Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[C:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[CH:12][CH:13]=2)[C@H:8]([NH2:27])[CH2:7][C@@H:6]1[CH3:28])(=[O:4])[CH3:3].Br[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=1.CC(C)([O-])C.[Na+].CN(C)C1C=CC=CC=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>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]>[C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[C:16][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:24]([CH3:26])[CH3:25])=[CH:12][CH:13]=2)[C@H:8]([NH:27][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=2)[CH2:7][C@@H:6]1[CH3:28])(=[O:4])[CH3:3]
Reactant: Cc1ccc(Br)nc1
Reactant: CC(=O)N1c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: CC(=O)N1c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2[C@H](Nc2ccc(C)cn2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
A flask was charged with (2S,4R)-1-acetyl-2-methyl-6-{[tris(1-methylethyl)silyl]ethynyl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (for a preparation see Intermediate 108) (130 mg, 0.309 mmol), 2-bromo-5-methylpyridine (159 mg, 0.926 mmol), sodium tert-butoxide (148 mg, 1.544 mmol), 2-(dimethylamino)-2′-(dicyclohexylphosphino)biphenyl (DavePhos) (243 mg, 0.617 mmol) and tris(dibenzylideneacetone)dipalladium(0) (283 mg, 0.309 mmol) then flushed with nitrogen and filled with degassed toluene (3 mL). The resulting mixture was stirred at 100° C. for 1.5 h then cooled to room temperature and filtered through celite. The insoluble material was washed with AcOEt and the combined filtrate and washings were concentrated in vacuo. The residue was partitioned between water and AcOEt and the layers were separated. The aqueous phase was extracted with AcOEt and the combined organic phases were washed with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient:13 to 63% AcOEt in Hexanes) gave (2S,4R)-1-acetyl-2-methyl-N-(5-methyl-2-pyridinyl)-6-{[tris(1-methylethyl)silyl]ethynyl}-1,2,3,4-tetrahydro-4-quinolinamine (120 mg, 0.252 mmol, 82% yield) as a yellow foam which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[CH:12][C:11]([CH3:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:16])[NH:9]2)[CH:2]=[CH2:3].[Br:17]N1C(=O)CCC1=O.O.O1CCCC1>C(Cl)(Cl)Cl>[Br:17][CH2:3][CH:2]1[O:14][C:13]2[C:4](=[C:5]3[C:10](=[C:11]([CH3:15])[CH:12]=2)[NH:9][C:8](=[O:16])[CH:7]=[CH:6]3)[CH2:1]1
Reactant: C=CCc1c(O)cc(C)c2[nH]c(=O)ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)CC(CBr)O2
Yield: 38.3 %

Procedure:
5-Allyl-6-hydroxy-8-methylcarbostyril (9.36 g, 43.5 mmol) was dissolved in chloroform (11) with heat. To the obtained solution, N-bromosuccinimide (7.75 g, 43.5 mmol) was added, and the mixture was refluxed for 2 hours. After completion of the reaction, water was added to the reaction mixture, and unreacted 5-allyl-6-hydroxy-8-methylcarbostyril (2.2 g, 23.5%) was separated as an insoluble matter by filtration. The filtrate was washed with water, dried and condensed. The resultant residue was subjected to a recrystallizing procedure using tetrahydrofuran to obtain 4.90 g of 2-bromomethyl-5-methyl-1,2-dihydrofuro-[3,2-f]quinoline-7-one as pale yellow crystals (38.3%).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])=[CH:7]2.Br[CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:30][C:31]#[N:32])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])=[CH:7]2
Reactant: N#CCBr
Reactant: CCCCc1oc2ccccc2c1C(=O)Nc1ccc2c(Br)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)Nc1ccc2c(Br)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-yl)-amide (351 mg, 0.801 mmol), prepared in the previous step, bromoacetonitrile (67 μL, 0.962 mmol) and potassium carbonate (559 mg, 4.05 mmol) in 15 mL of DMF was stirred under nitrogen at room temperature for 19 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, washed five times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-yl)-amide (364 mg, 95%) as a yellow solid, mp 155-159° C.
Reaction SMILES: C1([N:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21]C=2)[C:8]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=2)=[O:9])C=CC=CC=1.C1(C)C=CC=CC=1.N1CCCCC1.Cl.C(OCC)(=O)C>CCOCC.CCCCCC.C(O)(=O)C>[N:7]1([C:8]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=2)=[O:9])[CH2:19][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(NC(=O)N(c1ccccc1)c1ccccc1)c1cccnc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(NC(=O)N1CCCCC1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-(diphenylaminocarbonyl)nicotinamide (1.6 g., 0.005 mole), toluene (50 ml.), piperidine (1.28 g., 0.015 mole) and glacial acetic acid (0.86 ml.) is heated and stirred at 95°-97° C. for one hour. The mixture is cooled to room temperature and extracted with 1 N sodium hydroxide (50 ml.). The extract is acidified with glacial acetic acid and the oil which separates extracted with ethyl acetate. Evaporation of the extract under reduced pressure gives 1.9 g. of oil. The oil is taken up in ether (20 ml.), the solution made acid with ethyl acetate-HCl and then diluted with an equal volume of hexane to precipitate a gum. Trituration of the gum with acetone (10 ml.) affords the crystalline product; m.p. 162°-164° C.
Reaction SMILES: N#N.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:34][CH2:35][C:36]([OH:38])=O)[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31].[N+:39]([C:42]1[CH:43]=[C:44]([NH2:48])[CH:45]=[CH:46][CH:47]=1)([O-:41])=[O:40]>ClCCl.CN(C1C=CN=CC=1)C>[N+:39]([C:42]1[CH:43]=[C:44]([NH:48][C:36](=[O:38])[CH2:35][CH2:34][C:26]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=2)[CH:45]=[CH:46][CH:47]=1)([O-:41])=[O:40]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CCC(=O)Nc2cccc([N+](=O)[O-])c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.5 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDC hydrochloride (402 mg, 2.10 mmol) and Et3N (293 μL, 2.10 mmol) in anhydrous dichloromethane (17.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-trimethoxy-phenyl)-propionic acid (481 mg, 2.00 mmol) and DMAP (24 mg, 0.20 mmol) and stir the resulting solution for 5 min. Add 3-nitro-phenylamine (90) (414 mg, 3.00 mmol) and stir the reaction solution 24 h at rt. Quench reaction solution with sat. aqu. NH2Cl and water, separate layers and extract aqu. layer with EtOAc (3 times). Wash the combined organic layer with water and brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel 60PF, EtOAc/CyH 1+1) to obtain N-(3-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-propionamide (91) (508 mg, 70%) as a yellowish solid. 1H NMR (400 MHz, CDCl3): 2.65 (t, 2H, J=7.3 Hz); 2.98 (t, 2H, J=7.3 Hz); 3.79 (s, 6H); 3.81 (s, 3H), 6.42 (s, 2H); 7.41 (s, 1H); 7.45 (t, 1H, J=8.0 Hz); 7.84 (d, 1H, J=8.0 Hz); 7.92 (d, 1H, J=8.01 Hz); 8.31 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([Li])(C)(C)C.CCCCC.[CH3:24][C:25]([CH3:27])=[O:26]>C(OCC)C>[Cl:8][C:6]1[CH:7]=[C:2]([C:25]([OH:26])([CH3:27])[CH3:24])[CH:3]=[C:4]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=1
Reactant: CC(C)=O
Reactant: Clc1cc(Br)cc(C2OCCO2)c1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)(O)c1cc(Cl)cc(C2OCCO2)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-(3-bromo-5-chlorophenyl)-1,3-dioxolane (3.34 g, 12.68 mmol) in anhydrous diethyl ether (40 mL) in a dried flask was slowly added a 1.70 M solution of tert-butyl lithium in pentane (15.0 mL, 25.50 mmol) at −78° C. under nitrogen to give a pinkish-yellow suspension. The reaction mixture was stirred at −78° C. for 45 min under nitrogen atmosphere. After 45 min, the reaction mixture was warmed to −30° C. and stirred at that temperature for 2 h. Acetone (2.0 mL, 25.35 mmol) was added drop wise to the above solution and the reaction mixture stirred at −30° C. for another 3 h. The reaction mixture was quenched with a saturated NH4Cl solution (20 mL) at −30° C. and the reaction mixture was warmed slowly to room temperature (30 min) and then diluted with diethyl ether (25.0 mL). The ether layer was separated and then washed with water (1×25 mL), dried over anhydrous Na2SO4, filtered and evaporated on the rot-yap to give a pale yellow viscous liquid (5.45 g from two runs). GC-MS analysis (EI mode) of the product shows the desired product's mass: m/z 241 (35ClM+) and m/z 243 (37ClM+), Calcd for C12H15BrClO3: 242.67. LC-MS analysis of the crude product shows the desired product's mass: m/z 243 (35ClM+H), m/z 245 (37ClM+H), m/z 225 (35ClM+H−H2O), m/z 227 (37ClM+H−H2O). 1H NMR (400 MHz, CDCl3): δ 1.54 (s, 6H, (CH3)2C—OH), 3.90-4.25 (M, 4H, 2×—CH2—O—), 5.75 (s, 1H, O—CH-0), 7.34 (s, 1H), 7.43 (d, 2H). 1H NMR spectrum of the sample was consistent with the suggested structure of the product.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:13])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12.O1CCOC[CH2:18]1.[OH-].[K+].S([O-])(OC)(=O)=O>CO>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]([S:13][CH3:18])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12
Reactant: CN1c2ccccc2NC(=S)c2cscc21
Reactant: C1COCCO1
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSC1=Nc2ccccc2N(C)c2cscc21
Reaction time: 3 h

Procedure:
To a stirred suspension of 0.7 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-thione in 10 ml. of dioxane is added dropwise and simultaneously at 30°-40° C., a solution of 0.95 g. of potassium hydroxide in 10 ml. of methanol and 0.8 ml. of methyl sulfate. After addition is complete the mixture is stirred for 3 hours, diluted with methanol and filtered. The filtrate is concentrated to about 20 ml., diluted with water and extracted with chloroform. The chloroform solution is concentrated to give a solid, which is recrystallized from methanol-water to give orgnae crystals, m.p. 113°-115° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH:25]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[C:28]=2[CH:27]=[CH:26]1.C(=O)([O-])O.[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>[NH:25]1[C:33]2[C:28](=[C:29]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: OB(O)c1cccc2[nH]ccc12
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: CN1CCN(Cc2cc3nc(-c4cccc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 120 °C
Yield: 19 %

Procedure:
A mixture of 2-chloro-6-(4-methyl-piperazin-1-yl methyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (72) (100 mg, 0.27 mmol), indole-4-boronic acid (1.1 eq., 48 mg), sodium hydrogen carbonate (3 eq., 69 mg) and bis(triphenylphosphine)palladium(II) chloride (0.05 eq., 10 mg) in toluene (2.5 mL), ethanol (1.5 mL) and water (0.7 mL) was flushed with argon and heated under microwave irradiation at 120° C. for 1 hour. The reaction mixture was partitioned between dichloromethane and water, organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting residue was purified using flash chromatography to yield the title compound 61 (23 mg, 19%).
Reaction SMILES: [C:1]1([CH3:41])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=4)[N:21](S(C4C=CC(C)=CC=4)(=O)=O)[CH:20]=3)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.CO.O>[C:1]1([CH3:41])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=4)[NH:21][CH:20]=3)=[CH:11]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ccc([N+](=O)[O-])cc34)c3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c[nH]c4ccc([N+](=O)[O-])cc34)c3ccccc32)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a solution of 223 (0.2 g, 0.34 mmol) in THF/MeOH/H2O (5:5:1) was added LiOH (0.052 g, 2.2 mmol) (Scheme 16). The reaction mixture was stirred at 50° C. for 0.5 h. The solution was cooled to room temperature and concentrated. Water (10 mL) was added and pH was adjusted to 7 with 1N HCl. The aqueous phase was extracted with ethyl acetate (3×10mL). The combined organic phase was dried with MgSO4, and the solvent was removed in vacuo. The residue was purified by flash chromatography (ethyl acetate/hexane, 1:1, V:V) to yield QR-0170 (0.13 g, 89%), 1H NMR (DMSO): 2.30 (s, 3H), 7.33-7.39 (m, 3H), 7.45 (t, 1H, J=7.6), 7.66 (d, 1H, J=9.0), 7.80 (d, 1H, J=7.8), 7.96 (d, 2H, J=8.3), 8.06-8.10 (m, 3H), 8.13 (s, 1H), 8.60 (d, 1H, J=1.7), 12.18 (s, 1H); 13C NMR (DMSO): 21.49, 109.45, 112.89, 114.04, 116.56, 116.89, 117.64, 121.21, 123.24, 124.33, 125.48, 125.78, 127.29, 128.41, 129.84, 130.71, 134.52, 135.20, 139.97, 141.60, 146.03.
Reaction SMILES: Br[C:2]1[C:3](=[O:12])[C:4]([C:9]([OH:11])=[O:10])=[CH:5][NH:6][C:7]=1[CH3:8].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:8][C:7]1[NH:6][CH:5]=[C:4]([C:9]([OH:11])=[O:10])[C:3](=[O:12])[C:2]=1[C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:25])([F:24])[F:13])[CH:20]=1
Reactant: Cc1[nH]cc(C(=O)O)c(=O)c1Br
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1[nH]cc(C(=O)O)c(=O)c1-c1cccc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
To a solution of 5-bromo-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 5a, 12.05 g, 51.9 mmol), 3-(trifluoromethyl)phenylboronic acid (13.6 g, 71.6 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.60 g, 4.92 mmol) in acetonitrile (100 mL) is added 2 M aqueous K2CO3 solution (47 mL, 94 mmol). After stirring for 6 h at 75° C., the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in dichloromethane and extracted several times with water. The combined aqueous layer is acidified with 4 N aqueous HCl. The formed precipitate is filtered off, washed with 50 mL hexanes/ethyl acetate (4:1) and dried. Yield: 13.5 g (88% of theory); ESI mass spectrum: [M+H]+=298; Retention time HPLC: 0.80 min (Z003—001).
Reaction SMILES: Br.Br[C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:6][NH:5][C:4]=1[NH2:14].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([N:22]=[C:23]=[S:24])=[O:21].N1C=CC=CC=1.CS(C)=O>O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:3]2[S:24][C:23]([NH:22][C:20]([C:16]3[O:15][CH:19]=[CH:18][CH:17]=3)=[O:21])=[N:14][C:4]=2[NH:5][N:6]=1
Reactant: O=C(N=C=S)c1ccco1
Reactant: Nc1[nH]nc(-c2ccccn2)c1Br
Agent: Br
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1nc2[nH]nc(-c3ccccn3)c2s1)c1ccco1
Reaction time: 0.08 h

Procedure:
A mixture of 4-bromo-5-pyridin-2-yl-2H-pyrazol-3-ylamine hydrobromide salt (193 mg, 0.60 mmol), furan-2-carbonyl isothiocyanate (0.07 mL), pyridine (0.1 mL), and DMSO (2 mL) was placed in a Smith process vial. The reaction was run in a Personal Chemistry SmithCreator microwave at 160° C. for five minutes. The reaction mixture was then added to an excess of water and the resulting precipitate was filtered. Purification by preparative HPLC afforded 10 mg of furan-2-carboxylic acid (3-pyridin-2-yl-1H-pyrazolo[3,4-d]thiazol-5-yl)-amide as a white solid. 1H-NMR (d6-DMSO) δ: 8.60 (dd, 1H), 7.92 (m, 2H), 7.80 (d, 1H), 7.46 (d, 1H), 7.26 (m, 2H), 6.60 (dd, 1H); HPLC/MS m/z: 312 [MH]+.
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[Br:26][C:27]1[CH:28]=[C:29]([C:33]2[S:37][C:36]([NH:38][C:39]3[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=3)=[N:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1.Cl.Cl[CH2:48][CH2:49][N:50]([CH2:53][CH3:54])[CH2:51][CH3:52]>>[Br:26][C:27]1[CH:28]=[C:29]([C:33]2[S:37][C:36]([NH:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:48][CH2:49][N:50]([CH2:53][CH3:54])[CH2:51][CH3:52])=[CH:41][CH:40]=3)=[N:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CCN(CC)CCCl
Reactant: Oc1ccc(Nc2ncc(-c3cccc(Br)c3)s2)cc1
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Product: CCN(CC)CCOc1ccc(Nc2ncc(-c3cccc(Br)c3)s2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-[5-(3-bromo-phenyl)-thiazol-2-ylamino]-phenol and using (2-chloroethyl)-diethylamine hydrochloride. After stirring the reaction mixture for 30 min at 70° C., purification of the crude material by silica gel column chromatography (CH2Cl2/MeOH, 95/5 then 90/10) affords the title compound: ES-MS: 447.9 [M+2]+; single peak at tR=3.77 min (System 2); Rf=0.14 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: Cl[C:2]#[C:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]([F:16])([F:15])[F:14].[OH2:17]>C(O)CO>[F:14][C:13]([F:16])([F:15])[O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[O:5][CH2:4][CH2:3][C:2]2=[O:17]
Reactant: O
Reactant: FC(F)(F)Oc1ccccc1OCC#CCl
Solvent: OCCO
Product: O=C1CCOc2c(OC(F)(F)F)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
A solution of the product of Example 6B (12.8 g, 51.2 mmol) in ethylene glycol (200 mL) was heated at reflux for 6 hours, cooled to ambient temperature, stirred for 16 hours at ambient temperature, then heated at reflux for an additional 3 hours. After cooling, the reaction mixture was poured into water (100 mL) and extracted with diethyl ether (250 mL). The mixture was partitioned and the organic portion was concentrated. The resulting residue was purified by silica gel chromatography (gradient elution, 0%-20% EtOAc/hexanes) to obtain the title compound (3.62 g, 28% for three steps). 1H NMR (300 MHz, CDCl3) δ 7.86 (dd, J=8.1, 1.7 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.05-6.98 (m, 1H), 4.66-4.60 (m, 2H), 2.90-2.84 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=1.Br[C:11]1[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=[C:15]([Br:17])[CH:16]=1.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:17][C:15]1[CH:16]=[C:11]([NH:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[N:8]=2)[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=1
Reactant: COc1nccc(N)n1
Reactant: Cn1cc(Br)cc(Br)c1=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: COc1nccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 100 °C
Yield: 100.9 %

Procedure:
Following Example 121a, 2-methoxypyrimidin-4-amine (0.625 g, 5 mmol), 3,5-dibromo-1-methyl-1H-pyridin-2-one (1.34 g, 5 mmol), cesium carbonate (4.88 g, 15 mmol), tris(dibenzylideneacetone)-dipalladium(0) (0.465 g, 0.5 mmol), Xantphos (0.58 g, 1 mmol) and 1,4-dioxane (50 mL) were reacted. The reaction mixture was heated at 100° C. for 24 hours, then cool to room temperature, and filtered through a pad of Celite 521. The filter cake was washed with 9:1 methylene chloride/methanol (2×25 mL), and the combined filtrates were concentrated to dryness. The residue was dissolve in methylene chloride, diethyl ethyl was added, and the resulting precipitate was filtered to give a quantitative yield (1.57 g) of 300a as a green solid: MS (ESI+) m/z 313.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([CH2:23][N:24]([CH2:26][C:27](O)=[O:28])[CH3:25])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH:31]([CH3:33])[CH3:32].Cl>>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([CH2:23][N:24]([CH2:26][C:27]([N:31]([CH3:33])[CH3:32])=[O:28])[CH3:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:30])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN(CC(=O)O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CNC
Agent: Cl
Product: CN(CC(=O)N(C)C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 56 using [({5-[(1R)-1-(2-tert-butoxy-2-oxoethyl)-4-cyclohexylbutyl]-1,2,4-oxadiazol-3-yl}methyl)(methyl)amino]acetic acid (preparation 133) (725 mg, 1.71 mmol) and Me2NH.HCl (106 mg, 1.30 mmol) as starting materials.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:19])([F:18])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])=[O:9]>>[CH3:17][C:12]1[CH:13]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:15]=[CH:16][C:11]=1[NH:10][C:8](=[O:9])[C:7]([F:6])([F:18])[F:19]
Reactant: Cc1ccccc1NC(=O)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 69 %

Procedure:
16.43 mL (5.00 equiv.) Chlorosulfonic acid was cooled in an aceton/ice-bath and 10.00 g 2,2,2-trifluoro-N-o-tolyl-acetamide was added in three portions, keeping the reaction mixture temperature below 5° C. The ice-bath was removed, the pale yellow mixture was allowed to warm to room temperature and then heated on an oil bath of 70° C. for 5.5 hours. The oil bath was removed and at about 30-35° C. the brown mixture was poured very carefully into a beaker with ice (exotermic, copious amounts of HCl evolve), giving a thick, gummy and very sticky precipitate. The mixture was extracted three times with DCM and the combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated onto silica. Purification with flash chromatography (EtOAc/PA 1:9→1:4) yielded 10.3 g (69%) of a white solid. 1H NMR (400 MHz, CDCl3) δ 2.46 (s, 3H), 7.90 (br.s., 1H), 7.94 (s, 1H), 7.98 (dd, J=8.6, 2.15 Hz, 1H), 8.35 (d, J=8.6 Hz, 1H).