Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])[CH:2]=1.[K].[O-]CCCC.[CH3:24][N:25]=[C:26]=[S:27]>O1CCCC1>[CH3:24][NH:25][C:26]([C:11]1([C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])=[S:27]
Reactant: O=C1CCCCC1c1cnc2ccccc2c1
Reactant: CN=C=S
Agent: CCCC[O-]
Agent: [K]
Solvent: C1CCOC1
Product: CNC(=S)C1(c2cnc3ccccc3c2)CCCCC1=O
Yield: 9.4 %

Procedure:
A solution of (±)-2-(3-quinolinyl)cyclohexanone (0.78 g, 3.5 mmol) in tetrahydrofuran (10 ml) at -5° C. was treated with potassium t.-butoxide (0.43 g, 3.9 mmol) in one portion. After 25 minutes at -5° C. the deep red mixture was treated dropwise during 1 minute with a solution of methyl isothiocyanate (0.28 g, 3.9 mmol) in tetrahydrofuran (2 ml). After 4 hours at 0° C. the reaction mixture was partitioned between saturated aqueous ammonium chloride solution (50 ml) and chloroform (50 ml). The aqueous layer was extracted again with chloroform (50 ml). The combined organic extracts were then dried over sodium sulphate and concentrated in vacuo (20° C.; 14 mmHg) to give a crude oil which was purified by flash chromatography over silica gel eluting with ethyl acetate to give (±)-N -methyl-2-oxo-1-(3-quinolinyl)cyclohexanecarbothioamide (0.1 g, 0.33 mmol), m.p. 235°-236° C. N.M.R. (CDCl3) 1.7-2.18 (c, 4H), 2.46-2.64 (m, 2H) 2.72-2.90 (m, 1H), 2.96-3.16 (m, 1H), 3.16-3.22 (d, 3H), 7.50-7.62 (ddd, 1H), 7.66-7.76 (ddd, 1H), 7.76-8.02 (dd, 1M), 8.0 (d, 1M), 8.04-8.12 (dd, 1H), 8.78-8.80 (d, 1H), 8.92-9.18 (broad singlet, 1H). Calculated for C17H18N2OS: C,68.4; H, 6.08; N, 9.4; S, 10.7%: Found C, 68.0; H, 5.8; N, 9.0; S, 10.4%.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15].C(N(C(C)C)CC)(C)C>C(#N)C.CCOC(C)=O>[CH2:12]([NH:16][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Clc1ccc2ccccc2n1
Reactant: CCCCN
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCNc1ccc2ccccc2n1
Yield: 30.7 %

Procedure:
2-Chloroquinoline (500 mg, 3.06 mmol), butylamine (0.90 nrL, 9.16 mmol), and diisopropylethylamine (0.82 mL, 4.58 mmol) were dissolved in acetonitrile (5 mL), and solution refluxed 2 days. Reaction cooled and diluted with EtOAc. Reaction washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo. Residue purified by flash chromatography on silica gel eluting with 15% EtOAc/Hexanes to afford the desired product as a pale yellow oil (188 mg, 31% ). m/e (DCI) 201 (MH+)
Reaction SMILES: [CH3:1][NH:2][CH3:3].O1CCCC1.[F:9][C:10]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12](Cl)=[O:13]>ClCCl>[F:9][C:10]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12]([N:2]([CH3:3])[CH3:1])=[O:13]
Reactant: O=C(Cl)c1cc(I)ccc1F
Reactant: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Add a 2.0 M solution of dimethylamine in tetrahydrofuran (5 mL, 10.1 mmol) to a solution of 2-fluoro-5-iodobenzoylchloride (1.3 g, 4.6 mmol) in dichloromethane (20 mL) and stir at room temperature for 0.5 h. Sequentially wash the reaction mixture with a 1 N hydrochloric acid (50 mL), a 1 N sodium hydroxide (50 mL), and an aqueous saturated solution of sodium chloride (50 mL). Dry (sodium sulfate), filter, and concentrate to give the title compound as a white solid (1.3 g, 98%).
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[Cl:21])(=O)C(C)(C)C.[OH-].[Na+]>CO.C1COCC1.C(OCC)(=O)C>[C:23]([O:22][C@@H:9]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[Cl:21])[CH2:8][OH:7])([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cc2ccccc2c(Cl)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc2ccccc2c(Cl)c1[C@@H](CO)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
(S)-2-tert-Butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)ethyl pivalate (4G, 1.72 g, 4.56 mmol) was dissolved in MeOH (10 mL) and THF (10 mL). Sodium hydroxide (2 M, 9.13 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organics were dried (MgSO4), concentrated in vacuo and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give a colorless liquid (1.12 g, 84%). 1H-NMR: 300 MHz, (CD3OD) δ: 8.23 (d, 1H), 7.78 (d, 1H), 7.60 (s, 1H), 7.52 (dd, 2H), 5.69 (m, 1H), 3.83 (dd, 1H), 3.61 (m, 1H), 2.71 (s, 3H), 1.18 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[N+:7]([O-:18])=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)ccc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(F)ccc(Br)[n+]1[O-]
Temperature: 0 °C
Reaction time: 48 h
Yield: 95.5 %

Procedure:
A solution of 6-bromo-3-fluoro-2-methylpyridine (2.84 g, 14.94 mmol, 1 eq.) was dissolved in DCM (250 ml) and cooled to 0° C. Then mCPBA (7.34 g, 29.89 mmol, 2 eq.) was added by portions and the reaction was warmed to r.t. and stirred for 48 h. A sat. aqueous solution of NaHCO3/Na2S2O3 (1/1) was added and stirring allowed for 5 min. Then DCM was added and the layers separated. The aqueous layer was extracted with DCM then the organics were combined, dried over MgSO4 and concentrated. 6-bromo-3-fluoro-2-methylpyridine 1-oxide (2.94 g, 89%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]([CH3:25])[CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)=[CH:10][CH:9]=2)=[C:4]([F:26])[CH:3]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:29])C.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)(=O)C.C(OC(=O)C)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]([F:26])[C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]([CH3:25])[CH:15]3[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:21])([CH3:22])[CH2:20]3)=[CH:10][CH:9]=2)=[C:6]([OH:29])[CH:7]=1
Reactant: CN(c1ccc(-c2ccc(Cl)cc2F)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN(c1ccc(-c2c(O)cc(Cl)cc2F)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 40 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
6-(4-Chloro-2-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (50 mg, 0.13 mmol), PhI(OAc)2(60 mg, 0.19 mmol), and Pd(OAc)2(8.9 mg, 0.013 mmol) were dissolved in a mixture of acetic acid (0.6 mL) and acetic anhydride (0.6 mL). The mixture was stirred at 40° C. overnight. A solution of sodium thiosulfate was added and the mixture was stirred for 8 days at RT. A solution of potassium carbonate was added and the reaction pH was adjusted to 10. The aqueous phase was extracted (2×) with dichloromethane and methanol (9:1). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase preparative HPLC (10 to 30% acetonitrile in water, 0.1% trifluoroacetic acid as modifier). The appropriate fractions containing product were free based by catch and release using SiliaBond Propylsulphonic Acid® (4 eq, CH3CN as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was concentrated in vacuo and the resulting solid was suspended in CH3CN/H2O (3/1 mL). 1 M aqueous HCl (3 equivalents) was added, and the volatiles were concentrated in vacuo to afford the hydrochloride salt of 5-chloro-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol as a yellow solid (19 mg, 33%). LCMS Rt=0.57 min [Method Q]; [M+H]: 393.2; 1H NMR (400 MHz, MeOD) δ 8.21 (d, J=10.0 Hz, 1H), 7.99 (d, J=10.0 Hz, 1H), 6.99 (dd, J=10.0, 2.0 Hz, 1H), 6.94 (t, J=2.0 Hz, 1H), 5.09 (bs, 1H), 3.18 (s, 3H), 1.98-2.12 (m, 4H), 1.65 (s, 6H), 1.57 (s, 6H).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH:5]([N:13]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:23][CH2:22][N:21]([CH2:33][C:34]([O:36]CC)=[O:35])[CH2:20][C:19]2[N:39]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH2:14]1)[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])C.[OH-].[Na+]>C(O)C.O>[C:28]([CH2:27][N:24]1[CH2:23][CH2:22][N:21]([CH2:33][C:34]([OH:36])=[O:35])[CH2:20][C:19]2[N:39]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH2:14][N:13]([CH:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:4]([OH:40])=[O:3])[CH2:26][CH2:25]1)([OH:30])=[O:29]
Reactant: CCOC(=O)CCC(C(=O)OCC)N1CCN(CC(=O)OCC)CCN(CC(=O)OCC)Cc2cccc(n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(C(=O)O)N1CCN(CC(=O)O)CCN(CC(=O)O)Cc2cccc(n2)C1
Yield: 60 %

Procedure:
15 mg of the compound obtained in stage 2 (26.5 μmol) are dissolved in 40 μl of ethanol and 53 μl of 5N sodium hydroxide are added dropwise rapidly. The mixture is brought to reflux for 24 h. The reaction medium is diluted 10-fold with water and the pH is then adjusted to 6.5 by adding weakly acidic resin. The resin is filtered off and washed with water. A strongly basic resin is added to the filtrate and then filtered off and washed twice with water. The product is eluted with 50% acetic acid. After evaporation to dryness, the product is obtained in the form of brown crystals. m=8 mg. Yield=60%.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]([CH3:13])([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:14][CH:15]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CNC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)C(C)(C)Oc1ccc(OCc2cccc(F)c2)cc1

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of 2-(4-hydroxy-phenoxy)-2,N-dimethyl-propionamide with 3-fluoro-benzylbromide in 2-butanone using potassium carbonate as the base yielded the 2-[4-(3-fluoro-benzyloxy)-phenoxy]-2,N-dimethyl-propionamide as an brown oil; MS: m/e=318 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18]C(C4CC4)=O)[N:17]=3)[N:14]=2)=[CH:6][C:5]([NH:24][C:25]([C:27]2[N:31]([CH3:32])[N:30]=[C:29]([CH3:33])[CH:28]=2)=[O:26])=[C:4]([F:34])[CH:3]=1.Cl.C(OCC)(=O)C>CO>[ClH:1].[NH2:18][C:16]1[N:17]=[C:12]2[CH:11]=[CH:10][C:9]([O:8][C:7]3[CH:2]=[CH:3][C:4]([F:34])=[C:5]([NH:24][C:25]([C:27]4[N:31]([CH3:32])[N:30]=[C:29]([CH3:33])[CH:28]=4)=[O:26])[CH:6]=3)=[N:14][N:13]2[CH:15]=1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c(Cl)cc2F)n(C)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2F)n(C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.4 %

Procedure:
To a suspension of N-[4-chloro-5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (2.0 g, 4.72 mmol) in methanol (20 mL) was added 4N hydrochloric acid/ethyl acetate (16 mL) solution. After stirring at room temperature for 4 hr, the mixture was stirred at 50° C. for 12 hr. The solvent was evaporated under reduced pressure, and diisopropyl ether/ethanol (8 mL/2 mL) was added to the residue. The mixture was stirred at room temperature for 2 hr. The precipitate was collected by filtration and washed with diisopropyl ether to give the title compound (2.0 g, quant.) as a brown powder.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.O.O.O.O.O.O.[Cl-].[Al+3:29].[Cl-].[Cl-]>O>[O:1]=[C:2]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([O-:20])=[O:19])=[CH:13][CH:12]=1.[Al+3:29].[O:1]=[C:2]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([O-:20])=[O:19])=[CH:13][CH:12]=1.[O:1]=[C:2]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([O-:20])=[O:19])=[CH:13][CH:12]=1
Reactant: CC(C(=O)O)c1ccc(N2CC3=C(CC=CC3)C2=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C(=O)[O-])c1ccc(N2CC3=C(CC=CC3)C2=O)cc1
Reaction time: 1 h
Yield: 103 %

Procedure:
A mixture of 8.37 g (0.03 mole) of α-[4-(1-oxo-4,7-dihydro-2-isoindolinyl)phenyl]propionic acid and 30 ml of water was stirred for about 1 hour. At the end of this time, a solution of 2.41 g (0.01 mole) of aluminium chloride hexahydrate in 50 ml of water was added to the resulting solution. The white precipitate which was produced was collected by filtration and washed with 75 ml of water. The resulting white solid was then dried at 105° C. for 4 hours. There were obtained 9.0 g of a white solid, sparingly soluble in most organic solvents, slightly soluble in dimethyl sulphoxide and having a melting point above 300° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].C(N(CC)CC)C.[NH2:21][C:22]1[CH:43]=[CH:42][C:25]([C:26]([N:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][N:31]3[CH:39]=[CH:40][CH:41]=[C:30]3[CH2:29]2)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl>[CH:41]1[CH:40]=[CH:39][N:31]2[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N:28]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:7]([C:6]4[S:5][C:4]5[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=5[C:2]=4[Cl:1])=[O:8])=[CH:43][CH:42]=3)=[O:27])[CH2:29][C:30]=12
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1sc2ccccc2c1Cl
Reaction time: 0.25 h
Yield: 61.5 %

Procedure:
To a stirred solution of 0.440 g of 3-chlorobenzo[b]thiophen-2-carbonyl chloride in 10 ml of methylene chloride is added 0.33 ml of triethylamine. After stirring for 15 minutes, 0.485 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours. The reaction mixture is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.49 g of solid, m.p. 220°-222° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(S[C:15](=[O:28])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18])(C)(C)C>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH:16]([C:17](=[O:19])[CH3:18])[C:15]([NH:1][C:2]2[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=2[F:8])=[O:28])=[CH:26][CH:25]=1
Reactant: Nc1cc(O)ccc1F
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2-(4-chlorobenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:33])=[CH:27][CH:26]=1)[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: CCc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Yield: 56 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, 4-ethylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 90 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 42 mg of the title compound (yield: 56%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:23][C:17]=2[C:16]([CH2:31][CH:32]([CH3:34])[CH3:33])=[N:15]1.CC1C=CC(S(=O)([S:44][CH2:45][CH2:46][CH2:47][O:48][Si](C(C)(C)C)(C)C)=O)=CC=1>O1CCCC1>[OH:48][CH2:47][CH2:46][CH2:45][S:44][C:21]1[C:18]2[C:19](=[O:20])[N:14]([CH3:13])[N:15]=[C:16]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:17]=2[S:23][C:22]=1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)Cc1nn(C)c(=O)c2cc(Cc3ccccc3)sc12
Reactant: Cc1ccc(S(=O)(=O)SCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)Cc1nn(C)c(=O)c2c(SCCCO)c(Cc3ccccc3)sc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of butyl lithium in hexanes (2.5M, 1.3 ml) was added to a solution of diisopropylamine (0.45 ml) in tetrahydrofuran (6 ml) at 0° C. under nitrogen. After 30 minutes, 5 ml of the resulting solution was added to a solution of 5-methyl-7-(2-methylpropyl)-2-phenylmethylthieno[2,3-d]pyridazin-4(5H)-one (example 15, 0.50 g) and S-[3-{[(1,1-dimethylethyl)dimethylsilyl]oxy}propyl] 4methylbenzenesulfonothioate, (J. Med. Chem. 1995, 38, 2557., 0.85 g) in tetrahydrofuran (10 ml) at −78° C. under nitrogen. The reaction mixture was warmed to room temperature, quenched with saturated aqueous ammonium chloride solution (25 ml) and extracted with ethyl acetate (50 ml). The organic extracts were washed twice with saturated aqueous ammonium chloride solution, twice with saturated sodium hydrogen carbonate solution, then with brine, dried, filtered and evaporated. The residue was dissolved in acetonitrile (20 ml) and treated with 40% hydrofluoric acid (1 ml). After 16 hours, saturated sodium hydrogen carbonate solution (50 ml) was added and the mixture was extracted with ethyl acetate (50 ml). The organic extracts were washed with brine, dried, filtered and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate:isohexane (1:2 then 1:1) to give the title compound (0.51 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[N:10]=2)[N:7]=1.S(=O)(=O)(O)O.[OH2:17].[OH2:18].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:18])=[O:17])[N:10]=2)[N:7]=1
Reactant: Cc1nc2ccc(Cl)nn2n1
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1nc2ccc(Cl)nn2n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 82.7 %

Procedure:
10.0 g of 6-chloro-2-methyl[1,2,4]triazolo[1,5-b]pyridazine was added to 55 ml of concentrated sulfuric acid under ice cooling conditions; 19.4 g of sodium dichromate dihydrate was added little by little at constant temperature, followed by stirring at room temperature for 4 days. Under ice cooling conditions, about 200 ml of ice water was added; the crystal precipitated was collected by filtration, washed with water and ethyl ether and dried to yield 9.74 g of the title compound.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33](O)=[O:34])[CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([CH:29]3[CH2:30][CH2:31][CH2:32][O:27][CH2:28]3)=[O:34])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)C1CCCOC1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CCCOC1

Procedure:
The title compound, light yellow solid (78 mg, 71%), MS (ISP) m/z=439.3 [(M+H)+], mp 188° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (RS)-tetrahydro-pyran-3-carboxylic acid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O)(=O)C(O)=O.[CH2:25]1[C:28]2([CH2:32][CH2:31][CH2:30][NH:29]2)[CH2:27][O:26]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([N:29]3[CH2:30][CH2:31][CH2:32][C:28]43[CH2:25][O:26][CH2:27]4)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: C1CNC2(C1)COC2
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Agent: O=C(O)C(=O)O
Product: O=C(c1cc(OCC(F)(F)F)c(C2CC2)cn1)N1CCCC12COC2

Procedure:
The title compound was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-Oxa-5-aza-spiro[3.4]octane oxalate (CAN 1380571-82-3) as starting materials and isolated (37.6 mg, 46%) as colorless oil; MS (ESI, m/z): 357.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[O:5]>CC(O)=O.[Fe]>[NH2:16][C:14]1[CH:13]=[CH:12][C:3]([C:4]([NH:6][C@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[O:5])=[C:2]([F:1])[CH:15]=1
Reactant: C[C@@H](NC(=O)c1ccc([N+](=O)[O-])cc1F)C(=O)O
Agent: [Fe]
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)c1ccc(N)cc1F)C(=O)O
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 71.8 %

Procedure:
To a suspension of iron powder (656 mg, 11.71 mmol) in AcOH (6 mL) was added (R)-2-(2-fluoro-4-nitrobenzamido)propanoic acid (300 mg, 1.17 mmol) at rt and stirred at 60-70° C. for 20 min. Work-up of the reaction mixture as described in example 6 gave the product as a white color solid (190 mg, 72%). 1H NMR (400 MHz, DMSO-d6): δ 7.68 (1H, br s, exchangeable with D2O), 7.56 (1H, t, J=9.0 Hz), 6.41 (1H, d, J=8.8 Hz), 6.31 (1H, d, J=15.2 Hz), 5.99 (2H, br s, exchangeable with D2O), 4.15 (1H, br s), 1.30 (3H, d, J=6.8 Hz); LC-MS (negative ion mode): m/z 225 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH:25]([Sn](CCCC)(CCCC)CCCC)=[CH2:26]>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH:25]=[CH2:26])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: COC(=O)c1cc(Br)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Product: C=Cc1cc(C)c(NS(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1
Yield: 81.9 %

Procedure:
In the same manner as described in Example 139, 700 mg (1.69 mmol) of the product of Example 10 and 0.73 ml (2.5 mmol) of vinyltributyltin provided 500 mg (82%) of the desired product as a white solid. Electrospray Mass Spec 362 (M+H).