Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC([C:10]2[C:11]([S:20](C3C(C4C=CC([N+]([O-])=O)=CC=4)=CC4C(=CC=CC=4)N=3)(=O)=[O:21])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=CC=1)([O-])=O.C[N:43]([CH:45]=O)C>C(O)C.[Pd]>[NH2:43][C:45]1[CH:17]=[CH:18][C:13]([S:20]([C:11]2[CH:10]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[O:21])=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc(-c2cc3ccccc3nc2S(=O)(=O)c2nc3ccccc3cc2-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)c2ccc3ccccc3n2)cc1

Procedure:
4--Nitrophenyl-2-quinolylsulfone (9.0 mmoles, 2.7 g) was dissolved in 200 ml ethanol and 75 ml DMF and was then hydrogenated over 2.2 g 5% Pd/C at room temperature for 3 hr. The reaction mixture was then filtered through celite and condensed to afford 2-(4-aminophenylsulfinyl)quinoline.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(#N)C.C(OCC)(=O)C>[CH:26]1([NH:25][C:23]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=3)[C:7]=2[CH2:6][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:24])[CH2:27][CH2:28]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.3 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (195 mg, 0.479 mmol) obtained in Example 126a), potassium carbonate (66.1 mg, 0.479 mmol, 1.0 eq.) and morpholine (0.085 ml, 0.957 mmol, 2.0 eq.) were suspended in acetonitrile (4.0 ml), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with 2% aqueous sodium carbonate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The aqueous layers were each extracted with ethyl acetate (15 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added and the precipitate was collected by filtration and crystallized from ethyl acetate. The precipitate was collected by filtration and crystallized from ethanol again to give the title compound as a white powder (142 mg, 0.356 mmol, 74.4%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:22]=1[CH3:39].Cl.O1CCOCC1>CN1C(=O)CCC1>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=4[F:31])[N:24]=[C:23]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[C:22]=3[CH3:39])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (118 mg, 0.45 mmol; described herein), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (130 mg, 0.45 mmol; described herein), 4.0M hydrogen chloride in 1,4-dioxane (110 μL, 0.45 mmol), and NMP (450 μL). Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 8.66-8.74 (1H, m), 7.85-7.94 (2H, m), 7.73 (1H, d, J=11.0 Hz), 7.57-7.66 (2H, m), 7.38 (1H, ddd, J=6.0, 4.9, 2.8 Hz), 7.02 (1H, ddd, J=13.4, 8.5, 2.6 Hz), 6.44 (1H, d, J=2.9 Hz), 3.86-3.98 (4H, m), 3.76-3.85 (4H, m), 2.91-3.47 (8H, m), 2.21 (3H, s). Mass Spectrum (ESI) m/e=519.0 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([F:15])([F:14])[F:13])[NH:5][CH:4]=[C:3]1[C:16]([O:18]CC)=[O:17].[OH-].[Na+]>[Pd]>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([F:15])([F:13])[F:14])[NH:5][CH:4]=[C:3]1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Temperature: 80 °C
Yield: 92 %

Procedure:
Ethyl 4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxylate 16 (58 g, 0.2 mol, crude reaction slurry containing Pd/C) was suspended in NaOH (814 mL of 5 M, 4.1 mol) in a 1-L flask with a reflux condenser and heated at 80° C. for 18 h, followed by further heating at 100° C. for 5 h. The reaction was filtered warm through packed Celite to remove Pd/C and the Celite was rinsed with 1 N NaOH. The filtrate was acidified to about pH 1 to obtain a thick, white precipitate. The precipitate was filtered then rinsed with water and cold acetonitrile. The solid was then dried under vacuum to provide 4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid 17 as a white solid (48 g, 92% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 15.26 (s, 1H), 13.66 (s, 1H), 8.98 (s, 1H), 8.13 (dd, J=1.6, 7.8 Hz, 1H), 8.06-7.99 (m, 2H).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:15]([O:31][CH3:32])=[C:16]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH3:30])[CH3:29])=[N:26][CH:27]=2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:20][C:18]1[C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[N:26][C:25]([N:28]([CH3:30])[CH3:29])=[N:24][CH:23]=2)[C:15]([O:31][CH3:32])=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:19]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1-c1cnc(N(C)C)nc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1-c1cnc(N(C)C)nc1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (41 mg, 0.20 mmol), 5-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-N,N-dimethylpyrimidin-2-amine (60 mg, 0.2 mmol), and N,N-diisopropylethylamine (0.065 mL, 0.37 mmol) in isopropyl alcohol (0.7 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H24ClN8O (M+H)+: m/z=439.2. found: 439.1. 1H NMR (DMSO-d6, 400 MHz) δ 12.91 (1H, br s), 8.29 (2H, s), 8.20 (1H, m), 8.13 (1H, s), 8.10 (1H, s), 7.61 (1H, s), 5.73 (1H, m), 3.46 (3H, s), 3.16 (6H, s), 2.06 (3H, s), 1.47 (3H, d, J=6.8 Hz) ppm.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][N:9]=1.[CH3:19][C:20]1[C:21]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=1>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[N:9]=[CH:10][C:11]([C:12]([N:31]2[CH2:32][CH2:33][N:28]([C:21]3[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=3)[CH2:29][CH2:30]2)=[O:14])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(CN2CCCS2(=O)=O)nc1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)nc3)CC2)nc1C
Yield: 67.4 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)nicotinate (107 mg) described in Preparation Example 45 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (81 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Example 109, the title compound (118 mg) was obtained.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([N:19]([CH2:21][CH2:22][O:23][CH3:24])[CH3:20])[CH:16]=[CH:15][C:14]=1[O:25][CH3:26])=[S:11])(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[CH3:26][O:25][C:14]1[CH:15]=[CH:16][C:17]([N:19]([CH2:21][CH2:22][O:23][CH3:24])[CH3:20])=[CH:18][C:13]=1[NH:12][C:10]([NH2:9])=[S:11]
Reactant: COCCN(C)c1ccc(OC)c(NC(=S)NC(=O)c2ccccc2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCN(C)c1ccc(OC)c(NC(N)=S)c1
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred suspension of 2.00 g (5.36 mmol) 1-benzoyl-3-{2-methoxy-5-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-thiourea in 13 ml methanol was added dropwise 0.15 ml (0.80 mmol) 5.4 M sodium methylate solution and stirring continued for 1 h at room temperature. The mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 1.40 g (97%) {2-methoxy-5-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-thiourea as an amber oil. ES-MS m/e (%): 270 (M+H+, 100).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[S:9]1[CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([CH2:11][CH2:10][SH:9])[CH2:5]1
Reactant: C1CS1
Reactant: CC1CNCC(C)O1
Solvent: Cc1ccccc1
Product: CC1CN(CCS)CC(C)O1

Procedure:
In a 500 ml three necked flask 115.2 g (1 mol) 2,6-dimethylmorpholine in 250 ml of toluene is heated at 90° C. Then 60.12 g (1 mol) thiirane is added to the resulting reaction mixture dropwise and the reaction mixture is heated for 5 hours under reflux. The reaction mixture is concentrated in vacuum with a rotary evaporator and is fractionally distilled using a Vigreux column.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[N:21]S(C(C)(C)C)=O)[CH2:17][CH2:16]2)OCC1>>[NH2:21][C:18]1([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:19][CH2:20][C:15](=[O:11])[CH2:16][CH2:17]1
Reactant: CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2
Reactant: COc1ccc([Mg]Br)cc1
Product: COc1ccc(C2(N)CCC(=O)CC2)cc1

Procedure:
The title compound was prepared as a white solid from addition of 4-methoxy-phenyl magnesium bromide (Aldrich) to 2-methyl-propane-2-sulfinic acid (1,4-dioxa-spiro[4.5]dec-8-ylidene)-amide (as prepared in Example 84, Step A) followed by the hydrolysis using the procedure described in Step B of Example 84.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12](=O)[CH3:13])[CH:3]=1.Cl.[NH2:16][OH:17].CC([O-])=O.[Na+]>CCO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12](=[N:16][OH:17])[CH3:13])[CH:3]=1
Reactant: NO
Reactant: CC(=O)c1cc(F)cc2c1cnn2C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NO)c1cc(F)cc2c1cnn2C
Temperature: 40 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To the solution of 1-(6-fluoro-1-methyl-1H-indazol-4-yl)ethanone (900 mg, 4.68 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (1.64 g, 23.4 mmol, 5.0 eq.) and NaOAc (3.84 g, 46.8 mmol, 10 eq.). The mixture was stirred at 40° C. overnight, and the solvent was concentrated in vacuo to afford 1-(6-fluoro-1-methyl-1H-indazol-4-yl)ethanone oxime as a white solid (848 mg, 87%). MS (ESI): m/z=208.2 [M+1]+.
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].C(O)(=O)C>CO>[Cl:4][C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[C:1]#[N:2])[CH:10]=[CH:11][CH:12]=1
Reactant: [C-]#N
Reactant: O=Cc1cccc(Cl)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: N#CC(O)c1cccc(Cl)c1
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of potassium cyanide (5.04 g, 78 mmol) in methanol (20 mL) was added 3-chlorobenzaldehyde (7.0 g, 50 mmol) at 0° C. under nitrogen atmosphere. Then acetic acid (4.4 mL) was added dropwise at 0° C. After 30 minutes, the mixture was warmed to 15° C. and stirred for 5 hours. Then the reaction mixture was concentrated to dryness and extracted with ethyl acetate (200 mL). The organic solution was washed with water (3×25 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The resulting residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:15) to afford (3-chloro-phenyl)-hydroxy-acetonitrile. (Yield 8.2 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([CH:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][O:7][C:6]1=[O:25])=[O:4].CC(C)([O-])C.[K+].I[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40].Cl>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:9]([CH:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][O:7][C:6]1=[O:25])=[O:4]
Reactant: COC(=O)CCCCCCI
Reactant: CCCCC/C=C/C(Sc1ccccc1)C1COC(=O)C1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCC/C=C/C(Sc1ccccc1)C1COC(=O)C1(CCCCCCC(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
2.88 g (7.94 mmols) of 3-methoxycarbonyl-4-(1-phenylthiotrans-2-octenyl)-oxolane-2-one and 0.98 g (8.73 mmols) of potassium t-butoxide were dissolved in 47 ml of dimethyl sulfoxide in an argon atmosphere and the mixture was stirred for 10 minutes at room temperature. A solution of 2.36 g (8.73 mmols) of methyl 7-iodoheptanoate in 3 ml of dimethyl sulfoxide was added to the above reaction mixture followed by stirring for 19 hours at room temperature. The reaction mixture was then rendered neutral with diluted hydrochloric acid while cooling with ice-water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The extract was filtered and the solvent was removed from the filtrate under reduced pressure. The residue thus obtained was purified by silica gel column chromatography using a mixture of ethyl acetate and n-hexane as an eluent to obtain 3.93 g (98% yield) of 3-methoxycarbonyl-3-(6-methoxycarbonylhexyl)-4-(1-phenylthio-trans- 2-octenyl)-oxolane-2-one as an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=3)[N:11]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]=2)[CH:6]=[CH:5][N:4]=1>CO.C1(C)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=3)[N:11]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)ccn1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(N)cc23)ccn1

Procedure:
To the stirred suspension of 3-(2-Methoxy-pyridin-4-yl)-5-nitro-1-trityl-1H-indazole 4BV (5.125 g, 10.0 mmole) in MeOH/toluene (50 mL/50 mL) was added 10% Pd/C (Degussa type, 0.5 g) at r.t. under dry N2 gas. The mixture was degassed and was stirred under a balloon inflated with H2 gas overnight. The catalyst was filtered through microfiber filter and was washed with MeOH and CH2Cl2. The filtrate was evaporated to dryness and a brown solid 5BV was obtained (5.0 g).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]([F:18])([F:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([F:20])[C:3]=1[CH2:21][CH2:22][OH:23].N([O-])=O.[Na+].C(O)(=O)C.[ClH:32]>O.Cl[Cu]>[Cl:32][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]([F:18])([F:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([F:20])[C:3]=1[CH2:21][CH2:22][OH:23]
Reactant: Cl
Reactant: Nc1ccc(NC(=O)C(F)(F)c2ccccc2)c(F)c1CCO
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cl)c(CCO)c1F)C(F)(F)c1ccccc1
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A suspension of N-[4-amino-2-fluoro-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-phenylacetamide (1.63 g, 5.00 mmol), as prepared according to the procedure of the preceding step, in 6N HCl (9 mL) was cooled in an ice-bath, and then a solution of NaNO2 (434 mg, 6.30 mmol) in H2O (2.4 mL) was added over a period of 5 minutes. After 30 minutes, acetic acid (2.9 mL) and concentrated HCl (2.9 mL) were added and the reaction mixture stirred for 1 hour. To this mixture was added a solution of CuCl (848 mg, 8.55 mmol) in concentrated HCl (5 mL) over a period of 20 minutes. After stirring in an ice-bath for 3 hours, the reaction mixture was extracted with EtOAc (200 mL×3). The extracts were combined, washed with H2O (2 times) and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0, 2.5, and 5%) to deliver the title compound (0.845 g, 48% yield) as a pale orange oil. 1H-NMR (400 MHz, CDCl3)δ 8.31 (s, 1H), 8.14 (t, J=8.6 Hz, 1H), 7.68-7.66 (m, 2H), 7.54-7.46 (m, 3H), 7.19 (dd, J=8.9, 1.7 Hz, 1H), 3.86 (dd, J=12.6, 6.5 Hz., 2H), 3.09 (dt, J=6.7, 2.3 Hz, 2H), 1.58 (t, J=5.7 Hz, 1H). Mass spectrum (LCMS, ESI) calc'd for C16H14ClF3NO2 (M+H): 344.1. Found: 344.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.O.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)=[N:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(-c2cn3nc(Cl)ccc3n2)cc1
Reactant: CN1CCNCC1
Solvent: O
Product: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)cn3n2)CC1

Procedure:
After heating a suspension of 32 g (97.4 mmol) of 6-chloro-2-(4-fluorophenyl)imidazo[1,2-b]pyridazine (CAS No.: 2069-47-8) in 200 ml of 1-methylpiperazine at 160° C. for 16 hours, the mixture is poured into 1.5 L of water. The yellowish precipitate formed is separated out by filtration and rinsed with cold isopropanol and then with diisopropyl ether. 30 g of a beige-colored powder are thus isolated after drying under vacuum.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[N:6][C:7]([Cl:11])=[C:8]([CH3:10])[CH:9]=1.[CH3:12][N:13]([CH3:28])[C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[C:19]2[S:24](Cl)(=[O:26])=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COCCOC>[CH3:12][N:13]([CH3:28])[C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[C:19]2[S:24]([NH:3][C:4]1[N:5]=[N:6][C:7]([Cl:11])=[C:8]([CH3:10])[CH:9]=1)(=[O:26])=[O:25]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: Cc1cc(N)nnc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)nnc1Cl
Reaction time: 0.75 h
Yield: 21.4 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.25 g) was added to a solution of 3-amino-6-chloro-5-methylpyridazine (0.36 g) in dry 1,2-dimethoxyethane (10 ml). When evolution of gas ceased, 5-dimethylamino-1-naphthalenesulphonyl chloride (0.67 g) was added and the reaction mixture was stirred for 45 minutes. 7% aqueous citric acid solution (10 ml) was added, the organic phase was separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The combined organic phases were washed with water (10 ml) and dried (MgSO4). Volatile material was removed by evaporation to give a gum which was triturated first with dichloromethane and then ether to give 5-dimethylamino-N-(6-chloro-5-methyl-3-pyridazinyl)-1-naphthalenesulphonamide (0.2 g), m.p. 110-112° C.; 1H NMR (d6 -DMSO): 2.30 (s,3H), 2.8 (s,6H), 7.23 (d,1H), 7.52-7.7 (m,3H), 8.3-8.5 (m,3H); mass spectrum (+ve FAB, methanol/dichloromethane/NBA): 376 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:18][C:3]1[C:4]([CH3:17])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)[C:6]([CH3:8])=[CH:7][C:2]=1[OH:1]
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)c(Cl)c(C)c1-c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 65 %

Procedure:
To a solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (11.3 g, 50.0 mmol) in N,N-dimethylformamide (50 mL) was added N-chlorosuccinimide (6.68 g, 50.0 mmol) by small portions under ice-cooling, and the mixture was stirred at room temperature for 13 hr, and then at 50° C. for 3 hr. N-Chlorosuccinimide (1.34 g, 10.0 mmol) was added to the reaction mixture, and the mixture was stirred at the same temperature for 3 hr. N-Chlorosuccinimide (0.668 g, 5.00 mmol) was added again, and the mixture was further stirred at the same temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60), and the obtained crystals were recrystallized from ethyl acetate-heptane to give the title compound (8.47 g, yield 65%) as colorless crystals.
Reaction SMILES: CC(C(N[C@@:8]([CH3:20])([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:9](O)=[O:10])=O)(C)C.C1OC2C=CC([NH2:26])=CC=2O1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([CH3:20])[C:9]([NH2:26])=[O:10])=[CH:13][CH:14]=1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: COc1ccc([C@](C)(NC(=O)C(C)(C)C)C(=O)O)cc1
Product: COc1ccc(C(C)C(N)=O)cc1

Procedure:
(S)-α-[N-[(1,1-Dimethylethyl)carbonyl]amino]-4-methoxy-α-methylbenzeneacetic acid (preparation described in step A of Example 101) was condensed with 3,4-(methylenedioxy)aniline following the procedure described in step A of Example 99. Pure (S)-N-(1,3-benzodioxol-5-yl)-α-[N-[(1,1-dimethylethyl)carbonyl]]amino!-4-methoxy-α-methyl-benzeneacetamide, obtained after chromatography on silica gel using 30% EtOAc/hexane as eluant, was converted to the title compound following the procedure described in step A of Example 98.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[F:32])[CH:24]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1-c1ccccc1F
Yield: 57.9 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 mL)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-fluorophenylboronic acid (26 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a beige solid (30 mg, 58%). LC-MS m/e 425.28 (M+H+)