Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:14])([CH3:13])[CH:6]=[C:5]2[C:15]([F:18])([F:17])[F:16].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][CH2:27][CH2:28][OH:29]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:26][CH2:27][CH2:28][OH:29])[O:8][C:7]([CH3:14])([CH3:13])[CH:6]=[C:5]2[C:15]([F:16])([F:18])[F:17]
Reactant: CC1(C)C=C(C(F)(F)F)c2cc(Cl)c(O)cc2O1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)C=C(C(F)(F)F)c2cc(Cl)c(OCCCO)cc2O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.9 %

Procedure:
To a solution of 6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-ol (10 g, 36.23 mmol) in 150 mL DMF was added cesium carbonate (24.8 g, 76.11 mmol) followed by 3-bromo-1-propanol (7.6 g, 54.3 mmol) and the mixture stirred at ambient temperature for 24 h. Dilution with water followed by extraction with AcOE and washing the organic extracts with water, drying over anhydrous Na2SO4 and finally concentrating under reduced pressure gave crude alkylated product. Purification over silica gel using AcOEt/hexanes provided the desired 3-((6-chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propan-1-ol (9.5 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])=[C:10]([N:23]([CH3:25])[CH3:24])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[CH:42][N:41]=[N:40]2)[CH:34]=1)C>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:13]([NH:14][C:30](=[O:29])[CH2:31][C:32](=[O:44])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N:39]3[CH:43]=[CH:42][N:41]=[N:40]3)[CH:34]=2)=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])=[C:10]([N:23]([CH3:24])[CH3:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1-c1cccc(F)c1F
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1-c1cccc(F)c1F

Procedure:
The title compound was prepared from (5-amino-2-dimethylamino-2′,3′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example J3) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example K1) according to the general procedure M. Obtained as a yellow solid (253 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N+:12]([O-])=O>[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][C:3]=1[NH2:12]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Product: Cc1cc(F)c(N)cc1N
Reaction time: 24 h
Yield: 87.5 %

Procedure:
Example 48(a) was prepared in a similar manner as Example 41(a) from the starting material described below. 1H NMR (300 MHz, CD3OD) δ 8.54 (d, 1H, J=4.8 Hz), 7.95 (d, 1H, J=9.49 Hz), 7.84 (td, 1H, 1=7.71 Hz, =1.78 Hz), 7.70 (d, 1H, J=7.95 Hz), 7.53 (d, 1H, J=16.59 Hz), 7.40 (d, 1H, J=7.92 Hz), 7.29 (qd, 1H, 1=7.45 Hz, J=1.07 Hz), 7.11 (d, 1H, 1=11.8), 7.03-7.06 (m, 2H), 6.71 (s, 1H), 4.50 (q, 2H, J=7.16 Hz), 2.27 (s, 3H), 2.26 (s, 3H), 1.38 (t, 3H, 1=7.11 Hz). MS (ESI+) [M+H]/z Calc'd 496, found 496. Anal. Calc'd: C, 67.86; H, 5.29; N, 19.79. Found: C, 66.24; H, 5.50; N, 18.61. The starting material was prepared as follows: A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (1.0 g, 5 mmol) and 10% Pd/C (200 mg) in MEOH (20 ml) was hydrogenated at 23° C. for 24 h. The reaction mixture was filtered through celite and concentrated. Purification by silica gel chromatography (1:1 ethyl acetate-hexane) gave 4-fluoro-6-methyl-benzene-1,3-diamine (613 mg, 87%). To a solution of carbonic acid 4-nitro-phenyl ester 2-trimethylsilanyl-ethyl ester (566 mg, 2 mmol) in DMF (4 ml) at 23° C. under an atmosphere of argon was added DMAP (12 mg. 0.1 mmol), DIEA (0.35 ml, 2 mmol) and 4-fluoro-6-methyl-benzene-1,3-diamine. The resulting solution was heated to 50° C. for 48 h. The reaction mixture was quenched with saturated NaHCO3 (aq), extracted with EtOAc (3×20 ml). The EtOAc was removed in-vacuo, and the residue was re-dissolved in Et2O then washed with 3 N NaOH (aq), water, brine, dried with Na2SO4, filtered and concentrated. Purification by silica gel chromatography (2:8-7:3 ethyl acetate-hexane) gave (5-amino-4-fluoro-2-methyl-phenyl)carbamic acid 2-trimethylsilanyl-ethyl ester (160 mg, 28%). MS (ESI+) [M+H]/z Calc'd 634, found 634.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH3:32][C:33]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:46]4[CH2:47][CH2:48][N:43]([C:41]5[C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:34]=[C:33]([CH3:32])[CH:42]=5)[CH2:44][CH2:45]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: Cc1cc(N2CCNCC2)c2ccccc2n1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: Cc1cc(N2CCN(C(=O)c3ccc(-c4cnc5c(c4)N(Cc4cc(Cl)ccc4C(F)(F)F)CCN5)cc3)CC2)c2ccccc2n1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-methyl-4-(1-piperazinyl)quinoline as in General Procedure 10 to give the title compound. LCMS: m/z=656.96 (M+H+); retention time=0.62 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH:13]([CH2:17][O:18][CH3:19])[CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C@@H:30]2[C@@H:35]3[CH2:36][C@@H:32]([CH:33]=[CH:34]3)[C@@H:31]2[C:37]([NH2:39])=[O:38])[C:26]([Cl:40])=[CH:25][N:24]=1>>[Cl:40][C:26]1[C:27]([NH:29][C@@H:30]2[C@@H:35]3[CH2:36][C@@H:32]([CH:33]=[CH:34]3)[C@@H:31]2[C:37]([NH2:39])=[O:38])=[N:28][C:23]([NH:21][C:4]2[C:3]([O:2][CH3:1])=[CH:20][C:7]3[CH2:8][CH2:9][N:10]([CH:13]([CH2:14][O:15][CH3:16])[CH2:17][O:18][CH3:19])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:24][CH:25]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COCC(COC)N1CCc2cc(N)c(OC)cc2CC1
Product: COCC(COC)N1CCc2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-1-methoxymethyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.050 g, 49%). MP: 106-125° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.17 (s, 1H), 7.88 (s, 1H), 7.38 (s, 1H), 6.63 (s, 1H), 6.50 (d, 1H, J=8.6 Hz), 6.34-6.28 (m, 2H), 5.54 (br s, 1H), 5.26 (br s, 1H), 4.46 (t, 1H, J=8.3 Hz), 3.86 (s, 3H), 3.57-3.51 (m, 2H), 3.47-3.41 (m, 2H), 3.32 (s, 6H), 3.07 (s, 1H), 3.05-2.98 (m, 1H), 2.88-2.78 (m, 9H), 2.52 (d, 1H, J=8.1 Hz), 2.26 (d, 1H, J=9.1 Hz), 1.65 (d, 1H, J=9.1 Hz). MS: 557.46 (MH)+.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:12][C:13]([NH:15]C(C)(C)C)=[S:14])[C@H:9](O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.O>[CH2:1]([C@@H:8]1[C@@H:9]([CH3:10])[S:14][C:13]([NH2:15])=[N:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](O)[C@@H](Cc1ccccc1)NC(=S)NC(C)(C)C
Agent: Cl
Solvent: O
Product: C[C@H]1SC(N)=N[C@@H]1Cc1ccccc1
Temperature: 100 °C
Yield: 85.5 %

Procedure:
A suspension of 6.5 g of N-[(1R,2R)-1-benzyl-2-hydroxypropyl]-N′-tert-butylthiourea (diastereoisomer B) in 77 cm3 of 6N hydrochloric acid is heated at a temperature in the region of 100° C. for 10 hours. The reaction medium is then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. to give a yellow oil which is taken up in 100 cm3 of water. This aqueous phase is washed with twice 50 cm3 of dichloromethane and is then basified to a pH in the region of 10 by addition of 5 cm3 of concentrated sodium hydroxide. The resulting mixture is then extracted with 3 times 50 cm3 of dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 4.09 g of (+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine are obtained in the form of white crystals melting at 89° C. [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.22 (d, J=7 Hz: 3H); 2.66 (dd, J=13 and 7 Hz: 1H); 2.76 (dd, J=13 and 7 Hz: 1H); 3.54 (mt: 1H); 3.95 (mt: 1H); from 5.60 to 6.45 (unres. mult.: 2H); from 7.10 to 7,40 (mt: 5H). The relative stereochemistry in positions 4 and 5 was validated by NOE. A strong response of the proton H4 is noted after irradiating the methyl; (αD20=+83.9±1.3 at a concentration of 0.5% in methanol)].
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OOC(C)(C)C)(C)(C)C>>[C:7]1([CH2:13][O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccccc1
Reactant: CCCCCO
Agent: CC(C)(C)OOC(C)(C)C
Product: CCCCCOCc1ccccc1
Temperature: 90 °C
Yield: 20 %

Procedure:
Into a pressure vessel 1-pentanol (109 μL, 1 mmol, 1 eq) was added and diluted with toluene (1.063 mL, 10 mmol, 10 eq). To this stirring solution was added 1 mol % of a stock solution of {[Cl2NN]Cu}2(benzene) from the catalyst stock solution described in Example 4 (200 μL=0.01 mmol). After adding of tert-butyl peroxide (220 μL, 1.2 mmol), the pressure vessel was sealed and heated to 90° C. for 24 hr. The catalyst was separated by exposing the mixture to air and filtering through Celite®. After removing toluene under vacuum, the residue was analyzed by 1H NMR and GC/MS to determine the yield and consumption of starting materials. 1H NMR Yield: 20%.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:21][C:22]([F:28])([F:27])[C:23](OC)=[O:24].[Cl-].[NH4+].Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:23](=[O:24])[C:22]([F:28])([F:27])[F:21])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(F)(F)F
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Reaction time: 0.25 h

Procedure:
At −78° C., 182.4 ml of a 2.5 M butyllithium solution were added dropwise to a solution of 100 g of 4-benzyloxy-1-bromobenzene in 500 ml of dry tetrahydrofuran. Stirring was continued at −78° C. for 15 min, and 68.0 g of methyl trifluoroacetate were then added dropwise at this temperature. Stirring was subsequently continued at −20° C. for 2 hours. For work-up, 80 ml of saturated aqueous ammonium chloride were added dropwise, the mixture was mixed with 250 ml of dilute hydrochloric acid and diluted with 500 ml of toluene, and the organic phase was washed with water, dried and concentrated, to give the title product as a colourless oil which crystallised on digestion with heptane.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][CH:7]([CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[OH:14])[C:8]([O:10]CC)=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:13]([OH:14])[CH:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:23][CH:22]=2)[C:8]([OH:10])=[O:9])=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a solution of ethyl (2RS,3RS)-2-(4-fluorobenzyl)-3-(4-fluorophenyl)-3-hydroxypropionate (16.5 g, 51.5 mmol) in methanol (50 ml) was added 2N aqueous sodium hydroxide solution (51.5 ml, 0.103 mol) and the mixture was stirred at room temperature for 3 hrs. The reaction solution was acidified with 1N hydrochloric acid (130 ml) and extracted with ethyl acetate (200, 100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from, hexane to give (2RS,3RS)-3-(4-fluorophenyl)-2-(4-fluorobenzyl)-3-hydroxypropionic acid (14.2 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[C:10]([CH3:12])[O:9][C:8]=12.C1C(=O)N([Br:20])C(=O)C1>C(#N)C>[Br:20][C:6]1[CH:5]=[N:4][C:3]([O:2][CH3:1])=[C:8]2[O:9][C:10]([CH3:12])=[CH:11][C:7]=12
Reactant: COc1nccc2cc(C)oc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ncc(Br)c2cc(C)oc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
A solution of 7-methoxy-2-methylfuro[2,3-c]pyridine (3.2 g, 19.6 mmol) in ACN (30 mL) was treated with NBS (3.5 g, 19.7 mmol). After the mixture was stirred at rt for 18 h, it was concentrated in vacuo and purified by silica gel chromatography (PE/EA=30:1-5:1) to afford the title compound (3.0 g, 64%) as a yellow solid. LCMS (M+H)+=243.
Reaction SMILES: [CH:1]([N:4]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([OH:29])=[CH:23][C:22]=2[O:21]1>N1C(C)=CC(C)=CC=1C.C(OCC)(=O)C>[CH:14]1([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([O:29][C:24]3[CH:25]=[CH:26][C:27]4[O:28][CH2:20][O:21][C:22]=4[CH:23]=3)=[CH:8][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)N(C(=O)c1ccc(Oc2ccc3c(c2)OCO3)cc1)C1CCCCC1

Procedure:
The reaction was carried out in the same manner as described in Example 1 using p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (2.904 g, 8.96 mmol), 3,4-methylenedioxyphenol (1.354 g, 9.80 mmol) and cuprous oxide (641 mg, 4.48 mmol) in 2,4,6-collidine (15 ml). After 24 hr of refluxing, the reaction was cooled, diluted with ethyl acetate, and extracted with 0.5N HCl. A precipitate that formed on extraction was filtered and the aqueous filtrate was re-extracted with ethyl acetate. The organic layers were combined and washed three times with 6N HCl, twice with H2O, three times with 5% NaOH, twice with H2O and dried (Na2SO4) The drying agent was removed by filtration, and the filtrate concentrated in vacuo to give the crude product as a black oil. This was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[N+:26]([O-])([OH:28])=[O:27]>C(O)(=O)C>[F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[N:15]([CH3:24])[C:14]2=[O:25])=[C:11]([N+:26]([O-:28])=[O:27])[C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc3c(c2[N+](=O)[O-])NC(=O)CO3)c1=O

Procedure:
3-[7-Fluoro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-1-methyl-6-trifluoromethyl-2,4-(1H, 3H)-pyrimidinedione (3.5 g) was slowly added to a mixture of acetic acid (15 ml) and fuming nitric acid (45 ml) at 0° C. with stirring. After stirring for 2 hr at room temperature, the solution was poured on ice-water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel using hexane-ethyl acetate (6:4) as eluent to afford the title compound (3.25 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH:7](O)[CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:12]([OH:15])(=[S:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)(Cl)Cl>[O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH:7]([S:14][C:12](=[O:15])[CH3:13])[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(O)=S
Reactant: OC1CC2(CCS1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)SC1CC2(CCS1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.545 g of product from Example 394, 0.23 ml of thioacetic acid, 0.16 g of p-toluenesulfonic acid and 8 ml of carbon tetrachloride is stirred at room temperature for 1 hour. After work up concentration in vacuo gives 0.556 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([CH:11](Br)Br)[CH:3]=1.Cl.C([OH:17])C.O>[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([CH:11]=[O:17])[CH:3]=1
Reactant: CCO
Reactant: COC(=O)c1sc(Br)cc1C(Br)Br
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: COC(=O)c1sc(Br)cc1C=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Silver nitrate (1.43 g, 8.39 mmol) was added to a mixed solution of methyl 5-bromo-3-(dibromomethyl)thiophene-2-carboxylate obtained in Example (246a) (1.57 g, 4.00 mmol) in ethanol/water (30 mL/10 mL), and the mixture was stirred at 80° C. for three hours. Concentrated hydrochloric acid was added to the reaction solution at 0° C., and then the mixture was filtered. The filtrate was concentrated under reduced pressure. Then, saturated aqueous sodium bicarbonate solution was added to the resulting residue, and the aqueous layer was extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and then the filtrate was concentrated under reduced pressure to obtain 980 mg of the title compound as a pale yellow solid (98%).
Reaction SMILES: ClC1N=C(C2SC(C(C)(C)C)=NC=2C2C=C(NS(C3C=C(F)C=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:35][C:36]1[N:41]=[C:40]([CH2:42][C:43]([C:45]2[C:46]([F:63])=[C:47]([NH:51][S:52]([C:55]3[C:60]([F:61])=[CH:59][CH:58]=[CH:57][C:56]=3[F:62])(=[O:54])=[O:53])[CH:48]=[CH:49][CH:50]=2)=O)[CH:39]=[CH:38][N:37]=1.C1C(=O)N(Br)C(=O)C1.[OH:72][CH2:73][C:74]([CH3:79])([CH3:78])[C:75](=[S:77])[NH2:76]>>[Cl:35][C:36]1[N:41]=[C:40]([C:42]2[S:77][C:75]([C:74]([CH3:79])([CH3:78])[CH2:73][OH:72])=[N:76][C:43]=2[C:45]2[C:46]([F:63])=[C:47]([NH:51][S:52]([C:55]3[C:60]([F:61])=[CH:59][CH:58]=[CH:57][C:56]=3[F:62])(=[O:54])=[O:53])[CH:48]=[CH:49][CH:50]=2)[CH:39]=[CH:38][N:37]=1
Reactant: CC(C)(CO)C(N)=S
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Agent: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=C1CCC(=O)N1Br
Product: CC(C)(CO)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described for Intermediate 9 using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (750 mg, 1.7 mmol), NBS (317 mg, 1.782 mmol), and 3-hydroxy-2,2-dimethylpropanethioamide (248 mg, 1.86 mmol), the title compound was obtained as an yellow foam (460 mg, 45%). A portion of the sample was crystallized from ethyl acetate-hexanes. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H) 8.54 (d, J=5.31 Hz, 1H) 7.64-7.74 (m, 1H) 7.41-7.50 (m, 2H) 7.31-7.36 (m, 1H) 7.24 (t, J=8.97 Hz, 2H) 6.87 (d, J=5.31 Hz, 1H) 5.2-5.4 (br s, 1H) 3.54 (s, 2H) 1.36 (s, 6H). MS (ESI): 555.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:60][C:61]1[CH:70]=[CH:69][C:64]([C:65]([NH:67][CH3:68])=[O:66])=[CH:63][CH:62]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:60][C:61]3[CH:62]=[CH:63][C:64]([C:65](=[O:66])[NH:67][CH3:68])=[CH:69][CH:70]=3)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: CNC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(NC(=O)c2cccc(-c3cc(Nc4ccc(OC)c(OC)n4)c4nccn4n3)c2)cc1
Reaction time: 1 h
Yield: 28.4 %

Procedure:
3-(8-(5,6-Dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (58 mg, 148 μmol), HOBt (34.0 mg, 222 μmol) and EDCI (42.6 mg, 222 μmol) were combined with DMF (10 mL) to give a light yellow suspension. After 1 h, a clear yellow solution had been generated. DIPEA (47.9 mg, 64.7 μL, 370 μmol) and 4-amino-N-methylbenzamide (31.2 mg, 207 μmol) were added. After 15 h the mixture was concentrated in vacuo then diluted with water (10 mL) and filtered. The collected solid was washed with water (3×3 mL) and dried in vacuo. Purification by chromatography (silica, 50 g, Supelco VersaFlash, 0-5% methanol in dichloromethane, gradient over 15 min) gave a residue that was recrystallized from methanol to give 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(4-(methylcarbamoyl)phenyl)benzamide (22 mg, 42.0 μmol, 28%) as an off-white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.60 (s, 1H) 9.98 (s, 1H) 8.62 (s, 1H) 8.53 (s, 1H) 8.36 (d, J=4.91 Hz, 1H) 8.16-8.27 (m, 2H) 8.10 (d, J=7.93 Hz, 1H) 7.87 (d, J=1.51 Hz, 4H) 7.61-7.76 (m, 2H) 7.42 (d, J=8.31 Hz, 1H) 7.13 (d, J=8.31 Hz, 1H) 4.03 (s, 3H) 3.77 (s, 3H) 2.79 (d, J=4.53 Hz, 3H); LC/MS: 524.1 [MH]+.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[S:12])=[N:6][N:5]=[N:4]1>O>[CH3:2][N:3]1[C:7]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[S:12])=[N:6][N:5]=[N:4]1
Reactant: COC(=S)CCCc1nnnn1C
Agent: Cl
Solvent: O
Product: Cn1nnnc1CCCC(O)=S

Procedure:
20% Hydrochloric acid (150 ml) is added to methyl 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyrate (17 g) and the mixture is refluxed for 2 hours. After cooling, the reaction mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off to obtain 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid as colorless liquid, nD26 =1.5133
Reaction SMILES: [CH2:1]([NH:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([N:18]=[C:19]=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17]>C1C=CC=CC=1>[OH:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:19]([NH:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=1)=[O:20]
Reactant: ONCc1ccccc1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N(O)Cc1ccccc1
Yield: 83.9 %

Procedure:
A mixture of 13.3 g of N-benzyl-hydroxylamine in 260 ml of anhydrous benzene was added to a solution of 20.3 g of 3,4-dichlorophenyl isocyanate in 400 ml of anhydrous benzene and the mixture was refluxed for half an hour and then was cooled with stirring. The mixture was vacuum filtered and the recovered crystals were empasted with benzene to obtain 28.2 g of N-hydroxy-N-benzyl-N'-(3',4'-dichlorophenyl)-urea melting at 157° C.