Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16](C(OC(C)(C)C)=O)[N:15]=[C:14]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:13]=1.[CH2:36]1[CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45][N:40]2[CH2:39][CH2:38][N:37]1[C:46]1[CH:55]=[CH:54][C:49]([C:50](OC)=[O:51])=[CH:48][CH:47]=1>C1COCC1>[CH2:36]1[CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45][N:40]2[CH2:39][CH2:38][N:37]1[C:46]1[CH:55]=[CH:54][C:49]([C:50]([NH:11][C:12]2[NH:16][N:15]=[C:14]([CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=3)[CH:13]=2)=[O:51])=[CH:48][CH:47]=1
Reactant: COC(=O)c1ccc(N2CCN3CCCCC3C2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN5CCCCC5C4)cc3)[nH]n2)cc(OC)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 9.3 %

Procedure:
A 1M solution of NaHMDS in THF (1.13 ml, 1.05 mmol) was added to a stirred solution of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244 mg, 0.7 mmol) and methyl 4-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)benzoate (231 mg, 0.84 mmol) in THF (5 ml) at 0° C. under nitrogen, over 5 minutes. The reaction mixture was stirred for an additional 5 minutes at 0° C., then stirred at 20° C. for 18 h. An additional amount of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (80 mg, 0.23 mmol) was added with 1M NaHMDS in THF (1.13 ml, 1.13 mmol). The reaction mixture was stirred for an additional 3 h. The reaction mixture was quenched with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3×20 ml). The extracts were washed with saturated brine solution (15 ml), dried (MgSO4) and evaporated to give crude product. The crude product was purified by reverse phase prep. HPLC (basic) using a 38-58% gradient of acetonitrile in water containing 1% 0.880 ammonium hydroxide. The clean fractions were taken and evaporated to afford the title compound as a white solid (32 mg, 9%); 1H NMR (500.13 MHz, DMSO-d6) δ 1.25 (1H, s), 1.62 (2H, t), 1.72 (1H, d), 1.93-1.95 (2H, m), 2.19-2.20 (1H, m), 2.44 (1H, s), 2.81 (3H, q), 2.87 (4H, s), 3.28 (1H, s), 3.69 (1H, s), 3.72 (6H, s), 3.77 (1H, d), 6.33 (1H, t), 6.42 (2H, d), 6.44 (1H, s), 6.96 (2H, d), 7.89 (2H, d), 10.29 (1H, s), 12.07 (1H, s). MS: m/z 490 (MH+).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[CH:31]=[CH:30][C:21]3[O:22][C:23]([CH3:29])([CH3:28])[C@@:24]4([CH3:27])[O:26][C@H:25]4[C:20]=3[CH:19]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([OH:40])=[N:34]1.N1C=CC=CC=1>O1CCOCC1>[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([O:40][C@H:25]2[C@@:24]([OH:26])([CH3:27])[C:23]([CH3:28])([CH3:29])[O:22][C:21]3[CH:30]=[CH:31][C:18]([S:15]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)(=[O:16])=[O:17])=[CH:19][C:20]2=3)=[N:34]1
Reactant: Cn1nc(O)ccc1=O
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2[C@@H]2O[C@@]21C
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Cn1nc(O[C@@H]2c3cc(S(=O)(=O)c4ccc(O)cc4)ccc3OC(C)(C)[C@@]2(C)O)ccc1=O
Yield: 21.2 %

Procedure:
(3S,4S)-6-(4-tert-Butyidimethylsilyloxyphenyl)sulphonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (1.618 g) (see Preparation 14) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazine (1.33 g) (see J.Org.Chem, 1971, 36, 3372) were suspended in dry 1,4-dioxane (15 ml), pyridine (0.275 ml) was added and the mixture was heated under reflux (a calcium chloride drying tube was attached to the flask) for 3 days. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was separated and dried (anhydrous sodium sulphate), the solvent was removed under reduced pressure and the crude product was chromatographed on silica using. 1:99 methanol: ethyl acetate as the eluent to yield (3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridazin-6-yl)oxy-3-hydroxy-6-(4-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (0.352 g) as a white solid. Found: C,58.13; H,5.00; N,5.70. C23H24N2O7S requires C,58.46; H,5.12; N,5.93%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]2[CH2:19][O:18]2)[CH2:11][CH2:10]1.[N:20](CC(O)CCN1CCN(C2C=CC=C(Cl)C=2Cl)CC1)=[N+:21]=[N-:22]>>[N:20]([CH2:19][CH:17]([OH:18])[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)=[N+:21]=[N-:22]
Reactant: COc1ccccc1N1CCN(CCC2CO2)CC1
Reactant: [N-]=[N+]=NCC(O)CCN1CCN(c2cccc(Cl)c2Cl)CC1
Product: COc1ccccc1N1CCN(CCC(O)CN=[N+]=[N-])CC1
Yield: 15 %

Procedure:
Prepared from 28b in a similar fashion as described above for 29a. Yield: 15%, 1H NMR (CDCl3): δ 1.55 (ddd, J 14.6, 6.7, 3.6, 1H), 1.80 (m, 1H), 2.62 (s, 2H), 2.74 (m, 2H), 2.89 (s, 2H), 3.09 (s, 4H), 3.24 (dd, J 11.6, 4.1, 1H), 3.29 (dd, J 11.6, 4.9, 1H), 3.86 (s, 3H), 4.03 (dtd, J 9.8, 5.5, 2.5, 1H), 6.86 (d, J 8.0, 1H), 6.89-6.95 (m, 2H), 7.01 (ddd, J 8.0, 5.1, 4.1, 1H), 13C NMR (CDCl3): δ 28.4, 50.7, 53.5, 53.5, 55.4, 56.6, 57.4, 73.0, 111.2, 118.3, 121.1, 123.2, 140.9, 152.3.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:19][CH:18]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COc1ccc(NN=C(Cl)C(C)=O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(NN=C(Sc2ccc(Cl)cc2)C(C)=O)cc1

Procedure:
A suspension of 31.7 g (0.139 mol) of 1-chloro-1-[(4-methoxyphenyl)hydrazono]-2-propanone in 400 ml of ethanol was treated with 23.4 g (0.161 mole) of 4-chlorothiophenol followed by 23.4 ml of triethylamine. The suspension was heated at reflux for 2 hours and cooled. The resultant suspension was filtered and the precipitate was washed with 1 portion of cold ethanol. The solids were dried in vacuo to yield 1-[(4-chlorophenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone, mp 111.5-113.5° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[O:26]=[S:25]1(=[O:27])[CH2:24][CH2:23][CH2:22][N:2]1[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CN2CCCS2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-aminomethylbenzoate hydrochloride (1.61 g) and triethylamine (2.45 mL) were dissolved in dichloromethane (40 mL), 3-chloropropane-1-sulfonyl chloride (1.17 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (8 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.46 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 0.5N hydrochloric acid, and the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:ethyl acetate) to give the title compound (1.95 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]([C:23]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[S:24])[NH2:22].CN(C)C=O>Cl.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:22][NH:21][C:23]([NH:25][C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)=[S:24])[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Yield: 48.8 %

Procedure:
1-[5-(4-tert-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.163 mmol, 44.4 mg) synthesized in Synthetic Example 3 and 4-hydrazinocarbonothioylaminobenzoic acid (0.163 mmol, 34.4 mg) were stirred with dimethylformamide (3 mL) and two drops of concentrated hydrochloric acid at room temperature for 20 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a yellow solid (37 mg, yield 48%).
Reaction SMILES: Br[C:2]1[C:3]([C:17]#[N:18])=[N:4][N:5]([CH3:16])[C:6]=1[CH2:7][NH:8]C(=O)OC(C)(C)C.[ClH:19].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.COC(C)(C)C>C(OCC)C>[ClH:19].[NH2:8][CH2:7][C:6]1[N:5]([CH3:16])[N:4]=[C:3]2[C:2]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]=[C:17]2[NH2:18]
Reactant: Nc1ccccc1B(O)O
Reactant: Cn1nc(C#N)c(Br)c1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: Cn1nc2c(N)nc3ccccc3c2c1CN
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 94.6 %

Procedure:
A modification of the method described in Example 1283 was used to couple tert-butyl (4-bromo-3-cyano-1-methyl-1H-pyrazol-5-yl)methylcarbamate (1.43 g, 4.53 mmol) with 2-aminophenylboronic acid hydrochloride (1.57 g, 9.06 mmol). The reaction was completed in 70 minutes. tert-Butyl methyl ether was used instead of chloroform in the work-up procedure. The coupling product was purified by IFC (silica cartridge, eluting with 40% to 60% ethyl acetate in hexane). The reaction with hydrogen chloride was heated at reflux for 24 hours. Diethyl ether (50 mL) was added after the reaction cooled to room temperature. A precipitate was present and was isolated by filtration and dried on the vacuum filter funnel for three hours to provide 1.13 g of 1-(aminomethyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine hydrochloride as a white solid, mp>250° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[OH:14])([CH3:6])([CH3:5])[CH3:4].[CH2:15]([O:17][P:18](Cl)(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16]>C1COCC1>[P:18]([O:19][CH2:20][CH3:21])([O:17][CH2:15][CH3:16])([O:14][C:8]1[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=1[C:3]([CH3:6])([CH3:5])[CH3:4])=[O:22]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)Oc1ccc(C)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To a suspension of NaH (60% in mineral oil, 8.4 g, 0.21 mol) in THF (200 mL) was added dropwise a solution of 2-tert-butyl-4-methylphenol (33 g, 0.20 mol) in THF (100 mL) at 0° C. The mixture was stirred at 0° C. for 15 min and then phosphorochloridic acid diethyl ester (37 g, 0.21 mol) was added dropwise at 0° C. After addition, the mixture was stirred at ambient temperature for 30 min. The reaction was quenched with sat. NH4Cl (300 mL) and then extracted with Et2O (350 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and then evaporated under vacuum to give 2-tert-butyl-4-methylphenyl diethyl phosphate (contaminated with mineral oil) as a colorless oil (60 g, ˜100%), which was used directly in the next step.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[Cl-].[CH:19](=[N+:26]([CH3:28])[CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:19]([N:26]([CH3:28])[CH3:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: C[N+](C)=Cc1ccccc1
Reactant: CCn1c(-c2ccccc2)cc2ccccc21
Agent: [Cl-]
Product: CCn1c(-c2ccccc2)c(C(c2ccccc2)N(C)C)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-2-phenyl-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[S:4]
Reactant: NNC(N)=S
Reactant: CC(=O)NCCCC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=O)NCCCC(=NNC(N)=S)c1ccccc1
Yield: 60.7 %

Procedure:
Thiosemicarbazide (2.85 g, 31.3 mmol) was added to a solution of N-(4-oxo-4-phenyl-butyl)-acetamide (4.28 g, 20.9 mmol), prepared in the previous step, in 75 ml of methanol plus 5.6 ml of 1 N HCl, plus 5.6 ml of water and the reaction stirred at room temperature for 42 hours. The reaction was concentrated under reduced pressure to remove the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, washed five times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 4.77 g of a yellow solid Recrystallization of this solid from ethyl acetate gave the title compound (3.53 g, 61%) as an off-white solid, mp 74-83° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:10]([CH2:11][C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)=[O:13])[C:9]2[CH:27]=[CH:28][CH:29]=[CH:30][C:8]=2[N:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:6](=[O:37])[CH2:5]1.Br[CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[N:41]=1.O>CN(C=O)C>[C:52]([O:51][C:49]([N:42]1[C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40]([CH2:39][CH:5]2[C:4](=[O:3])[N:10]([CH2:11][C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][O:23][C:17]=4[CH:16]=3)=[O:13])[C:9]3[CH:27]=[CH:28][CH:29]=[CH:30][C:8]=3[N:7]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:6]2=[O:37])=[N:41]1)=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: CC(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc2c(c1)OCO2
Reaction time: 22 h
Yield: 27.6 %

Procedure:
31 mg of Sodium Hydride (60% in oil) is added to a solution of 2-(-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(3,4-methylenedioxy-phenyl) acetamide (300 mg. 0.636 mmol) in DMF (10 mL ) and the resultant mixture stirred at RT for 0.5 h prior to the addition of 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole (197 mg, 0.636 mmol) to the reaction mixture. After 22 h, 10 mL of water is added and the resultant mixture extracted into ethyl acetate (3×10 mL). The combined organics were washed with water (3×10 mL), brine (10 mL), dried (MgSO4), and concentrated in vacuo to afford the crude product (460 mg) as a brown foam. Purification by silica gel flash column chromatography using 2% methanol in methylene chloride as eluent gave the desired product (123 mg) as a beige solid: 1H NMR (300 MHz, CDCl3) δ8.10 (d, 1H, J=8.6), 7.91 (d, 1H, J=8.0), 6.8-7.6 (m, 14H), 6.09 (s, 2H), 5.01 (m, 1H, J=6.9), 4.36 (m, 3H), 3.90 (dd, 1H, J=16.4, 8.8), 3.58 (m, 1H), 1.67 (s, 9H), 1.08 (m, 6H).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.N1C=CN2C=C(C=O)C=CC=12.[F:28][C:29]1[C:38]([CH:39]=O)=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2>>[F:28][C:29]1[C:38]([CH2:39][C:2]2[N:6]3[N:7]=[C:8]([C:11]4[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=4)[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2
Reactant: Cn1cc(-c2ccc3ncc(Br)n3n2)cn1
Reactant: O=Cc1ccc2ncccc2c1F
Agent: O=Cc1ccc2nccn2c1
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncccc5c4F)n3n2)cn1

Procedure:
(rac)-(5-Fluoro-quinolin-6-yl)-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-methanol was obtained analogously to Stage 9.1 by replacing 3-bromo-6-chloro-imidazo[1,2-b]pyridazine with 3-bromo-6-(1-methyl-1h-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Stage 8.1) and imidazo[1,2-a]pyridine-6-carbaldehyde with 5-fluoro-quinoline-6-carbaldehyde (Intermediate A) (tR 0.90 min (conditions 1), (MH+=375).
Reaction SMILES: [C:1]1([CH2:13][CH2:14][NH2:15])[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]3[O:10][CH2:11][CH2:12][C:6]=3[C:5]=12.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]1([CH2:13][CH2:14][NH:15][C:23](=[O:25])[CH3:24])[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]3[O:10][CH2:11][CH2:12][C:6]=3[C:5]=12
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1cnn2ccc3c(c12)CCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCc1cnn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a solution of 2-(8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)ethanamine (75.0 mg, 0.369 mmol) and triethylamine (105 μL, 0.753 mmol) in tetrahydrofuran (4 mL) was added acetic anhydride (70.0 μL, 0.741 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. A saturated aqueous sodium hydrogen carbonate solution (50 μL) was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) and recrystallization (ethyl acetate/diisopropyl ether) to give the title compound (42.1 mg, yield 47%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([O:11][C@H:10]([CH2:12][O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][C@H:7]1[OH:8])[OH:6].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][C:5]1([O:11][C@H:10]([CH2:12][O:13][C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C@H:7]1[O:8][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[OH:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCCC1(O)O[C@H](COC(=O)c2ccccc2)C[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COCCC1(O)O[C@H](COC(=O)c2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (2-methoxyethyl)-5-O-benzoyl-3-deoxy-D-xylofuranose (example 122) (9.59 g, 32.40 mmol) and imidazole (3.980 g, 58.47 mmol) in DMF (40 mL ) at room temperature was added t-butyldimethylsilyl chloride (6.35 g, 42.12 mmol). The solution was stirred for 3 h and saturated NaHCO3 wasadded. The mixture was concentrated under vacuo. The residue was then partitioned between ether (100 mL) and water (50 mL). The aqueous phase was further extracted with ether (2×50 mL). The combined extracts were washed with brine (2×50 mL) dried (MgSO4) and concentrated to give the title compound (13.3 g, 100%)
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1([C:18]([S:20]C)=S)[CH2:17][CH2:16][CH2:15][S:14]1.C>C(O)C>[CH3:1][NH:2][C:18]([C:13]1([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:3]=2)[CH2:17][CH2:16][CH2:15][S:14]1)=[S:20]
Reactant: CSC(=S)C1(c2ccc3ccccc3n2)CCCS1
Reactant: CN
Solvent: CCO
Product: CNC(=S)C1(c2ccc3ccccc3n2)CCCS1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A 33% (weight/volume) solution of methylamine in ethanol (13.5 cc) is added dropwise and in the course of 10 minutes to a suspension of methyl 2-(quinol-2-yl)-tetrahydrothiophen-2-carbodithioate (20 g) in ethanol (42 cc), kept at a temperature of about 20° C. The reaction mixture is then stirred for 15 hours at a temperature of about 20° C. The resulting crystals are filtered off, washed twice with ethanol (24 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. A crystalline crude product (12.1 g) is thus obtained. This product is redissolved in boiling ethanol (75 cc); decolourising charcoal (0.6 g) is added to the solution, which is filtered hot, and the filtrate is then cooled for 3 hours at a temperature of about 5° C. The resulting crystals are filtered off, washed twice with ethanol (24 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. N-Methyl-2-(quinol-2-yl)-tetrahydrothiophen-2-carbothioamide (11 g), melting at 124° C., is thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[CH:34]=[CH:33][C:22]([CH2:23][NH:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][N:24]([CH2:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:17][CH:16]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(Cc1ccc(Br)cc1)C(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Prepared using General Procedure 6: To a stirred solution of 4-((tert-butoxycarbonyl)amino)benzoic acid (2.0 g, 8.43 mmol), tert-butyl 2-((4-bromobenzyl)amino)acetate INT-60 (2.53 g, 8.43 mmol) and TEA (1.76 mL, 12.6 mmol) in DMF (15 mL) was added HATU (3.53 g, 9.27 mmol) at room temperature. After stirring at room temperature for 2 h the reaction mixture was diluted with EA (150 mL) and washed with brine (200 mL). The organics were concentrated in vacuo and the residue was purified by chromatography (EA/hexanes) to afford 3.97 g (91%) of tert-butyl 2-(N-(4-bromobenzyl)-4-((tert-butoxycarbonyl)amino)benzamido)acetate INT-61 as a viscous oil. LCMS-ESI (m/z) calculated for C25H31BrN2O5: 519; found: 517/519 [M−H]−, tR=2.68 min (Method 10).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:24])[NH:11][CH2:12][C@@H:13]([OH:23])[C@@H:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:25]([NH:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[CH:36]=1)[C:31](O)=[O:32])[CH3:26]>>[CH2:2]([O:9][C:10](=[O:24])[NH:11][CH2:12][C@@H:13]([OH:23])[C@@H:14]([NH:22][C:31]([C:30]1[CH:34]=[C:35]([N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[CH:36]=[C:28]([NH:27][CH2:25][CH3:26])[CH:29]=1)=[O:32])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCNc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNC(=O)OCc1ccccc1
Agent: Cl
Product: CCNc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNC(=O)OCc2ccccc2)cc(N2CCCC2=O)c1

Procedure:
Description 106 was prepared in an analogous manner to Description 105 from 3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-benzoic acid hydrochloride (D104) and 3-ethylamino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (A31).