CH:38][C:37]=1[F:45])#[N:35].C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl.CO>[Si:1]([O:8][CH2:9][C:10]1[N:11]([CH:42]([C:39]2[CH:40]=[CH:41][C:36]([C:34]#[N:35])=[C:37]([F:45])[CH:38]=2)[CH3:43])[CH:12]=[N:13][CH:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(O)c1ccc(C#N)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(c1ccc(C#N)c(F)c1)n1cncc1CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(tert-butyldimethylsilyloxymethyl)-1-(triphenylmethyl)imidazole, as described above in Step D, (485 mg, 1.07 mmol), 1-(4-cyano-3-fluorophenyl)ethanol, as described above in Step C, (160 mg, 0.969 mmol), and N,N-diisopropylethylamine (0.219 mL, 1.26 mmol) in CH2Cl2 (12 mL) was cooled to −78° C., under argon. Trifluoromethanesulfonic anhydride (0.196 mL, 1.17 mmol) was added dropwise, and the mixture was stirred for 18 hours while it slowly warmed to ambient temperature. Methanol (15 mL) was added and the CH2Cl2 was distilled off in vacuo. The resulting methanolic solution was heated to reflux for 3 hours, then concentrated in vacuo to give a residue which was partitioned between saturated aqueous Na2CO3 (10 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted further with CH2Cl2 (20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2—0% to 5% MeOH, to yield the titled product as a pale foam.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]32[N:15]=[C:14]([CH3:16])[C:13](=S)[NH:12]3)=[CH:4][CH:3]=1.[NH3:18]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]32[N:12]=[C:13]([NH2:18])[C:14]([CH3:16])=[N:15]3)=[CH:4][CH:3]=1
Reactant: CC1=NC2(CCCc3ccc(Br)cc32)NC1=S
Reactant: N
Product: CC1=NC2(CCCc3ccc(Br)cc32)N=C1N
Temperature: 110 °C
Yield: 65.6 %

Procedure:
7′-Bromo-4-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalene]-5(1 H)-thione (Example 51 Step 3, 1 g, 3.23 mmol) was taken up in ammonia (7M in MeOH, 15 mL, 105 mmol) and the resulting mixture was heated in the microwave reactor at 110° C. for 30 min. The solvent was evaporated. Ammonia (7M in MeOH, 15 mL, 105 mmol) was added and the reaction was heated again using MW for 30 min at 110° C. The solvent was evaporated. Ammonia (7M in MeOH, 15 mL, 105 mmol) was added and the reaction was heated again using MW for 30 min at 110° C. The solvent was evaporated and the residue was dissolved in EtOAc (20 mL). The resulting mixture was extracted with 0.1 M citric acid (2×10 mL). The organic layer was discarded while the aqueous phase was basified to pH 12 by addition of 50% NaOH (aq) and extracted with iii DCM (3×20 mL). The organic phase was dried with a phase separator and concentrated in vacuo to give the title compound (0.619 g, 65% yield). 20 mg of the product was purified using flash chromatography (4 g SiO2, DCM in 0.1M NH3 in MeOH) to give the title compound (10 mg). 1H NMR (500 MHz, CDCl3) δ ppm 1.88-1.99 (m, 2 H), 2.07-2.16 (m, 1 H), 2.20 (dqd, 1 H), 2.31-2.37 (m, 3 H), 2.92 (t, 2 H), 6.68 (d, 1 H), 7.04 (d, 1 H), 7.25 (dd, 1 H); 1H NMR (500 MHz, CD3OD) δ ppm 1.84 (ddd, 1 H), 1.94 (ddd, 1 H), 2.03-2.12 (m, 1 H), 2.15 (dtd, 1 H), 2.34 (s, 3 H), 2.91 (t, 2 H), 6.69 (d, 1 H), 7.11 (d, 1 H), 7.29 (dd, 1 H), MS (ES+) m/z 292 [M+H]1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:11]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:10][CH:9]=1)[NH2:6])[CH3:2].[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>>[CH2:1]([O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:11]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:10][CH:9]=1)[NH:6][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCCCc1ncc(C[C@H](N)C(=O)OCC)n1Cc1ccccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCCc1ncc(C[C@H](NCc2ccccc2)C(=O)OCC)n1Cc1ccccc1Cl

Procedure:
The title compound is prepared by reductive alkylation of 2-n-butyl-3-(2-chlorophenyl)methylhistidine ethyl ester with benzaldehyde in the presence of sodium cyanoborohydride to give 3-[(2-chlorophenyl)methyl]-2-n-butyl-N-benzylhistidine ethyl ester. Hydrolysis of the ester group is accomplished according to Example 2 (iii) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:16]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([CH3:20])[C:17](Cl)=[O:18].[CH3:28][NH2:29].O.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:16]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([CH3:20])[C:17]([NH:29][CH3:28])=[O:18]
Reactant: CN
Reactant: CC(C(=O)Cl)(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CNC(=O)C(C)(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
A solution of (±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetyl chloride (0.007 mol) in CH2Cl2 (20 ml) was added at RT to methanamine 40% in water (0.105 mol). The mixture was stirred at RT for 4 hours, then poured out into water, acidified with HCl (3N) and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 1.25 g (43%) of (±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α,N-dimethylbenzeneacetamide (comp. 1.14).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.I[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=1>C1COCC1.C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:20][Si:19]([C:18]#[C:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1)([CH3:22])[CH3:21]
Reactant: C#Cc1ccc(C)cc1
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.1 %

Procedure:
Into a 50 ml round bottom flask was placed a mixture of 0.64 g (0.0054 mole) of 4-methylphenylacetylene, 1.50 g (0.005 mole) of 4-iodophenyltrimethylsilylacetylene, 0.011 g (0.0058 mmole) of CuI, 0.103 g (0.146 mmole) of bis(triphenylphosphine)palladium(II)dichloride in 10 ml of THF and 10 ml of triethylamine. The brown solution turned to an orange-yellow suspension when solid started to form. The mixture was stirred at room temperature under nitrogen for 3 days. It was filtered and the filtrate concentrated under reduced pressure. The residue was redissolved in 25 ml of chloroform and the solution was washed two times with water (15 ml each) and then dried over anhydrous MgSO4, filtered and concentrated, 1.43 g (quantitative yield) of solid was obtained. 1HNMR indicated ˜10% of by product present. The solid product was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH2:30])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.Cl[C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH:30][C:32](=[O:33])[O:34][CH3:35])=[N:9][N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:4]=2[CH:3]=1
Reactant: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A 100 mL round bottom flask charged with 6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (1500 mg, 3.65 mmol) in DCM (30 ml) and pyridine (3 mL) was cooled to 0° C. using an ice bath. Methyl chloroformate (0.564 ml, 7.30 mmol) was added and the reaction mixture was stirred for 16 h warming to ambient temperature. The mixture was washed with saturated copper sulfate solution (2×50 mL), dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (ISCO; 40 g prepacked) eluting with ethyl acetate/hexanes to afford methyl (6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (1492 mg, 3.18 mmol, 87% yield) as a white solid. MS ESI calc'd. For C27H22ClN4O2 [M+H]+ 469. found 469.
Reaction SMILES: C[O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].[OH-].[Na+].CO.Cl>O>[N+:16]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1/[CH:5]=[CH:4]/[C:3]([OH:19])=[O:2])[N:13]=[CH:12][CH:11]=[CH:10]2)([O-:18])=[O:17]
Reactant: COC(=O)/C=C/c1cc2ncccc2cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)/C=C/c1cc2ncccc2cc1[N+](=O)[O-]

Procedure:
(E)-3-(6-Nitroquinolin-7-yl)-acrylic acid methyl ester (1 g; 3.9 mmol) was suspended in 2N NaOH (2.9 ml; 5.8 mmol) and MeOH (39 ml) and stirred at 55° C. for 1 h. The clear solution was cooled, treated with 2N HCl (3.2 ml; 6.4 mmol), diluted with water (70 ml) and the precipitated title compound filtered and dried (900 mg; 94%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1.[Li+].[BH4-].N#N>C1COCC1.CO>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([CH2:12][N:13]([CH:14]2[C:23]3[N:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:17][CH2:16][CH2:15]2)[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])=[C:4]([CH2:3][OH:2])[CH:9]=1)#[N:11]
Reactant: COC(=O)c1cc(C#N)ccc1CN(C1CCCc2cccnc21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: N#N
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(CN(C2CCCc3cccnc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])c(CO)c1
Yield: 84.8 %

Procedure:
To a solution of 5-cyano-2-{[(2-nitro-benzenesulfonyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino}-methyl}-benzoic acid methyl ester (2.32 g, 5.72 mmol) dissolved in THF (50 mL) and MeOH (50 mL), LiBH4 (1.26 g, 57.2 mmol) was slowly added. The mixture was stirred at room temperature under a positive pressure of N2 for 2 hours. The mixture was concentrated in vacuo and redissolved in CH2Cl2 (50 mL). Brine (30 mL) was added and the resulting mixture was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a yellow solid. Purification via column chromatography on silica gel (hexanes:EtOAc, 1:1, v/v) afforded N-(4-cyano-2-hydroxymethyl-benzyl)-2-nitro-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-benzenesulfonamide as a yellow solid (2.32 g, 85%). 1H NMR (CDCl3) δ 1.56 (s, 9H), 1.91 (m, 2H), 2.36 (m, 1H), 2.61 (m, 2H), 2.98 (m, 1H), 4.23 (d, 1H, J=16.7 Hz), 4.61 (m, 2H), 4.90 (d, 1H, J=16.2 Hz), 5.21 (m, 1H), 7.03 (dd, 1H, J=5.3, 9.7 Hz), 7.37 (m, 3H), 7.67 (m, 4H), 7.95 (d, 1H, J=7.9 Hz), 8.16 (d, 1H, J=4.4 Hz).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.S(OCC)(OCC)(=O)=O.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29].Cl.[I-].[Na+].Cl[Si](C)(C)C>ClC1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([C:4](=[O:5])/[CH:3]=[CH:2]/[C:1]([OH:6])=[O:7])[CH:25]=[CH:24][C:23]=1[O:28][CH3:29]
Reactant: COc1ccccc1Cl
Reactant: O=C1C=CC(=O)O1
Agent: CCOS(=O)(=O)OCC
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: Clc1ccccc1
Product: COc1ccc(C(=O)/C=C/C(=O)O)cc1Cl
Temperature: 10 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
Into a 500 ml four-neck flask were charged 66.9 g (0.682 mol) of maleic anhydride, 150 ml of chlorobenzene, and 71.6 ml (0.546 mol) of diethyl sulfate under a nitrogen atmosphere. Then, the whole was cooled to 10° C. or lower and 67.6 g (0.507 mol) of aluminum chloride was added thereto. While temperature was maintained at 10 to 15° C., 23.2 ml (0.195 mol) of 1-chloro-2-methoxybenzene was added dropwise, followed by 4 hours of reaction. After termination of the reaction was confirmed by HPLC analysis, the reaction solution was added dropwise to 200 ml of a 1N hydrochloric acid aqueous solution cooled to 0° C. to decompose excess aluminum chloride. After liquid separation, the organic layer was washed with 200 ml of a 10% sodium bicarbonate aqueous solution to remove excess maleic anhydride. Then, 42.9 g (0.286 mol) of sodium iodide and 31.1 g (0.286 mol) of chlorotrimethylsilane were added to the organic layer, followed by heating and refluxing. After completion of the reaction, the organic layer was washed with 100 ml of a 5% sodium thiosulfate aqueous solution and 100 ml of a saturated sodium hydrogen carbonate aqueous solution to extract (E)-4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoic acid into the aqueous layer, followed by adjusting the aqueous layer to pH 2.0. After 24 h of stirring at 5° C., filtration was conducted to obtain 21.1 g (yield 45.0%) of the aimed compound as light yellow crystals. As a result of HPLC analysis, the purity was found to be 99.1%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I>[CH3:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]=2[CH:10]=1
Reactant: Cc1cc(N)c2cn[nH]c2c1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cc(N)c2cnn(-c3ccccc3)c2c1
Temperature: 100 °C
Yield: 30.6 %

Procedure:
6-Methyl-1H-indazol-4-amine (75 mg, 0.51 mmol) and iodobenzene (104 mg, 0.51 mmol) were dissolved in DMF (0.55 ml) in a microwave tube. Copper (I) iodide (19 mg, 0.1 mmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (28.5 mg, 0.2 mmol) and potassium carbonate (140.9 mg, 1.02 mmol) were added and the mixture heated by microwave (250 W) at 100° C. for 20 minutes. The mixture was filtered through a cartridge, washing with DCM (5 ml) and the filtrate was evaporated to dryness and purified by mass-directed autopreparation (system B). The appropriate fractions were combined, extracted with DCM, washed with aqueous sodium bicarbonate, dried through a hydrophobic frit and evaporated to give the title compound (34.9 mg).
Reaction SMILES: COC1C=C(C)C(S(N2CCCCC2COCC(O)=O)(=O)=O)=C(C)C=1.N1C=CC=C(C2(O)CCNCC2)C=1.C(=O)(O)[O-].[Na+].[OH:44][C:45]1([C:75]2[CH:76]=[N:77][CH:78]=[CH:79][CH:80]=2)[CH2:50][CH2:49][N:48]([C:51](=[O:74])[CH2:52][O:53][CH2:54][CH:55]2[CH2:60][CH2:59][CH2:58][CH2:57][N:56]2[S:61]([C:64]2[C:69]([CH3:70])=[CH:68][C:67]([O:71][CH3:72])=[CH:66][C:65]=2[CH3:73])(=[O:63])=[O:62])[CH2:47][CH2:46]1.[Cl:81][Si](C)(C)C>C(Cl)Cl.C(C(C)=O)C.C(OCC)C>[ClH:81].[OH:44][C:45]1([C:75]2[CH:76]=[N:77][CH:78]=[CH:79][CH:80]=2)[CH2:50][CH2:49][N:48]([C:51](=[O:74])[CH2:52][O:53][CH2:54][CH:55]2[CH2:60][CH2:59][CH2:58][CH2:57][N:56]2[S:61]([C:64]2[C:65]([CH3:73])=[CH:66][C:67]([O:71][CH3:72])=[CH:68][C:69]=2[CH3:70])(=[O:62])=[O:63])[CH2:47][CH2:46]1
Reactant: C[Si](C)(C)Cl
Agent: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCC(O)(c3cccnc3)CC2)c(C)c1
Agent: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)O)c(C)c1
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CCC(C)=O
Solvent: ClCCl
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (68 mg, 0.424 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (150 mg, 0.404 mmol) in methylene chloride (5 ml) and the mixture was stirred for 1 h at room temperature. A solution of 4-(pyridin-3-yl)piperidin-4-ol (A2) (72 mg, 0.404 mmol) in methylene chloride (2 ml) was subsequently added and the reaction mixture was stirred for 15 h at room temperature. Thereafter, saturated sodium bicarbonate solution (10 ml) was added to the reaction mixture and the aqueous phase was subsequently extracted with methylene chloride (2×10 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography with ethyl acetate/methanol (20:1). 1-(4-Hydroxy-4-(pyridin-3-yl)piperidin-1-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone (100 mg, 0.188 mmol) was dissolved in methyl ethyl ketone (3 ml), and chlorotrimethylsilane (28 μl, 0.226 mmol) was slowly added. Diethyl ether (10 ml) was subsequently added and the mixture was stirred for 1 h at 0° C. The precipitate formed was filtered off, dried with exclusion of air and washed with diethyl ether.
Reaction SMILES: C([O:3][CH:4]=[C:5](C(OCC)=O)[C:6](OCC)=O)C.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>Cl>[Br:16][C:17]1[CH:18]=[C:19]2[C:21]([C:4]([OH:3])=[CH:5][CH:6]=[N:20]2)=[CH:22][CH:23]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Product: Oc1ccnc2cc(Br)ccc12
Temperature: 125 °C
Yield: 94.6 %

Procedure:
Diethyl ethoxymethylenemalonate (677 g, 3.13 moles (mol)) was added to 3-bromoaniline (491 g, 2.85 mol) over a period of one hour, the temperature rose to 60° C. during the addition. The reaction was then heated at 115° C. for 30 minutes, 125° C. for 30 minutes, and 140° C. for 15 minutes while ethanol was distilled from the reaction. The reaction temperature was adjusted to 130° C., and the reaction mixture was added over a period of 45 minutes to heated DOWTHERM A heat transfer fluid (5 liters (L), 250° C.) while maintaining the temperature of the heat transfer fluid between 242° C. and 250° C. A precipitate formed at the end of the addition. The reaction mixture was heated at about 250° C. for one hour and then cooled to 80° C. Concentrated hydrochloric acid (500 mL) was added, and the reaction mixture was heated at 110° C. for five hours, 125° C. for two hours, and 150° C. for an addition two hours, and then allowed to cool to room temperature overnight. The mixture was then heated to 200° C. over a period of two hours, further heated to 250° C., maintained at 250° C. for one hour, and allowed to cool to room temperature. A precipitate was present and was isolated by filtration, washed sequentially with heptane (2 L), ethanol (1 L), and diethyl ether (1 L) to provide 604 g of 7-bromo quinolin-4-ol as a dark red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6](Br)[C:7]=1[NH2:8]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1c(Cl)cc(N=Nc2ccccc2)cc1Br
Solvent: CO
Product: Nc1ccc(N=Nc2ccccc2)cc1Cl

Procedure:
The 3-chloro-5-bromo-4-amino-azobenzene used in the present Example was obtained by bromination of 3-chloro-4-amino-azobenzene in methanol at 20°-25° C; melting point 152°-153° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:20](Cl)(=[O:22])=[O:21])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1.[OH-].[NH4+:27]>O1CCOCC1>[F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:20]([NH2:27])(=[O:22])=[O:21])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2cc(S(=O)(=O)Cl)ccc2c1C(=O)c1ccc(F)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2cc(S(N)(=O)=O)ccc2c1C(=O)c1ccc(F)cc1

Procedure:
A solution of 5-(4-fluorobenzoyl)-6-methoxy-2-naphthalenesulfonyl chloride (5.39 g, 14.2 mmol), [prepared as described in step 2 above], in dioxane (100 ml), was cooled in an ice bath under nitrogen, and concentrated ammonium hydroxide (20 ml) was added dropwise. After 1h, the dioxane was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (gradient elution, 20-60% ethyl acetate/hexane) and then recrystallized from ethyl acetate/hexane to afford 2.7 g of 5-(4-fluorobenzoyl)-6-methoxy-2-naphthalene-sulfonamide as white crystals.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18](C(F)(F)F)[CH:17]=[CH:16][C:15]=2[O:24][C@@H:25]([CH3:29])[C:26]([OH:28])=[O:27])=[CH:10][C:9]=1[F:30])=[O:7])([CH3:4])[CH3:3].B(C1C=C([Cl:46])C=CC=1O[C@@H](C)C(O)=O)(O)O>>[Cl:46][C:18]1[CH:17]=[CH:16][C:15]([O:24][C@@H:25]([CH3:29])[C:26]([OH:28])=[O:27])=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]([NH:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])=[C:9]([F:30])[CH:10]=2)[CH:19]=1
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1-c1ccc(C(=O)NC(C)(C)C)c(F)c1)C(=O)O
Reactant: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O
Product: C[C@H](Oc1ccc(Cl)cc1-c1ccc(C(=O)NC(C)(C)C)c(F)c1)C(=O)O

Procedure:
The title compound was prepared using the product of example 33 step a) and the product of example 28 step c) by the method of example 32 step b).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:43])[NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[C:20]([CH2:21][O:22][Si](C(C)(C)C)(C)C)=[CH:19][N:18]=[C:17]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38]([NH:40][CH2:41][CH3:42])=[O:39])[CH:32]=3)[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(O)C.Cl>[CH2:41]([NH:40][C:38]([NH:37][C:33]1[CH:32]=[C:31]([NH:30][C:17]2[N:16]=[C:15]([NH:14][CH2:13][CH2:12][CH2:11][NH:10][C:9](=[O:43])[O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:20]([CH2:21][OH:22])=[CH:19][N:18]=2)[CH:36]=[CH:35][CH:34]=1)=[O:39])[CH3:42]
Reactant: CCNC(=O)Nc1cccc(Nc2ncc(CO[Si](C)(C)C(C)(C)C)c(NCCCNC(=O)OCc3ccccc3)n2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCNC(=O)Nc1cccc(Nc2ncc(CO)c(NCCCNC(=O)OCc3ccccc3)n2)c1

Procedure:
Phenylmethyl[3-[[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-2-[[3[[(ethylamino)carbonyl]amino]phenyl]amino]pyrimidin-4-yl]amino]propyl]carbamate (145 mg) were stirred in a mixture of ethanol (10 ml) and hydrochloric acid (4 n; 1 ml) for 3 h at room temperature. Then halfconcentrated NaHCO3-solution and ethyl acetate were added.