Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@:9]1([CH3:16])[C:13]2([CH2:15][CH2:14]2)[CH2:12][NH:11][CH2:10]1)=O)(C)(C)C.F[C:18]1([N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28](F)[C:29]=3[CH3:31])[C:24](=[O:33])[C:23]([C:34]([OH:36])=[O:35])=[CH:22]2)[CH2:20][CH2:19]1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>Cl.CS(C)=O>[NH2:8][C@@:9]1([CH3:16])[C:13]2([CH2:14][CH2:15]2)[CH2:12][N:11]([C:28]2[C:29]([CH3:31])=[C:30]3[C:25]([C:24](=[O:33])[C:23]([C:34]([OH:36])=[O:35])=[CH:22][N:21]3[CH:18]3[CH2:19][CH2:20]3)=[CH:26][CH:27]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@]1(C)CNCC12CC2
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn(C3(F)CC3)c12
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(N2CC3(CC3)[C@](C)(N)C2)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 75 °C
Reaction time: 120 h

Procedure:
A mixture of (75)-7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptane (524 mg, 2.31 mmol), 1-fluorocyclopropyl-7-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (503 mg, 1.925 mmol), triethylamine (0.537 mL, 3.85 mmol), and dimethyl sulfoxide (6 mL) was stirred in nitrogen atmosphere in an oil bath at 75° C. for 5 days, and in an oil bath at 85° C. for 2 days. To the reaction mixture was added 10% aqueous solution of citric acid (10 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL×2) and saturated aqueous solution of sodium chloride (10 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, 10 g; elusion by chloroform→chloroform:methanol, 98:2) to obtain a pale yellow foam solid. The purified pale yellow foam solid was dissolved in concentrated hydrochloric acid (8 mL) at room temperature, and after transferring the resulting acidic aqueous solution to a separatory funnel while washing with 6N hydrochloric acid, the solution was washed with chloroform (50 mL×8). To the aqueous layer was added 10 mol/l aqueous solution of sodium hydroxide to pH 12.0 in an ice bath, and hydrochloric acid was added to adjust the pH to 7.4. The solution was extracted with a mixed solvent of chloroform and methanol (chloroform:methanol, 9:1) (100 mL×3), and the organic layer was dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was purified by recrystallization from ethanol, and dried under reduced pressure to obtain 268 mg (0.641 mmol, 2 steps, 33%) of the title compound as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH3:17])[C:11]=2[C:10](=O)[CH2:9]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:30][NH:31][C:32]([NH:34][CH3:35])=[NH:33].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH3:17])[C:11]=2[C:10](=[N:30][NH:31][C:32](=[NH:33])[NH:34][CH3:35])[CH2:9]1
Reactant: CNC(=N)NN
Reactant: Cc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: CNC(=N)NN=C1CC(c2ccccc2Cl)Cc2[nH]nc(C)c21
Temperature: 25 °C
Reaction time: 60 h
Yield: 145.6 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-4-oxo-4,5,6,7-tetrahydroindazole (78 mg), 1-amino-3-methylguanidine p-toluenesulfonate (86 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (1 ml) was stirred at room temperature for 60 hours, and crystals precipitated during the reaction were filtered and washed with ethanol. To the crystals were added ethyl acetate (60 ml) and 2 N sodium hydroxide (5 ml) to dissolve the crystals. The separated ethyl acetate layer was washed with water (10 ml, thrice), to which was added 2 N hydrochloric acid (0.3 ml). The mixture was concentrated under reduced pressure, and the residue was washed with a mixture of ether/ethanol=4/1 and dried to give 6-(2-chlorophenyl)-3-methyl-4-(1-methylguanidin-3-yl)imino-4,5,6,7-tetrahydroindazole hydrochloride (Compound 92) (80 mg) as colorless solid.
Reaction SMILES: CS(O[CH:6]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[Br:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>CN(C=O)C>[Br:33][C:34]1[CH:40]=[CH:39][C:37]([N:38]2[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[CH2:8][CH2:7][CH:6]2[C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:36][CH:35]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C2CCC(c3ccc([N+](=O)[O-])cc3)N2c2ccc(Br)cc2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
The product from Example 1C (0.7 g, 1.433 mmol) and 4-bromoaniline (2.54 g, 14.33 mmol) were suspended in DMF (6 mL) and stirred at 50° C. overnight. The resulting mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was washed with 1N HCl (2×50 mL) followed by a brine wash then dried over MgSO4 filtered and concentrated. The crude product was purified by chromatography on silica gel using a solvent gradient of 2-50% ethyl acetate in hexane to give the title compound as a mixture of stereoisomers (74.4 mg, 11% yield).
Reaction SMILES: [CH3:1][CH2:2][CH:3](P(OCC)(OCC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30]>O1CCCC1>[CH2:2]([C:3](=[CH:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[C:22]([N+:29]([O-:31])=[O:30])[CH:23]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:1]
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1ccc(OC)c([N+](=O)[O-])c1)CC
Yield: 93.3 %

Procedure:
Under an argon atmosphere, stirring and cooling with ice, a solution of triethyl 2-phosphonobutyrate (5.00 g, 19.8 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise slowly to a solution of sodium hydride (60% oil dispersion, 795 mg, 19.9 mmol) in anhydrous tetrahydrofuran (120 mL). After stirring for 1 hour at 0° C., a solution of 4-methoxy-3-nitrobenzaldehyde (3.26 g, 18.0 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise, and the mixture was stirred for 1 hour at 0° C. and for 3 hours at room temperature. The reaction mixture was concentrated and ice water was added to the residue, which was extracted with ethyl acetate. The extracte was washed with water, brine and dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent n-hexane:ethyl acetate=8:1→2:1 v/v) to obtain 4.69 g (93%) of ethyl 2-ethyl-3-(4-methoxy-3-nitrophenyl)acrylate as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:18]=1.Cl.O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][C:19]=3[O:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1ccc(F)cc1OC1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (8.5 g) and 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (7.4 g) (intermediate XX) in dioxane (100 ml) was added HCl in dioxan (4M; 0.9 ml). The reaction was stirred at 100° C. overnight. The reaction mixture was allowed to warm to room temperature and water (50 ml) was added. The precipitate was isolated by filtration
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=4)[CH:11]=3)=[CH:7][C:6]=2[CH:22]=1.[C:23](Cl)(=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=4)[CH:11]=3)=[C:7]([C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27])[C:6]=2[CH:22]=1
Reactant: CCCCC(=O)Cl
Reactant: COc1ccc2cc(-c3cc4cc(Cl)ccc4o3)ccc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)c1c(-c2ccc3cc(OC)ccc3c2)oc2ccc(Cl)cc12
Yield: 89.1 %

Procedure:
Following the procedure described in Step 2 of Example 1, the title compound was prepared by the acylation of 5-chloro-2-(6-methoxy-naphth-2-yl)-1-benzofuran (6.6 g, 21.37 mmol), with valeryl chloride (2.3 mL, 16 mmol) in presence of tin (IV) chloride in chloroform. Purification by flash chromatography on silica gel using 2.5% ethyl acetate in hexane as the mobile phase yielded the title compound as a white solid (5.6 g), mp 119-120° C. Mass spectrum (+ESI, [M+NH4]+) m/z 410. 1HNMR (400 MHz, DMSO-d6): δ8.36 (d, 1H, J=1.6 Hz), 8.02 (dd, 2H, J=7.0, 2.2 Hz), 7.99 (s, 1H), 7.81 (dd, 1H, J=8.6, 1.7 Hz), 7.77 (d, 1H, J=8.8 Hz), 7.48-7.44 (m, 2H), 7.27 (dd, 1H, J=8.8, 2.3 Hz), 3.92 (s, 3H), 2.69 (t, 2H, J=7.3 Hz), 1.51 (m, 2H), 1.1 (m, 2H), and 0.68 ppm (t, 3H, J=7.3 Hz). Elemental Analysis for C24H21 ClO3: Calculated: C, 73.37; H, 5.39; N, 0.00. Found: C, 73.34; H, 5.27; N, 0.03.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].O=[CH:14][C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1>CO>[OH:21][C:20]1[CH:22]=[CH:23][C:15]([CH:14]=[CH:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: CCCCCCCC(C)=O
Reactant: COc1cc(C=O)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCC(=O)C=Cc1ccc(O)c(OC)c1
Temperature: 35 °C
Yield: 43.5 %

Procedure:
100 g potassium hydroxide were dissolved in 500 g of methanol and heated up to reflux under stirring. A solution of 142 g of nonanone and 152 g of vanillin in 120 g of methanol were subsequently added continuously over a period of 1 hour. After that, the mixture was stirred for further 24 hours at the same temperature. After distilling 400 g of methanol from the mixture in vacuo, 400 g of toluene were added to the remaining residue, and after cooling to approximately 30-40° C. additionally 800 g of water were added. The mixture was then acidified with approximately 380 g of diluted sulphuric acid (20% in water) to a pH value of 4-5. After phase separation, the organic phase was washed with 200 g of water. After distillation, 120 g of the intermediate product 1-(4-hydroxy-3-methoxy-phenyl)-dec-1-en-3-one were obtained. Melting point: 45° C., yield: 42% of theory.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([CH2:19][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])=[CH:17][CH:18]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
(3,3,3-Trifluoropropyl)malononitrile (0.6 g) and 2-chloro-5-chloromethylpyridine (0.6 g) were dissolved in N,N-dimethylformamide (15 ml), potassium carbonate (0.51 g) was added thereto, and the mixture was stirred overnight at room temperature. Then, to the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed successively with water, saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained was subjected to silica gel column chromatography to give 0.62 g of 2-((6-Chloro-3-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (4)).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[NH:21][N:20]=2)=[CH:14][C:10]=1[C:11](O)=[O:12].Cl.[CH:31]1([O:36][CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CC(N(C)C)=O>[CH:31]1([O:36][CH:37]2[CH2:42][CH2:41][N:40]([C:11]([C:10]3[CH:14]=[C:15]([CH:16]=[CH:17][C:9]=3[F:8])[CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22](=[O:29])[NH:21][N:20]=3)=[O:12])[CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCC(OC2CCNCC2)C1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OC2CCCC2)CC1
Temperature: 20 °C
Reaction time: 72 h
Yield: 37.2 %

Procedure:
Triethylamine (0.280 ml, 2.01 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (200 mg, 0.67 mmol), 4-(cyclopentyloxy)piperidine hydrochloride (113 mg, 0.67 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (331 mg, 0.87 mmol) in DMA (2 ml) at 20° C. under air. The resulting mixture was stirred at 20° C. for 3 days. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (112 mg, 37.2% yield); 1H NMR (400.132 MHz, DMSO) δ 1.23-1.72 (11H, m), 1.81-1.87 (1H, m), 3.00-3.06 (1H, m), 3.22-3.27 (2H, m), 3.52-3.59 (1H, m), 3.96-4.04 (2H, m), 4.33 (2H, s), 7.18-7.23 (1H, m), 7.34 (1H, d), 7.38-7.42 (1H, m), 7.81-7.91 (2H, m), 7.97 (1H, d), 8.26 (1H, d), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=2.30 (M+H 450.1).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N:12]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:17][CH:16]=[CH:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH:16]12[O:9][CH:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:17]2
Reactant: O=C(OCc1ccccc1)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
mCPBA (14.6 g, 63.3 mmol) was added slowly to a stirred solution of benzyl 3,6-dihydropyridine-1(2H)-carboxylate (12.50 g, 57.5 mmol) in DCM (80 mL) which was cooled in an ice bath. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was then quenched with aq. Na2CO3 and the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound. LCMS calc. for C13H16NO3 (M+H)+: m/z=234.1. Found: 234.0.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:14][CH3:15])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:30]([CH3:35])[CH2:31][C:32]([OH:34])=O)[CH:26]=[CH:27][C:28]=1[Cl:29].C(N(CC)CC)C>ClCCl>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:14]([CH3:15])[C:32](=[O:34])[CH2:31][N:30]([C:25]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:23]([Cl:22])[CH:24]=2)[CH3:35])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1
Reactant: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Reactant: CN(CC(=O)O)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC(=O)N(C)C(CN1CCCC1)c1ccc(-c2ccccc2)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
[1-(4-biphenylyl)-2-(1-pyrrolidinyl)ethyl]methylamine (50 mg, 0.18 mmol) was added to a solution of N-(3,4-dichlorophenyl)-N-methylglycine (49 mg, 0.21 mmol), (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium-hexafluorophosphate (BOP) (118 mg, 0.27 mmol) and triethylamine (TEA) (54 mg, 0.54 mmol) in dichloromethane (DCM) (2.0 mL), The reaction mixture was stirred at room temperature for 3 h and was then concentrated in vacuo. To the residue was added 4 mL of saturated solution of Na2CO3 and then extracted by ethyl acetate (2×3 mL). The combined organic layers were concentrated in vacuo to give a brown solid, which was purified by using a Gilson preparative HPLC system (Phenomenex 75×30 mm column, 40 mL/min flow rate, A: 0.1% TFA in acetonitrile B: 0.1% TFA in water, A: 10 to 100% over 15 min, UV detection at 215 nm) to yield the title compound (52 mg, 58%). MS (ES) m/e 496 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([O:9][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The product from Example 11 (50.0 g; 178 mmol) is dissolved in anhydrous pyridine (910 ml). Methanesulphonyl chloride (18.6 ml; 241 mmol) is added dropwise while cooling in ice. Subsequently, the solution is stirred for 2.5 h during which it is allowed to warm to room temperature. The solution is then diluted with dichloromethane (3.6 l) and extracted twice by shaking with a 10% solution of sodium hydrogen carbonate (1.1 l on each occasion). The organic phase is dried (magnesium sulphate), concentrated and the residue subsequently distilled repeatedly with toluene. Yield: 64.0 g (quantitative).
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=O.Cl.[NH2:13][OH:14].[OH-].[Na+]>CCO>[Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[N:13][OH:14]
Reactant: O=Cc1c(O)ccc(O)c1Br
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ON=Cc1c(O)ccc(O)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a mixture of 2-bromo-3,6-dihydroxy-benzaldehyde (12A) (50 g, 0.23 mol) and hydroxylamine hydrochloride (19.2 g, 0.28 mol) was added 95% EtOH (500 mL), followed by NaOH (13.8 g, 0.345 mol). The reaction mixture was stirred at room temperature for 2 hours, then extracted with ethyl acetate and concentrated to give 2-bromo-3,6-dihydroxy-benzaldehyde oxime (12B) (45 g, 84.1% yield) as a solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([C:18]=1[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH:16][C:15]([Cl:28])=[CH:14][CH:13]=2)=[O:9].I[CH3:30]>CO.O1CCCC1>[CH3:30][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([C:18]=1[S:19]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:20])=[O:21])=[CH:16][C:15]([Cl:28])=[CH:14][CH:13]=2)=[O:9]
Reactant: O=C(NCc1ncc[nH]1)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Reactant: CI
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ccnc1CNC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a partial suspension of N-[(imidazol-2-yl)methyl] 3-phenylsulfonyl-5-chloroindole-2-carboxamide (Example 35) (42 mg, 0.1 mmol) in 1:1 methanol/tetrahydrofuran (4 mL) was added iodomethane (0.05 mL, 0.8 mmol). The reaction was stirred for three days at room temperature. The solvents were removed under reduced pressure, aq. NaHCO3 added and the product extracted into ethyl acetate/methanol. The organic layer was dried (Na2SO4), filtered, and the solvents evaporated. The residue was purified by chromatography and the product eluted with 3% methanol/chloroform. Appropriate fractions were combined, the solvents evaporated, and the residue triturated with methylene chloride to give pure product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:16]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][S:21]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)(=[O:23])=[O:22])[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1cccc(NS(=O)(=O)c2cccnc2)c1
Yield: 104.7 %

Procedure:
A solution of tert-butyl-3-aminobenzoate (100 mg, 0.5 mmol) and pyridine-3-sulfonylchloride (110 mg, 0.5 mmol) in pyridine (5 ml) was heated to 50° C. for 90 min. On cooling, the reaction was diluted with toluene (100 ml) and concentrated in vacuo. This was repeated with further aliquots of toluene until all the pyridine had been removed to afford the title compound as a yellow oil (175 mg). HPLC retention time 4.27 min. Mass spectrum (ES+) m/z 335 (M+H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]2[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:20]=[C:21]([CH3:22])[C:10]=12>O1CCCC1>[CH2:1]([O:5][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]2[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:20]=[C:21]([CH3:22])[C:10]=12)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Reactant: CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.7 %

Procedure:
To an ice-cold solution of 1-butanol (5.0 g, 68 mmol) in tetrahydrofuran (15 mL), sodium hydride (oiliness, content 60%, 0.41 g, 17 mmol) was added at room temperature and the mixture was stirred for 15 minutes. Subsequently, 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.0 g, 3.39 mmol) was added to the mixture at 0° C., and the mixture was heated under reflux for another 1 hour. After the reaction solution was cooled to room temperature, the reaction solvent was concentrated and evaporated under reduced pressure. To the reaction mixture was added iced water and the mixture was neutralized by the addition of dilute hydrochloric acid, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate) to give the title compound (0.29 g, 26% yield).