Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:33]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[C:25]([NH2:34])[C:24]=2[N:23]=[C:22]1[CH2:35][CH2:36][CH2:37][CH3:38]>ClCCl>[NH2:34][C:25]1[C:24]2[N:23]=[C:22]([CH2:35][CH2:36][CH2:37][CH3:38])[N:21]([CH2:20][CH2:19][CH2:18][CH2:17][NH:16][S:12]([C:7]3[C:6]4[CH:5]=[CH:4][N:3]=[CH:2][C:11]=4[CH:10]=[CH:9][CH:8]=3)(=[O:14])=[O:13])[C:33]=2[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:26]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C
Yield: 44.9 %

Procedure:
A suspension of isoquinoline-5-sulfonyl chloride hydrochloride (0.83 g in 50 ml of pyridine, 3.1 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (1.0 g, 3.2 mmol) and dichloromethane (175 ml). The solution turned a bright yellow color and was maintained at room temperature for 4 hours. An additional 0.18 g of isoquinoline-5-sulfonyl chloride hydrochloride was added and the reaction was maintained an additional 60 hours. The yellow solution was concentrated in vacuo, dissolved in dichloromethane, and washed sequentially with saturated aqueous sodium bicarbonate and water. The organic fraction was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane\methanol) to provide 0.7 g of N5-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-5-isoquinolinesulfonamide as a white crystalline solid, m.p. 96.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 9.44 (d, J=0.7 Hz, 1H), 8.64(d, J=6.1 Hz, 1H), 8.41–8.35 (m, 2H), 8.30 (dd, J=7.4, 1.2 Hz, 1H), 8.11 (t, J=5.6 Hz, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.75 (t, J=7.7 Hz, 1H), 7.61 (dd, J=8.3, 1.2 Hz, 1H), 7.41 (dt, J=7.7, 1.2 Hz, 1H), 7.22 (dt, J=7.6, 1.2 Hz, 1H), 6.47 (broad s, 2H), 4.38 (t, J=7.5 Hz, 2H), 2.86–2.74 (m, 4H), 1.78–1.63 (m, 4H), 1.50–1.34 (m, 4H), 0.94 (t, J=7.4 Hz, 3H); MS (EI) m/e 502.2151 (502.2151 calcd for C27H30N6O2S). Anal calcd for C27H30N6O2S: C, 64.52; H, 6.02; N, 16.72. Found: C, 64.03; H, 6.03; N, 16.55.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[CH2:34][CH2:35][CH2:36][NH2:37]>>[CH2:5]([C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:2]([OH:1])[CH2:3][NH:37][CH2:36][CH2:35][CH2:34][C:28]1[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=1[CH3:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: Cc1ccc(CCCN)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(CCCNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c(C)c1
Temperature: 22.5 °C

Procedure:
A stirred mixture of tert-butyl (1S)-1-[(2S)-oxiranyl]-2-phenylethylcarbamate (V, 247 mg, 0.939 mmol), sodium carbonate (299 mg, 2.82 mmol), and 3-(2,4-dimethylphenyl)propylamine (VI, 628 mg, 2.82 mmol) is heated at reflux overnight. The reaction mixture is cooled to 20-25 degrees C. and concentrated under reduced pressure. Purification by flash column chromatography (silica; methylene chloride/methanol/ammonium hydroxide, 98/2/1) gives tert-butyl (1S,2R)-1-benzyl-3-{[3-(2,4-dimethylphenyl)propyl]amino}-2-hydroxypropylcarbamate (VII), NMR (300 MHz, CD3OD): δ 7.22-7.16, 3.81, 3.18, 2.77, 2.54, 2.15, 2.13, 1.89 and 1.23.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23]3[NH:24][CH:25]=[C:26]([C:28](F)(F)F)[N:27]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.[NH2:32]O>CC#N>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([C:14]([N:16]2[CH2:17][CH2:18][CH:19]([CH2:22][C:23]3[NH:24][CH:25]=[C:26]([C:28]#[N:32])[N:27]=3)[CH2:20][CH2:21]2)=[O:15])=[CH:12][CH:13]=1
Reactant: NO
Reactant: O=C(c1ccc(-c2ccccc2F)cc1)N1CCC(Cc2nc(C(F)(F)F)c[nH]2)CC1
Solvent: CC#N
Product: N#Cc1c[nH]c(CC2CCN(C(=O)c3ccc(-c4ccccc4F)cc3)CC2)n1
Temperature: 60 °C
Yield: 12 %

Procedure:
This compound is synthesized as described by adaptation of the following reference: Matthews et al, J. Org. Chem., 1986, 51, 3228. To a stirred solution of (2′-fluorobiphenyl-4-yl)(4-{[4-(trifluoromethyl)-1H-imidazol-2-yl]methyl}piperidin-1-yl)methanone (0.114 g, 0.27 mmol) in MeCN (10 mL) is added hydroxylamine (5% aqueous solution, 40 mL). The reaction is heated at 60° C. for 4 h then allowed to cool to room temperature. The mixture is extracted with DCM and washed with saturated aqueous NaHCO3. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. Purification by column chromatography (silica, eluent: DCM, 0-4% MeOH) gives 12.8 mg (12%) of 2-({1-[(2′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-1H-imidazole-4-carbonitrile.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C(O)C>[F:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CNCC[C@@H]1F
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@@H]1F
Yield: 91 %

Procedure:
Method 1 of Example 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl (3S,4S)-4-fluoropiperidin-3-ylcarbamate and triethylamine in ethanol yielding tert-butyl (3S,4S)-4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (91%). LCMS (m/z): 341.0 (MH+); LC Rt=2.37 min.
Reaction SMILES: [N+:1]([C:4]1[CH:43]=[CH:42][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:13]([CH3:41])([CH3:40])[O:14][Si:15]([CH3:39])([CH3:38])[O:16][Si:17]([CH3:37])([CH3:36])[O:18][Si:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=2)([CH3:21])[CH3:20])=[CH:6][CH:5]=1)([O-])=O.[H][H]>>[NH2:1][C:4]1[CH:43]=[CH:42][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:13]([CH3:40])([CH3:41])[O:14][Si:15]([CH3:39])([CH3:38])[O:16][Si:17]([CH3:37])([CH3:36])[O:18][Si:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=2)([CH3:20])[CH3:21])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: C[Si](C)(CCCCOc1ccc([N+](=O)[O-])cc1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc([N+](=O)[O-])cc1
Product: C[Si](C)(CCCCOc1ccc(N)cc1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc(N)cc1
Yield: 99.6 %

Procedure:
2.26 g of the above 2b (3.38 mmol) and 15 mL of a 10 wt % Pd/C ethyl acetate solution (0.0209 g) were mixed, and stirred for 2 days in a hydrogen atmosphere at room temperature. The solution was filtrated by Celite and then concentrated to obtain a colorless oily material of 1,7-bis(4-aminophenoxybutyl)-1,1,3,3,5,5,7,7-octamethyltetrasiloxane (3c) (2.05 g, 99% of yield) represented by the following formula. Various measurements were carried out with regard to the obtained 1,7-bis(4-aminophenoxybutyl)-1,1,3,3,5,5,7,7-octamethyltetrasiloxane (3c), and results are shown below.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[N:32]([C:33]([C:35]4[C:36]([CH3:40])=[N:37][O:38][CH:39]=4)=[O:34])[CH2:31][CH2:30][N:16]2[C:17](=[O:29])[C:18]2[N:19]([CH:21]=[C:22]([C:24]4[NH:28][N:27]=[N:26][N:25]=4)[CH:23]=2)[CH2:20]3)=[CH:11][CH:10]=1.CI>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]23[N:32]([C:33]([C:35]4[C:36]([CH3:40])=[N:37][O:38][CH:39]=4)=[O:34])[CH2:31][CH2:30][N:16]2[C:17](=[O:29])[C:18]2[N:19]([CH:21]=[C:22]([C:24]4[N:25]([CH3:1])[N:26]=[N:27][N:28]=4)[CH:23]=2)[CH2:20]3)=[CH:13][CH:14]=1.[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]23[N:32]([C:33]([C:35]4[C:36]([CH3:40])=[N:37][O:38][CH:39]=4)=[O:34])[CH2:31][CH2:30][N:16]2[C:17](=[O:29])[C:18]2[N:19]([CH:21]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH3:1])[N:28]=4)[CH:23]=2)[CH2:20]3)=[CH:13][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C23Cn4cc(-c5nnn[nH]5)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C23Cn4cc(-c5nnn(C)n5)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Product: COc1ccc(C23Cn4cc(-c5nnnn5C)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Reaction time: 0.17 h
Yield: 29 %
Yield: 28 %

Procedure:
Potassium carbonate (2 equivalents) was added to a solution of 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-7-(1H-tetrazol-5-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (75) (150 mg, 0.33 mmol) in DMF. The mixture was stirred for 10 minutes and methyl iodide was added. The reaction was stirred at room temperature for 1 hour. The crude material was purified by preparative HPLC to give 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-7-(1-methyl-1H-tetrazol-5-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (145) as a white solid (45 mg, 29%) and 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-7-(2-methyl-2H-tetrazol-5-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (146) as a white solid (43 mg, 28%).
Reaction SMILES: C(O[C:4]1[C:5](=[O:14])[C:6](=[O:13])[C:7]=1[NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])C.[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[C:17]=1[CH2:18][NH2:19]>C(O)C>[C:9]([NH:8][C:7]1[C:6](=[O:13])[C:5](=[O:14])[C:4]=1[NH:19][CH2:18][C:17]1[C:20]([CH3:25])=[CH:21][C:22]([Cl:24])=[CH:23][C:16]=1[Cl:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: Cc1cc(Cl)cc(Cl)c1CN
Reactant: CCOc1c(NC(C)(C)C)c(=O)c1=O
Solvent: CCO
Product: Cc1cc(Cl)cc(Cl)c1CNc1c(NC(C)(C)C)c(=O)c1=O
Yield: 89 %

Procedure:
This compound was prepared in a procedure similar to the one described in Example 4. From 3-ethoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (0.22 g, 1.1 mmol) and 2,4-dichloro-6-methylbenzylamine (0.22 g, 1.2 mmol, containing approximately 5% of a compound which is regioisomeric with respect to the substitution on the aryl ring) in absolute ethanol (5.5 mL) there was obtained 0.34 g (89%) of 3-tert-butylamino-4-(2,4-dichloro-6-methyl-benzylamino)-cyclobut-3-ene-1,2-dione as a white solid, which contains approximately 5% of a compound which is regioisomeric with respect to substitution on the aryl ring: mp 264°-268° C.; 1H NMR (DMSO-d6) δ 7.54 (d, 1H), 7.46 (s, 1H), 7.43 (br t, 1H), 7.39 (d, 1H), 4.89 (d, 2H), 4.72 (d, minor isomer), 2.40 (s, 3H), 2.31 (s, minor isomer), 1.34 (s, 9H) ppm. IR (KBr): 3200, 2950, 1800, 1650 cm-1 ; MS (m/z) 340/342/344 (M+).
Reaction SMILES: [C:1]([NH:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:16][C:15]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[O:14][N:13]=2)=[CH:8][C:7]=1[CH3:29])(=[S:3])[NH2:2].[C:31](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[NH2:2][C:1]([S:3][CH3:31])=[N:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:16][C:15]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:18])[F:19])[O:14][N:13]=2)=[CH:8][C:7]=1[CH3:29]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC(N)=S
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CSC(N)=NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C

Procedure:
To a solution of 0.30 g of N-thiocarbamoyl-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl benzoic acid amide and 0.26 g of potassium carbonate in 10 mL of N,N-dimethylformamide, 0.107 g of methyl iodide was added and the resultant mixture was stirred at room temperature for 15 hours. After the completion of the reaction, the reaction mixture was diluted with 20 mL of water and the diluted reaction mixture was extracted with ethyl acetate (30 mL×1). The organic phase was dehydrated and dried with saturated brine and over anhydrous sodium sulfate, respectively, in this order, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:3) to obtain 0.28 g of the objective substance as a colorless resin-state substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]3[NH:17][C:16]2=[O:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:27][CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]3[N:17]([CH2:27][CH3:28])[C:16]2=[O:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: Cc1cnc2c(c1)[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(C)cc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.64 g), iodoethane (0.20 mL) and cesium carbonate (1.26 g) in DMF (5 mL) was stirred at 50° C. for 4 h. After stirring at room temperature over weekend, the mixture was poured into water, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 3-[4-(benzyloxy)phenyl]-1-ethyl-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.68 g) as a brown oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]([C:17]1[O:18][CH:19]=[CH:20][C:21]=1[C:22]([O:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[O:23])[CH2:13][CH:14]([CH3:16])[CH3:15].C(N(CC)CC)C>ClCCl>[CH3:15][CH:14]([CH3:16])[CH2:13][C:12]([C:17]1[O:18][CH:19]=[CH:20][C:21]=1[C:22]([O:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])=[O:23])=[O:11]
Reactant: CC(C)CC(O)c1occc1C(=O)OC[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)c1occc1C(=O)OC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
Dimethylsulfoxide (125 μl) was dissolved in dichloromethane (10 ml) and cooled to −78° C. Oxalyl chloride (80 μl) was added dropwise and the mixture was stirred for 15 minutes. Trimethylsilylmethyl 2-(1-hydroxy-3-methylbutyl)furan-3-carboxylate (200 mg) in dichloromethane (10 ml) was added and the mixture was stirred for 20 minutes. Triethylamine (0.49 ml) was added. The mixture was stirred for 20 minutes, and then allowed to warm to ambient temperature. The mixture was poured onto water and then extracted thrice with ethyl acetate. The organic phases were combined, washed with brine, dried, filtered and evaporated to give the sub-title compound (170 mg).
Reaction SMILES: BrCC1C=CC(C(OC)=O)=CC=1.[CH3:13][S:14]([CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=1)(=[O:16])=[O:15].[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.CS(CC1C=CC(C(O)=O)=CC=1)(=O)=O>>[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:22](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([CH2:17][S:14]([CH3:13])(=[O:15])=[O:16])=[CH:27][CH:26]=2)=[CH:31][C:30]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: COC(=O)c1ccc(CS(C)(=O)=O)cc1
Agent: COC(=O)c1ccc(CBr)cc1
Agent: CS(=O)(=O)Cc1ccc(C(=O)O)cc1
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
1 g of methyl 4-(bromomethyl)benzoate was reacted via Procedure O. 2.77 g of methyl 4-(methylsulfonylmethyl)benzoate was hydrolyzed via Procedure M. 1 g of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 1.15 g of 4-(methylsulfonylmethyl)benzoic acid via Procedure G. The crude product was subjected to basic workup and recrystallized with 1:1 Ratio of Isopropylacetate and Ether to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 401 (M)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:10]=1)[C:6]#[N:7].Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C>C(#N)C>[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N:11]=[C:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:14]=[CH:13]2)[CH:10]=1)[C:6]#[N:7]
Reactant: ClCCN1CCCCC1
Reactant: N#Cc1cc(N)cc(Nc2ccnc3cc(Cl)ccc23)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cc(N)cc(N=c2ccn(CCN3CCCCC3)c3cc(Cl)ccc23)c1
Yield: 2.9 %

Procedure:
3-Amino-5-[(7-chloroquinolin-4-yl)amino]benzonitrile hydrochloride prepared from step B of example 19 (200 mg, 0.68 mmol), 1-(2-chloroethyl)piperidine hydrochloride (125 mg, 1 eq), K2CO3 (468 mg, 5 eq) and DIEA (0.11 mL, 1 eq) were refluxed in 30 mL of acetonitrile for 72 h. The reaction mixture was then filtered. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel (AcOEt/MeOH//100/0 to 95/5) to yield expected compound as a yellow powder (8 mg, 3% yield). m/z (ESI) 406.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:8]=[C:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH2:2][CH2:3][CH3:4].[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[C:27]([Cl:34])[CH:26]=1>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]2[N:7]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:8]=[C:9]3[C:14]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)=[O:33])=[C:27]([Cl:34])[CH:26]=1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Reactant: CCCCNc1c2ccccc2nn1-c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CCCCN(C(=O)Nc1ccc(C(=O)OC)cc1Cl)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, butyl-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-amine (example 4.1) was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in toluene for 5 d under reflux conditions to give the title compound as colorless foam. MS: m/e=510.9 [M+H+].
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Br[CH2:31][C:32]([NH2:34])=[O:33]>>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([CH2:31][C:32]([NH2:34])=[O:33])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NC(=O)CBr
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: NC(=O)CN1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Yield: 52.9 %

Procedure:
The compound (0.15 g) obtained in Example 1 and bromoacetamide (0.094 g) were reacted and treated in the same manner as in the method described in Example 7 to obtain the title compound as colorless crystals (0.083 g, 52%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([NH:31][C:32](=[O:36])[O:33][CH2:34][CH3:35])=S)[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.C1(S(Cl)(=O)=O)C=CC=CC=1>O1CCCC1>[CH2:34]([O:33][C:32](=[O:36])[NH:31][C:29]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)[C:5]2=[N:6][CH:7]=[C:2]([I:1])[CH:3]=[C:4]2[N:28]=1)[CH3:35]
Reactant: CCOC(=O)NC(=S)Nc1cc(I)cnc1NCc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
To a stirred solution of ethyl N-({5-iodo-2-[({3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl}methyl)amino]pyridin-3-yl}carbamothioyl)carbamate (2.30 g, 3.69 mmol) and triethylamine (1.30 g, 1.8 mL, 12.85 mmol) in tetrahydrofuran (20 mL) was added benzenesulfonyl chloride (0.93 g, 5.27 mmol). The resulting mixture was allowed to stir at room temperature. After 12 h, a precipitate had formed. The mixture was filtered, and the filtercake was washed with water (2×10 mL) and methanol (10 mL). The solids were dried to provide 1.50 g (69%) of ethyl(6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a brown solid.
Reaction SMILES: [N:1]1[C:10]2C(=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)C=C[CH:2]=1.CI.C[O:18]C1C=NC2C(C=1)=CC=C1C=CC=CC=21.[CH2:33]([Li])[CH2:34][CH2:35][CH3:36].[NH4+].[Cl-]>CCOC(C)=O>[CH3:2][N:1]1[C:10]2[C:36](=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH:35]=[CH:34][CH:33]1[OH:18]
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)ccc1cccnc12
Reactant: COc1cnc2c(ccc3ccccc32)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1c2c(ccc3ccccc23)C=CC1O
Reaction time: 1 h

Procedure:
Compound 13 was alkylated with MeI according to a general amino group alkylation procedure as follows. The 3-methoxybenzoquinoline derivative (100 mg) 13 was suspended in 5 mL of dry TKF and cooled to −5° C. (ice/NaCl). 1.1 equivalents of n-butyl lithium (1 M) was added dropwise, and the reaction was stirred for 1 hour. 3 equivalents of the MeI alkylating agent was added slowly and the reaction was allowed to stir at room temperature for 2 hours. Aqueous work-up using NH4Cl and EtOAc gave a crude alkylated 3-methoxybenzoquinoline intermediate 14. Intermediate 14 was then purified by normal phase flash chromatography employing EtOAc: hexane (1:19) as the mobile phase (1HNMR: CD3Cl d 8.1 (broad d, 1 H, J=8.1 Hz), 7.68 (dd, 1 H, J=8.1, 1.8 Hz), 7.34 (m, 2 H), 6.8 (s, 1 H), 3.92 (s, 3 H), 3.21 (m, 2 H), 2.94 (s, 3 H), 2.77 (t, 2 H, J=6.6 Hz), 1.92 (m, 2 H)). Subsequent methoxy group deprotection by the general boron tribromide procedure described above in Example 1 resulted in the N-methyl-hydroxy benzoquinoline derivative 15.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([NH:16][CH2:17][C:18]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]2[C:19]=1[O:20][C:21]1[C:22]([CH2:38][C:39]([O:41]CC3C=CC=CC=3)=[O:40])=[C:23]([O:36][CH3:37])[CH:24]=[CH:25][C:26]=1[C:27]2([CH3:35])[CH3:34])=[O:15])[CH3:13])=O)C1C=CC=CC=1>C(O)C(F)(F)F.[Pd]>[NH2:11][C@H:12]([C:14]([NH:16][CH2:17][C:18]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]2[C:19]=1[O:20][C:21]1[C:22]([CH2:38][C:39]([OH:41])=[O:40])=[C:23]([O:36][CH3:37])[CH:24]=[CH:25][C:26]=1[C:27]2([CH3:35])[CH3:34])=[O:15])[CH3:13]
Reactant: COc1ccc2c(c1CNC(=O)[C@H](C)NC(=O)OCc1ccccc1)Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Agent: [Pd]
Solvent: OCC(F)(F)F
Product: COc1ccc2c(c1CNC(=O)[C@H](C)N)Oc1c(ccc(OC)c1CC(=O)O)C2(C)C
Yield: 91.4 %

Procedure:
A solution of 0.3 g of benzyl 5-[(N-benzyloxycarbonyl-L-alanyl)aminomethyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate in 85 ml of trifluoroethanol was stirred under hydrogen for 15 minutes in the presence of palladium/charcoal (10%). The catalyst was filtered off and rinsed with trifluoroethanol. The filtrate and wash solution were brought to dryness and the combined residue was chromatographed over silica gel in chloroform/methanol/water, whereby 0.18 g 5-(L-alanylaminomethyl)-3,6-dimethoxy-9,9-dimethylxanthene-4-acetic acid was obtained as a colourless foam, IR 3450-2400, 1679, 1606, 1575, 1493 cm-1.