Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](=[S:5])[S-:4].C[NH2+]C.C=O.[CH3:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16].[C:19](=S)=S>CO>[CH3:1][N:2]([CH3:6])[C:3](=[S:4])[S:5][CH2:19][C:14](=[C:13]([OH:18])[CH3:12])[C:15](=[O:17])[CH3:16]
Reactant: CN(C)C(=S)[S-]
Reactant: CC(=O)CC(C)=O
Reactant: S=C=S
Agent: C=O
Agent: C[NH2+]C
Solvent: CO
Product: CC(=O)C(CSC(=S)N(C)C)=C(C)O
Reaction time: 3 h

Procedure:
Dimethylammonium dimethyldithiocarbamate (33.2 grams, 0.20 mole), formaldehyde (16.2 grams of 37% aqueous solution, 0.20 mole), 2,4-pentanedione (20.0 grams, 0.20 mole), and carbon disulfide (15.2 grams, 0.20 mole) were dissolved in methanol (100 ml.). The temperature of the resulting reaction was kept below 27° C. with ice cooling. After three hours at 22° C.-29° C., the reaction mixture was cooled in ice and the precipitated product was filtered off, washed with cold methanol and water, and dried in air. The crude product, melting at 69.5° C.-71.5° C. (prior sintering) weighed 37.3 grams (80%). Repeated precipitation of the material from carbon tetrachloride solution by the addition of hexane gave pure 2-(1-hydroxyethylidene)-3-oxobutyl dimethyldithiocarbamate melting at 70° C.-72° C. The structure was determined from infrared and nuclear magnetic resonance spectra and elemental analysis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][NH3+:16].[Cl-]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[N:16][O:15][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[NH3+]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Cl-]
Solvent: c1ccncc1
Product: CON=C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
27 ml of anhydrous pyridine were added to a mixture of 2.0 g of 1-(t-butoxycarbonyl)-3-pyrrolidone and 992 mg of o-methylhydroxylamine hydrochloride, and the mixture was kept stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off and saturated aqueous sodium bicarbonate solution was added to the residue until it was basic. The mixture was extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed over silica gel, using a 3/1 mixture of benzene and ethyl acetate as eluent, giving 2.3 g of 1-(t-butoxycarbonyl)-3-methoxyiminopyrrolidine as a mixture of syn- and anti-isomers.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:28][CH2:29][C@@H:30]([CH2:32][OH:33])[OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C1C=CN=CC=1)C.CO>N1C=CC=CC=1>[CH2:21]([O:28][CH2:29][C@H:30]([CH2:32][O:33][C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC[C@@H](O)COCc1ccccc1
Agent: CCN(CC)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Product: O[C@H](COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Trityl chloride (56 g) was added portionswise to a solution of 1-O-benzyl-(R)-glycerol (36.4 g, 0.2 mol) and 4-diethylaminopyridine (1 g) in pyridine (300 mL) under stirring and cooling with ice. After 20 h stirring methanol (50 mL) was added, the mixture was stirred for 30 min and concentrated in vacuo to half of the original volume. Ethyl acetate (500 mL) was added and the mixture extracted with water (3×250 mL). The organic layer was briefly dried with MgSO4, filtered and evaporated in vacuo. The residue 4 was codistilled with toluene (200 ml portions) to remove the residual pyridine and used for further synthesis.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH2:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[N+:17]([C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=3)(=[O:27])=[O:28])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2N
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 63.6 %

Procedure:
Starting with (4-amino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester and 3-nitro-benzenesulfonyl chloride using the method analogous to the one described above for example 1-1, [4-(3-nitro-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (519 mg, 63.6%) was obtained as a white solid. MS cald. for C17H20N4O6S 408, obsd. (ESI+) [(M+H)+] 409.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([NH2:16])=[C:11]([NH2:17])[CH:10]=1.[O:18]1[C:22]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:21][C:20]([CH:28]=O)=[N:19]1.O>CN(C=O)C>[CH3:15][C:13]1[C:12]2[NH:16][C:28]([C:20]3[CH2:21][C:22]4([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)[O:18][N:19]=3)=[N:17][C:11]=2[CH:10]=[C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])[CH:14]=1
Reactant: Cc1cc(-c2c(F)cccc2F)cc(N)c1N
Reactant: O=CC1=NOC2(CCCCC2)C1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2c(F)cccc2F)cc2nc(C3=NOC4(CCCCC4)C3)[nH]c12
Temperature: 100 °C
Yield: 38 %

Procedure:
2′,6′-Difluoro-5-methyl-biphenyl-3,4-diamine (186 mg, 0.792 mmol, as prepared in the previous step) was placed in an 8 mL vial equipped with a stir bar, and dry DMF (2 mL) was added. 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde (122 mg, 0.730 mmol, as prepared in step B of this Example) was added as a solution in DMF (2 mL). Solid Na2S2O5 (153 mg, 0.803 mmol) was added, and the mixture was heated to 100° C. for 4 h. The cooled mixture was poured into water (100 mL) and extracted three times with EtOAc (50 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The residue was purified by column chromatography using a 4-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:17, v/v over 30 min, yielding 105 mg (38%) of the title compound. 1H-NMR (400 MHz, d6-DMSO) δ: 7.43-7.55 (m, 2H), 7.15-7.30 (m, 3H), 3.35 (s, 2H), 2.61 (s, 3H), 1.63-1.83 (m, 6H), 1.34-1.57 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H21F2N3O: 382.2 (M+H). found: 382.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:38]1([NH:44][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: NC1CCCCC1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CCCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and cyclohexylamine according to conditions described in general procedure C. Mp: 118-120° C.;
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:28])=[C:23]([CH2:25][CH2:26][OH:27])[CH:24]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>O1CCOCC1>[F:16][CH:15]([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:28])=[C:23]([CH2:25][CH2:26][OH:27])[CH:24]=3)=[N:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: FC(F)Oc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: Cc1ccc(N)cc1CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1CCO
Temperature: 25 °C

Procedure:
A solution of 2-chloro-5-(4-difluoromethoxy-phenyl)-pyrimidine 30 (1.3 mmol), 2-(5-Amino-2-methyl-phenyl)-ethanol 50 (1.3 mmol) and p-TSA (0.24 g, 1.3 mmol) in dioxane (10 mL) is heated at 100° C. for 12 h then cooled to rt. The reaction mixture is slowly added to water (100 mL) with stirring. The resulting precipitate is collected by filtration, washed with water and air dried. The crude precipitate is purified by column chromatography on silica with hexanes:EtOAc=1:1 as eluant to yield 2-{5-[5-(4-difluoromethoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-phenyl}-ethanol 51a as solid. MS (m/z) (M+1)+: 372.3.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[F:10][CH:11]1[CH2:14][N:13]([C:15]2[CH:16]=[C:17]([CH:21]3[C:30]([CH3:32])([CH3:31])[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33](O)=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:10][CH:11]1[CH2:14][N:13]([C:15]2[CH:16]=[C:17]([CH:21]3[C:30]([CH3:31])([CH3:32])[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:9][S:6]([CH:3]5[CH2:5][CH2:4]5)(=[O:8])=[O:7])=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:12]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CC(F)C2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cccc(N2CC(F)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a suspension of 60% sodium hydride (165 mg, 4.1 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (510 mg, 4.2 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-(3-fluoro-azetidin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.42 mmol) and 1,1′-carbonyldiimidazole (170 mg, 1.04 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {2-[3-(3-fluoro-azetidin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (38 mg, 20%) as a white solid: LC/MS m/e calcd for C24H28FN3O3S (M+H)+: 458.57, observed: 458.1.
Reaction SMILES: [Si](O[C@@:9]1([Cl:37])[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]([NH:20][CH:21]([C:24]2[O:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)=[N:27][N:28]=2)[CH2:22][CH3:23])[CH:14]=[CH:13][C@@H:10]1[C:11]#[N:12])(C(C)(C)C)(C)C.C[OH:39].[F-].[NH4+]>O.CCOC(C)=O.CC(OC)(C)C>[Cl:37][C:9]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]([NH:20][C@@H:21]([C:24]2[O:25][C:26]([C:29]3[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[CH:33][CH:34]=3)=[N:27][N:28]=2)[C@@H:22]([OH:39])[CH3:23])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: CO
Reactant: CCCC1=C(NC(CC)c2nnc(-c3ccc(C#N)cc3)o2)C=C[C@H](C#N)[C@@]1(Cl)O[Si](C)(C)C(C)(C)C
Agent: [F-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: CCCc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C

Procedure:
A 100 mL round bottom was charged with 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino-2-chloro-3-propylbenzonitrile (intermediate 1119-D) (0.344 g, 0.64 mmole) and methanol (10 mL) at room temperature. Ammonium fluoride (0.119 g, 3.20 mmol) was then added in one portion and the reaction mixture was brought to reflux. The reaction stirred at reflux for 65 h before being cooled to room temperature. To the resulting reaction mixture was added water (50 mL), TBME (30 mL), EtOAc (50 mL) and more water (40 mL). The biphasic mixture was separated and the aqueous layer was extracted with EtOAc (50 mL). The organic extracts were then combined, washed with water (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a brown solid. The brown solid was then purified by flash chromatography over silica gel [EtOAc-hexanes (50%:50%)→EtOAc-hexanes (100%:0%) as eluent] to provide the title compound with other minor impurities (200.7 mg, 74%). 1H NMR (400 MHz, CDCl3 δ in ppm): 8.07 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 1H), 6.60 (d, J=8.0 Hz, 1H), 5.45 (d, J=8.0 Hz, 1H), 4.80 (d, J=2.0, 8.0 Hz, 1H), 4.60 (m, 1H), 2.79 (t, J=8.0 Hz, 2H), 1.64 (sextet, J=8.0 Hz, 2H), 1.46 (d, J=4.0 Hz, 3H), 1.07 (t, J=8.0 Hz, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12][CH2:11]2)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:25]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26]1.O1CCC[CH2:34]1>>[NH:14]1[C:15]2[C:10](=[CH:9][C:8]([C@H:2]([NH:1][C:29]([CH2:28][CH2:27][CH2:26][C:25]([O:31][CH3:34])=[O:32])=[O:30])[CH2:3][C:4]([O:6][CH3:7])=[O:5])=[CH:17][CH:16]=2)[CH2:11][CH2:12][CH2:13]1
Reactant: C1CCOC1
Reactant: COC(=O)C[C@@H](N)c1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Reactant: O=C1CCCC(=O)O1
Product: COC(=O)CCCC(=O)N[C@H](CC(=O)OC)c1ccc2c(c1)CCCN2
Reaction time: 4 h

Procedure:
A stirred solution of methyl (R) 3-amino-3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)-propionate (1.7 g, Reference Example 14) in tetrahydrofuran (50 ml) was treated with glutaric anhydride. After stirring for 4 hours the mixture was evaporated to dryness the residue was dissolved in methanol (40 ml) and treated with conc. sulphuric acid (20 drops). This solution was stirred at reflux for 3 hours and then allowed to stand at room temperature overnight. After the addition of solid sodium bicarbonate (10 g) the mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The aqueous layer was extracted with fresh ethyl acetate. The combined organic layer and extracts were washed with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with ethyl acetate to give the title compound (1.6 g) as a yellow oil. MS (ES+) 363 (MH+), 385 (MNa+) MS (ES−) 361 (MH−).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.CS(O[CH:14]1[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1)(=O)=O.O>CN(C=O)C.CO>[O:18]1[C:17]2([CH2:22][CH2:23][CH:14]([N:6]3[CH:5]=[C:4]([I:3])[CH:8]=[N:7]3)[CH2:15][CH2:16]2)[O:21][CH2:20][CH2:19]1
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: Ic1cnn(C2CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
A suspension of sodium hydride (72.6 mg, 1.82 mmol) in DMF (1 mL); was cooled in an ice/water bath and treated with a solution of 4-iodopyrazole (242 mg, 1.21 mmol) in DMF (2 mL) added dropwise under an atmosphere of nitrogen in 5 min. After stirring in the cold for another 30 min, a solution of 1,4-dioxaspiro[4.5]dec-8-yl methanesulfonate (321 mg, 1.33 mmol) in DMF (2 mL) was added dropwise at 0° C. The mixture was warmed to RT and was then immersed in 150° C. oil bath and stirred for 2 h. The mixture was treated with water (15 mL), extracted with EtOAc (3×20 mL). The extracts were washed with water (3×15 mL), brine (15 mL), dried over MgSO4. After concentration in vacuo, a brown solid was obtained. It was dissolved in MeOH and after water was added, a solid formed, which was filtered off to give 266 mg (66%) of the title compound as a white crystalline solid. 1H NMR (400 MHz, CDCl3): δ 7.50 (s, 1 H), 7.49 (s, 1 H), 4.23 (tt, J=4.2, 11.2 Hz, 1 H), 2.34-2.20 (m, 1 H), 2.21-1.96 (m, 4 H), 1.95-1.81 (m, 2 H), 1.82-1.66 (m, 3 H), 1.33-1.22 (m, 2 H); MS (ESI): 334.96 [M+H]+; HPLC tR=3.26 min.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>O>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:5]3[O:6][C:2]([Br:1])=[CH:3][CH:4]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc(Br)o1
Yield: 73.6 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 5-bromo-2-furancarboxylic acid (2.9 g), N,N'-carbonyldiimidazole (2.4 g) and 2-amino-7-chloro-1,8-naphthyridine (1.8 g). The product obtained by precipitation in water is purified by recrystallization in a dimethylformamide/methanol (5:5 by volume) mixture (100 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-5-bromo-2-furancarboxamide (2.6 g), m.p. 285° C., is thereby obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([SH:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:21])=[N:6][CH:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[N:24]=1>>[ClH:29].[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:20][C:25]3[N:24]=[C:23]([NH2:22])[CH:28]=[CH:27][N:26]=3)=[CH:10][C:9]=2[F:21])=[N:6][CH:7]=1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3S)cc2F)cn1
Reactant: Nc1ccnc(Cl)n1
Product: Cl
Product: Nc1cnc(-c2ccc(-c3ccccc3Sc3nccc(N)n3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 213 utilizing 4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and 4-amino-2-chloropyrimidine. MS (ESI): mass calcd. for C20H15FN6S, 390.11; m/z found, 390.9 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.31 (m, 1H), 8.16 (s, 1H), 7.88 (m, 1H), 7.83-7.75 (m, 2H), 7.71-7.63 (m, 1H), 7.58-7.52 (m, 2H), 7.32-7.21 (m, 2H), 6.37 (d, J=7.2, 1H).
Reaction SMILES: Cl.[NH2:2]O.N.[C:5]([C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:39])[C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:38])[C@@H:22]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:9][CH:8]=1)#[N:6]>C(O)C>[C:5]([C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:39])[C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:38])[C@@H:22]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:9][CH:8]=1)(=[NH:2])[NH2:6]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc(C#N)nc1
Agent: Cl
Agent: N
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc(C(=N)N)nc1
Reaction time: 0.17 h

Procedure:
1.15 g (16.5 mmol) of hydroxylamine hydrochloride were suspended in 5 ml of ethanol, 1.2 g of 25% strength ammonia solution were added, and the mixture was stirred for 10 min. After addition of 45 ml of ethanol, the precipitated salt was filtered off with suction and 3.14 g (6.6 mmol) of the above compound (stage c) were added to the solution. The hydroxyamidine compound separated out after a short time and, after stirring for 30 minutes, was filtered off with suction and washed with a little cold water and ethanol. The residue moist with ethanol was dissolved in 40 ml of ethanol and 8 ml of glacial acetic acid, 250 mg of 10% Pd/C were added and hydrogenation was carried out at about 50° C. After 5 hours, TLC (CH2Cl2/MeOH/50% strength acetic acid, 20/5/1) showed no detectable starting material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[CH:5]/[CH2:6]Br.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.CCOC(C)=O>[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:6]/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:8])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: COC(=O)/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/COc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
Methyl-(2E)-4-bromobut-2-enoate (28.2 g, 0.158 mol) was added dropwise to 2-nitrophenol (20 g, 0.144 mol) and K2CO3 (29.8 g, 21.6 mol) in N,N-dimethylformamide (240 mL) at rt. The resulting mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc (2.0 L) and washed with water (1.0 L), sat. aq. Na2CO3 (1.0 L) and brine (1.0 L). The organic phase was separated, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to afford desired product (27.4 g, 80%) as a solid.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=3)[N:14]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH:2]=[CH2:3].O[Li].O.C(Cl)(Cl)Cl.CO>CO.O>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:32][CH:33]=3)[N:14]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCC(=O)OCC)cc3)ncc2F)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCC(=O)O)cc3)ncc2F)c1
Reaction time: 2 h
Yield: 40.9 %

Procedure:
A solution of ethyl 2-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)acetate (0.300 g) in methanol was cooled to 0° C. and a solution of LiOH.H2O (0.056 g) in water was added. The reaction mixture was stirred at room temperate for 2 hr. The reaction was monitored on TLC using CHCl3:methanol (8:2) as mobile phase. After completion of the reaction, methanol was removed under reduced pressure and water was added. The aqueous layer was washed with ethyl acetate, acidified with acetic acid and the solid precipitate was filtered and washed with water. Solid material was dried under vacuumed at 45° C. to give 0.115 g of 2-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)acetic acid. 1H NMR: DMSO-d6 (400 MHz): 4.492 (s, 2H), 5.740-5.767 (d, 1H, J=10.8), 6.238-6.280 (d, 1H, J=16.8), 6.446-6.513 (dd, 1H, J=6.8, 10), 6.717-6.739 (d, 2H, J=8.8), 7.252-7.292 (t, 1H, J=8), 7.377-7.396 (d, 1H, J=7.6), 7.502-7.523 (d, 3H, J=7.6), 7.961 (s, 1H), 8.060-8.068 (d, 1H, J=3.2), 8.988 (s, 1H), 9.386 (s, 1H), 10.191 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C:3]1=[O:9].[Cl:11][C:12]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:13]=1[C:14](C#N)=[O:15].C(N(CC)CC)C.Cl>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]([C:14](=[O:15])[C:13]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:12]=2[Cl:11])[C:3]1=[O:9]
Reactant: N#CC(=O)c1ccc(Cl)cc1Cl
Reactant: CC1(C)CCC(=O)CC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CCC(=O)C(C(=O)c2ccc(Cl)cc2Cl)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione [14.0 grams (g), 0.1 mole], 20.0 g (0.1 mole) 2,4-dichlorobenzoyl cyanide and 13.6 g (0.11 mole) anhydrous, powdered zinc chloride were combined in 100 milliliters (ml) methylene chloride. Triethylamine (10.1 g, 0.12 mole) was slowly added with cooling. The reaction mixture was stirred at room temperature for 5 hours and then poured into 2N hydrochloric acid. The aqueous phase was discarded and the organic phase was washed with 150 ml 5% Na2CO3 four times. The aqueous washings were combined and acidified with HCl, extracted with methylene chloride, dried and concentrated to yield 25.3 g of crude product. The crude product was chromatographed (2% AcOH/CH2Cl2) in 5 g aliquots then reduced on rotavap under reduced pressure at 50° C. for 30 minutes to remove AcOH. This yielded an oil (40% yield). The structure was confirmed by instrumental analysis.