Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:39](=[O:87])/[C:40](/[C:62]2[N:63]=[C:64]([NH:67]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:65][CH:66]=2)=[N:41]\[O:42][C:43](=[O:61])[C:44]2[CH:49]=[C:48]([O:50][C:51](=[O:54])[CH2:52][Cl:53])[C:47]([O:55][C:56](=[O:59])[CH2:57][Cl:58])=[CH:46][C:45]=2[CH3:60])[C:19]3=[O:88])=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClC(Cl)C>[NH2:67][C:64]1[S:65][CH:66]=[C:62](/[C:40](=[N:41]/[O:42][C:43](=[O:61])[C:44]2[CH:49]=[C:48]([O:50][C:51](=[O:54])[CH2:52][Cl:53])[C:47]([O:55][C:56](=[O:59])[CH2:57][Cl:58])=[CH:46][C:45]=2[CH3:60])/[C:39]([NH:38][C@@H:20]2[C:19](=[O:88])[N:18]3[C@@H:21]2[S:22][CH2:23][C:24]([CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)=[C:17]3[C:15]([OH:16])=[O:14])=[O:87])[N:63]=1
Reactant: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](NC(=O)/C(=N\OC(=O)c5cc(OC(=O)CCl)c(OC(=O)CCl)cc5C)c5csc(NC(c6ccccc6)(c6ccccc6)c6ccccc6)n5)[C@H]4SC3)sc2n1
Solvent: COc1ccccc1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(=O)n2nc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OC(=O)c5cc(OC(=O)CCl)c(OC(=O)CCl)cc5C)c5csc(N)n5)[C@H]4SC3)sc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.3 %

Procedure:
To a solution of the product obtained in Step 5 (0.47 g) in dichloroethane (3.5 ml) were added anisole (0.23 ml) and trifluoroacetic acid (0.47 ml) under ice cooling, and the resulting solution was stirred at room temperature for five hours. After removing the solvent under reduced pressure, the residue was crystallized with ether, giving 0.3 g of the objective compound (as trifluoroacetic acid salt).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]([CH3:15])[S:11]([NH2:14])(=[O:13])=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:14][S:11]([N:10]([CH3:15])[CH3:9])(=[O:13])=[O:12])[N:7]=1
Reactant: Brc1ccnc(Br)n1
Reactant: CN(C)S(N)(=O)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)Nc1nccc(Br)n1
Temperature: 100 °C

Procedure:
2,4-Dibromopyrimidine (0.50 g, 2.11 mmol), N,N-dimethylsulfamide (0.26 mg, 2.11 mmol), cesium carbonate (2.75 g, 8.44 mmol), Pd2(dba)3 (0.10 mg, 0.11 mmol), and Xantphos (0.18 mg, 0.32 mmol) were placed in a flask. Dioxane (24 mL) was added and argon was bubbled through the solution for several minutes. The reaction was then heated at 100° C. overnight. The reaction was cooled to ambient temperature, diluted with ethyl acetate, washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. Reverse phase HPLC was used for purification to yield the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@@H:22]([NH:24][C:25](=[O:38])[CH:26]([CH2:30][O:31]CC[Si](C)(C)C)[CH:27]([CH3:29])[CH3:28])[CH2:21][C@@H:20]([C:39](=[O:62])[N:40]([CH:59]4[CH2:61][CH2:60]4)[C:41]4[CH:42]=[CH:43][C:44]5[O:49][C:48]([CH3:51])([CH3:50])[C:47](=[O:52])[N:46]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:45]=5[CH:58]=4)[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@@H:22]([NH:24][C:25](=[O:38])[CH:26]([CH2:30][OH:31])[CH:27]([CH3:29])[CH3:28])[CH2:21][C@@H:20]([C:39](=[O:62])[N:40]([CH:59]4[CH2:60][CH2:61]4)[C:41]4[CH:42]=[CH:43][C:44]5[O:49][C:48]([CH3:51])([CH3:50])[C:47](=[O:52])[N:46]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:45]=5[CH:58]=4)[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COCCCN1C(=O)C(C)(C)Oc2ccc(N(C(=O)[C@@H]3C[C@H](NC(=O)C(COCC[Si](C)(C)C)C(C)C)CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)C3CC3)cc21
Solvent: O
Solvent: ClCCl
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(N(C(=O)[C@@H]3C[C@H](NC(=O)C(CO)C(C)C)CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (3R,5S)-3-{Cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-di hydro-2H-benzo[1,4]oxazin-6-yl]-carbamoyl}-5-[3-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-butyrylamino]-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester in CH2Cl2 is added BF3 Et2O at room temperature, then the mixture is stirred at room temperature. After 1.5 h, the reaction mixture is diluted with H2O (10 mL) and extracted with CH2Cl2 (20 mL). The organic phase is washed with 5% aqueous KHSO4 (10 mL), 5% aqueous NaHCO3, H2O, and brine, then dried over Na2SO4. The solution is filtered and the solvent is evaporated in vacuo to give the title compound as white amorphous material. MS: 767 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 1.55 min.
Reaction SMILES: P(=O)(O)(O)O.C(OC([NH:13][CH:14]1[CH2:17][N:16]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)[CH2:15]1)=O)(C)(C)C.C1COCC1.O>ClCCl>[NH2:13][CH:14]1[CH2:17][N:16]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)[CH2:15]1
Reactant: CCOC(=O)c1ccc2nc(N3CC(NC(=O)OC(C)(C)C)C3)sc2c1
Agent: O=P(O)(O)O
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2nc(N3CC(N)C3)sc2c1
Reaction time: 27 h
Yield: 87.8 %

Procedure:
85% phosphoric acid (0.23 mL, 1.96 mmol) was added to a solution of ethyl 2-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl)-1,3-benzothiazole-6-carboxylate obtained in Example (225b) (296 mg, 0.78 mmol) in dichloromethane (2 mL) at room temperature, followed by stirring for 27 hours. Then, THF (1 mL) and 85% phosphoric acid (0.23 mL, 1.96 mmol) were added, and the mixture was further stirred for five hours. Water was added to the reaction solution, and the mixture was washed with ethyl acetate. Then, a 1 N aqueous sodium hydroxide solution was added to the aqueous layer, followed by extraction with a chloroform/methanol mixed solvent. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. Thereafter, the solvent was evaporated under reduced pressure to obtain 190 mg of the title compound as a milk white solid (87%).
Reaction SMILES: [C:1]1([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11](Br)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([O-:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+].[Cl-].[K+].COCCOCCOC>[Cu].C1(C)C=CC=CC=1>[C:1]1([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-]c1ccccc1
Reactant: Fc1ccc(COc2ccccc2)cc1Br
Agent: [Cu]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COCCOCCOC
Product: Fc1ccc(COc2ccccc2)cc1Oc1ccccc1
Temperature: 160 °C
Yield: 80.1 %

Procedure:
A mixture of 84.3 g (0.3 mol) of 3-bromo-4-fluorobenzyl phenyl ether, 34.8 g (0.3 mol) of sodium phenolate, 7 g (0.11 mol) of copper powder, 10 g of potassium chloride and 50 ml of bis-(2-methoxyethyl) ether (diglyme) was heated to 160° C. for 5 hours, while stirring. The reaction batch was then cooled to 80° C., 300 ml of toluene were added and the mixture was filtered. The filtrate was washed once with 100 ml of 10% strength sodium sulphate and was then extracted twice by shaking with 300 ml of water each time. The organic phase was dried over magnesium sulphate and the solvent was stripped off under a waterpump vacuum. The oily residue was distilled in vacuo. 70.7 g (80.2% of theory) of 4-fluoro-3-phenoxy-benzyl phenyl ether with the boiling point 195°-197° C./3 mbars were obtained as a very viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=1[NH2:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=1[N:13]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Cc1cccc(C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cccc(C)c1-n1c(C)cc(O)cc1=O
Temperature: 140 °C

Procedure:
A mixture of 4-hydroxy-6-methyl-2-pyrone (2.5 g, 0.02 mol), 2,6 dimethylaniline (2.4 g, 0.02 mol), and p-toluenesulfonic acid (0.2 g) as heated at 140° C. for 3 h under nitrogen atmosphere. The reaction mixture was cooled, triturated with acetonitrile, cooled and filtered the solids.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[NH:25][C:26](=[O:29])[NH:27][NH2:28]>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[NH:25][C:26](=[O:29])[NH:27][N:28]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: COc1ccc(OC)c(NC(=O)NN)c1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: COc1ccc(OC)c(NC(=O)NN=c2c(=O)c3ccccc3c2=O)c1

Procedure:
ninhydrin, 4-(2,5-dimethoxyphenyl)-semicarbazide hydrochloride
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Li+].[OH-]>CO.C1COCC1.O>[C:11]([S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:30])=[O:2])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
A mixture of 2-tritylsulfanyl-benzoic acid methyl ester (9.6 g, 23.4 mmol) and LiOH (4.0 g, 95.2 mmol) in 110 mL of MeOH/THF/H2O (1/2/1) was stirred at rt overnight. The reaction mixture was concentrated to remove most organic solvents and diluted with water (150 mL). The solid was filtered off and the filtrate acidified to pH 4-5 using 3 N HCl and then 1 N HCl. The precipitate was collected by filtration, rinsed with water and then dissolved in hot EtOAc (1 L). After cooling, the organic solution was dried over MgSO4, filtered and concentrated to provide 2-tritylsulfanyl-benzoic acid (6.71 g). MS ESI(−) m/e: 395.12 (M−1).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:7]=1.[F:36][C:37]1[CH:38]=[C:39]([CH:57]=[CH:58][CH:59]=1)[CH2:40][N:41]1[C:45]([CH3:46])=[C:44](B2OC(C)(C)C(C)(C)O2)[C:43]([CH3:56])=[N:42]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:44]4[C:43]([CH3:56])=[N:42][N:41]([CH2:40][C:39]5[CH:57]=[CH:58][CH:59]=[C:37]([F:36])[CH:38]=5)[C:45]=4[CH3:46])=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cnc(NC(=O)OC(C)(C)C)c(F)c4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cnc(NC(=O)OC(C)(C)C)c(F)c4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl (3-fluoro-5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)carbamate (intermediate 66T) (150 mg, 0.24 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (89 mg, 0.27 mmol) using Pd(PPh3)2Cl2 (8.4 mg, 0.012 mol) and sodium carbonate (76 mg, 0.72 mmol) in toluene/ethanol/water (10/10/2 mL) to afford 110 mg (crude yield) of the titled compound. MS: m/z=685.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C1(P(=[CH:29][CH:30]=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:29][CH:30]=[O:31]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1Cl
Solvent: CC#N
Product: O=CC=Cc1ccccc1Cl
Yield: 68.6 %

Procedure:
Following a procedure similar to that described in the first part of Preparation 17, 3.00 g of 2-chlorobenzaldehyde and 7.5 g of (triphenylphosphoranylidene)acetaldehyde were reacted in 100 ml of acetonitrile. The crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.44 g (yield 68%) of 3-(2-chlorophenyl)-2-propenal as a solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:46]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccc(F)cc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-4-fluorobenzene and isolated as colorless gum (5.5 mg, 32%). MS (m/e): 425.4 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([F:24])[C:15]=1B1OC(C)(C)C(C)(C)O1>>[F:13][C:14]1[CH:19]=[C:18]([O:20][CH:21]([CH3:22])[CH3:23])[CH:17]=[C:16]([F:24])[C:15]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: CC(C)Oc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(OC(C)C)cc2F)n1

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (0.8 equiv.) and 2-(2,6-difluoro-4-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 equiv.) at 70° C. for 1 hour to give methyl 6-(2,6-difluoro-4-isopropoxyphenyl)-5-fluoropicolinate. LC/MS=325.9 (MH+), Rt=1.04 min.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:9]2[CH:18]=[CH:19][CH:20]=[C:8]2[C:7]=1[OH:21])=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[S:30]([NH2:33])(=[O:32])=[O:31].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[OH:21][C:7]1[C:8]2[N:9]([CH:18]=[CH:19][CH:20]=2)[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:11](=[O:12])[C:6]=1[C:4]1[NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[S:30](=[O:32])(=[O:31])[N:33]=1
Reactant: CCOC(=O)c1c(O)c2cccn2n(CCC(C)C)c1=O
Reactant: Nc1ccc(I)cc1S(N)(=O)=O
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn21
Temperature: 120 °C
Yield: 27.9 %

Procedure:
4-Hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 1f, 0.218 g, 0.75 mmol) was dissolved in pyridine (1.5 mL) and 2-amino-5-iodo-benzenesulfonamide (Example 4a, 0.222 g, 0.75 mmol) was added. The reaction mixture was heated at 120° C. for 16 h, and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL, 0.78 mmol) was added an heated for another 4 h. The pyridine was removed in vacuo to afford the crude desired product. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm, 5%-10% methanol in dichloromethane) afforded the desired product, 4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (0.110 g, 0.209 mmol, 28% yield) as a white solid. LC-MS (ESI) calcd for C19H19IN4O4S. found 526.02. found 527.20 [M+H+].
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21](=[O:40])[N:22]4[CH2:27][CH2:26][N:25]([C:28]5[CH:33]=[CH:32][C:31]([C:34]6[N:39]=[CH:38][CH:37]=[CH:36][N:35]=6)=[CH:30][CH:29]=5)[CH2:24][CH2:23]4)[CH2:16]3)=[O:14])[CH:10]=2)[N:5]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:4]=1)#[N:2].[N-:49]=[N+:50]=[N-:51].[Na+].[NH4+].[Cl-]>CN(C=O)C>[NH:49]1[C:1]([C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([CH:15]4[CH2:19][CH2:18][N:17]([CH2:20][C:21](=[O:40])[N:22]5[CH2:27][CH2:26][N:25]([C:28]6[CH:29]=[CH:30][C:31]([C:34]7[N:35]=[CH:36][CH:37]=[CH:38][N:39]=7)=[CH:32][CH:33]=6)[CH2:24][CH2:23]5)[CH2:16]4)=[O:14])[CH:10]=3)[N:5]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:4]=2)=[N:2][N:51]=[N:50]1
Reactant: [N-]=[N+]=[N-]
Reactant: C[Si](C)(C)CCOCn1nc(C#N)c2cc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)ccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(-c2nnn[nH]2)c2cc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)ccc21
Temperature: 100 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
To a solution of 29 from Example 62 Step 4 (40 mg, 0.061 mmol) in DMF was added NaN3 (12 mg, 0.18 mmol) and NH4Cl (13 mg, 0.24 mmol). The crude was stirred at 100° C. for 18 hrs. The crude was cool, evaporated, and filtered through a plug of cotton. The crude was evaporated and purified via preparation plate to give 31 mg of a mixture of two isomers.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=[C:14]3[NH:27][CH3:28])[CH:8]=[CH:9][CH:10]=1.[F:29][C:30]([F:34])([F:33])[CH2:31][NH2:32].[I-].[K+].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:28][NH:27][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][NH:32][CH2:31][C:30]([F:34])([F:33])[F:29])[CH:6]=3)[CH:12]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=1
Reactant: NCC(F)(F)F
Reactant: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(OCCCl)c3)cc12
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(OCCNCC(F)(F)F)c3)cc12
Yield: 51.7 %

Procedure:
In a 10 mL microwave vial was added 6-(3-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (50.0 mg, 0.128 mmol), 2,2,2-trifluoroethylamine (0.100 ml, 1.279 mmol), potassium iodide (42.5 mg, 0.256 mmol), and N,N′-diisopropylethylamine (0.045 ml, 0.256 mmol) in DMF (3 mL) to give a yellow suspension. The vial was irradiated at 150° C. in the microwave for 20 min. Water (10 mL) was added to the mixture and extracted with ethyl acetate (2×20 mL). The organic layers were combined and washed with water (1×20 mL) and brine (1×20 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with (CH2Cl2/CH2Cl2-MeOH-NH4OH=100:20:1 1:0 to 0:1). The product was converted to the HCl salt by addition of 4 M HCl-dioxane, then crystallization from IPA-H2O to give 30 mg of N-methyl-2-(pyridin-3-yl)-6-(3-(2-(2,2,2-trifluoroethylamino)ethoxy)phenyl)quinazolin-4-amine as a yellow powder (42%). LCMS m/z=454 (M+1) (Method C) (retention time=2.26 min). 1H NMR (300 MHz, DMSO) δ 10.73-10.36 (m, 1H), 9.65 (s, 1H), 9.13-8.98 (m, 2H), 8.93 (d, J=5.0 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.24 (d, J=7.7 Hz, 1H), 7.94-7.75 (m, 1H), 7.69-7.41 (m, 3H), 7.09 (d, J=8.1 Hz, 1H), 4.61-4.43 (m, 2H), 4.28-4.07 (m, 2H), 3.59-3.39 (m, 2H), 3.30 (d, J=2.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>O1CCCC1>[C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(N)cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCc1ccc(OCc2ccc(NC(=O)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 134.2 %

Procedure:
To a solution of methyl 4-[(4-aminophenyl) methoxy]benzenepropanoate (0.13 g, 0.44 mmol) and triethylamine (0.50 mL) in tetrahydrofuran (9 mL) was added benzoyl chloride (74 mg, 0.53 mmol), and the mixture was stirred at room temperature for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=18:1) to give the title compound (0.23 g, quantitative). oil.
Reaction SMILES: [N:1]([CH:4]([CH3:10])[CH2:5][CH2:6][C:7](O)=[O:8])=[N+:2]=[N-:3].S(Cl)([Cl:13])=O>>[N:1]([CH:4]([CH3:10])[CH2:5][CH2:6][C:7]([Cl:13])=[O:8])=[N+:2]=[N-:3]
Reactant: CC(CCC(=O)O)N=[N+]=[N-]
Reactant: O=S(Cl)Cl
Product: CC(CCC(=O)Cl)N=[N+]=[N-]
Yield: 75.1 %

Procedure:
A mixture of crude 4-azidopentanoic acid (8.0 g, 56 mmol) and thionyl chloride (10 g 84 mmol) was heated at 40°-45° C. for 1.5 h, followed by evaporation of excess thionylchloride in vacuo. The residual oil was distilled to give 6.8 g (75%) of the title compound, bp 60°-65° C./0.3 mm: 1Hmr (CDCl3) δ: 3.55 (1H, q, J=13 Hz), 3.03 (2H, t, J=13 Hz), 1.9 (2H, t, J=13 Hz and 1.3 ppm (3H, d, J=13 Hz); ir (neat) νmax : 2100, 1792 cm-1.