Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[CH:17]=1>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:18]2[CH:17]=[C:16]([CH3:15])[CH:21]=[CH:20][N:19]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)ccn1
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3cc(F)ccc3c(Cl)c2C)c1

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4-dichloro-7-fluoro-3-methylquinoline (0.109 g, 0.47 mmol), 4-methyl-2-(tributylstannyl)pyridine (0.199 g, 0.52 mmol), palladium tetrakistriphenylphosphine (0.055 g, 0.047 mmol) in toluene (2 mL) to give 4-chloro-7-fluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=287.0 (M+1).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][NH2:15])=[CH:7][CH:6]=1>C(O)C>[CH3:1][NH:2][C:3]([NH:15][CH2:14][CH2:13][NH:12][CH2:11][C:8]1[CH:7]=[CH:6][N:5]=[CH:10][CH:9]=1)=[S:4]
Reactant: CN=C=S
Reactant: NCCNCc1ccncc1
Solvent: CCO
Product: CNC(=S)NCCNCc1ccncc1

Procedure:
Methylisothiocyanate (1.46 g.) was added slowly to a solution of N-(4-picolyl)ethylenediamine (3.3 g.) in ethanol (25 ml.) The mixture was heated under reflux for 0.5 hours concentrated and extracted with isopropyl acetate to remove N-4-picolyl-N,N'-dimethylethane-1,2-bis thiourea (m.p. 173°-174°). The mother liquors were concentrated and the residue purified by column chromatography to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[CH3:19][N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1>>[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([O:14][C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:17])([F:1])[F:18])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:22][CH2:21]1
Reactant: CN1CCC(O)CC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: Cc1c(-c2ccc(C(=O)OC3CCN(C)CC3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 1-methyl-piperidin-4-ol by the method described in Example 41. Colorless solid (51 mg, 75%). 1H NMR (CD3OD) 1.85-1.98 (m, 2H), 2.03-2.15 (m, 2H), 2.38 (s, 3H), 2.43 (br q, J=1.3, 3H), 2.40-2.56 (m, 2H), 2.73-2.86 (m, 2H), 5.02-5.14 (m, 1H), 7.69 (d, J=4.0, 1H), 7.90 (d, J=4.0, 1H). 13C NMR 7.9, 31.4, 46.2, 53.5 (br), 71.9 (br), 116.8 (br), 120.3 (q, J=270), 130.7, 135.1, 136.0, 137.5, 159.4, 162.3. 19F NMR −64.8. LC/MS 4.75 min, [M+1]+ 375.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:9]=1)[C:5]#[N:6].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O1CCOCC1>[N:10]1([C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([F:27])([F:26])[F:15])=[CH:18][CH:19]=3)[N:9]=2)[C:5]#[N:6])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cc(Cl)nc(N2CCCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1
Temperature: 100 °C
Yield: 91.6 %

Procedure:
2-Chloro-6-pyrrolidin-1-yl-isonicotinonitrile (0.18 g, 0.87 mmol), 4-trifluoromethylphenylboronic acid (0.18 g, 0.95 mmol), palladium acetate (3.9 mg, 0.02 mmol), cesium carbonate (0.56 g, 1.73 mmol), and XPhos (17 mg, 0.04 mmol) were combined, placed under a nitrogen atmosphere and dioxane (1.0 mL) was added. The reaction vessel was sealed and heated to 100° C. for 2 hours. The reaction mixture was cooled to rt, filtered through celite, concentrated under reduced pressure and purified by flash column chromatography (0%-80% EtOAc in hexane) to provide the desired product (253 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.1 Hz, 2H), 7.70 (d, J=8.2 Hz, 2H), 7.15 (d, J=0.8 Hz, 1H), 6.54 (d, J=0.9 Hz, 1H), 3.55 (bs, 4H), 2.13-1.99 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[C:10]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)=[CH2:11].[I-].[CH3:19][S+](C)(C)=O.CCCCCCCCCCCCCC[N+](C)(C)C.[OH-].[Na+]>ClC(Cl)(Cl)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:10]1([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH2:19][CH2:11]1)=[O:17]
Reactant: C[S+](C)(C)=O
Reactant: C=C(C(=O)c1ccc(Cl)cc1Cl)n1cncn1
Agent: CCCCCCCCCCCCCC[N+](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CC(Cl)(Cl)Cl
Product: O=C(c1ccc(Cl)cc1Cl)C1(n2cncn2)CC1
Reaction time: 0.03 h

Procedure:
2',4'-Dichloro-2-(1H-1,2,4-triazol-1-yl)prop-2-enophenone (0.27 g, 1.0 mMole) was added dropwise in 1,1,1-trichloroethane (2 ml) to a refluxing mixture of trimethylsulphoxonium iodide (0.33 g, 1.5 mMole), cetrimide (0.03 g), 1,1,1-trichloroethane (5 ml) and aqueous 2N sodium hydroxide (3 ml) with vigorous stirring over 2 minutes. After refluxing for a further 15 minutes the organic phase, after cooling was separated. Evaporation gave a gum, weight 0.11 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:19]([OH:21])=[O:20])[C@@H:14]([F:15])[CH2:13][C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(Br)C=C>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:19]([O:21][CH2:14][CH:9]=[CH2:10])=[O:20])[C@@H:14]([F:15])[CH2:13][C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([O:18][CH2:3][CH:1]=[CH2:2])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C=CCBr
Solvent: O
Product: C=CCOC(=O)[C@H]1[C@@H]2C[C@H](F)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC=C)[C@@H]21
Reaction time: 18 h
Yield: 181.3 %

Procedure:
To a solution of (1S,2S,3S,5R,6S)-2-((tert-butoxycarbonyl)amino)-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (D-13-1, 1.30 g) in N,N-dimethylformamide (25 mL), allyl bromide (1.09 mL) and potassium carbonate (1.18 g) were added at room temperature, and the mixture was stirred at the same temperature for 18 hours. To the reaction solution, water was added, and the mixture was extracted three times with ethyl acetate. The combined organic layer was washed three times with 5% saline and once with brine, sequentially. After the organic layer was dried over anhydrous sodium sulfate, the insoluble was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel cartridge, hexane:ethyl acetate=100:0-60:40) to give (1S,2S,3S,5R,6S)-diallyl 2-((tert-butoxycarbonyl)amino)-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylate (D-13-2, 1.49 g) as a colorless oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:11]2[CH2:15][C:14]([CH3:25])([C:16]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[O:17])[O:13][N:12]=2)[CH:7]=[C:8]([F:10])[CH:9]=1.Br[CH2:27][C:28]#[N:29].S(=O)(=O)(O)O>CN(C=O)C>[C:28]([CH2:27][N:23]1[CH:24]=[C:20]([CH2:19][NH:18][C:16]([C:14]2([CH3:25])[O:13][N:12]=[C:11]([C:6]3[CH:5]=[C:4]([F:3])[CH:9]=[C:8]([F:10])[CH:7]=3)[CH2:15]2)=[O:17])[CH:21]=[N:22]1)#[N:29]
Reactant: N#CCBr
Reactant: CC1(C(=O)NCc2cn[nH]c2)CC(c2cc(F)cc(F)c2)=NO1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C(=O)NCc2cnn(CC#N)c2)CC(c2cc(F)cc(F)c2)=NO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
At 0° C., NaH (60% by weight suspension in mineral oil, 30 mg, 0.75 mmol) was added to a solution of 3-(3,5-difluorophenyl)-5-methyl-N-(1H-pyrazol-4-ylmethyl)-4,5-dihydro-1,2-oxazole-5-carboxamide (200 mg, 0.62 mmol) in DMF (10 ml), and the mixture was stirred for 15 min. The mixture was then warmed to RT, and bromoacetonitrile (225 mg, 1.87 mmol) was added. The mixture was stirred at RT for h and then at 60° C. for 4 h. After cooling to RT, sulfuric acid (0.5M, 10 ml) was added, and the mixture was extracted with EtOAc (3×20 ml). The combined organic phases were then dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using the mobile phase heptane/EtOAc, giving N-{[1-(cyanomethyl)-1H-pyrazol-4-yl]methyl}-3-(3,5-difluorophenyl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxamide (144 mg, 64%).
Reaction SMILES: C(O[CH2:9][CH:10]1[CH:14]([CH2:15][N:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([NH:28][C:29]4[N:34]=[C:33]([CH:35]([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[CH:22]=3)[CH:18]=[N:17]2)[O:13][C:12](=[O:38])[NH:11]1)C1C=CC=CC=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>>[F:42][C:41]([F:44])([F:43])[C:39]([O:45][CH2:9][CH:10]1[CH:14]([CH2:15][N:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([NH:28][C:29]4[N:34]=[C:33]([CH:35]([F:36])[F:37])[CH:32]=[CH:31][N:30]=4)[CH:22]=3)[CH:18]=[N:17]2)[O:13][C:12](=[O:38])[NH:11]1)=[O:40]
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC3OC(=O)NC3COCc3ccccc3)c2)c1
Reactant: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC3OC(=O)NC3COC(=O)C(F)(F)F)c2)c1
Temperature: 120 °C

Procedure:
A solution of 4-[(benzyloxy)methyl]-5-{[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]methyl}-1,3-oxazolidin-2-one (100 mg, 0.199 mmol) in TFA (1.0 mL) was stirred and heated at 120° C. in a microwave reactor for 40 minutes. The reaction mixture was concentrated under reduced pressure to afford (5-{[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]methyl}-2-oxo-1,3-oxazolidin-4-yl)methyl trifluoroacetate, which was used in the next step without further purification. MS ESI calc'd. for C22H20F5N6O4 [M+H]+ 527. found 527.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26](O)=[O:27])([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])[CH3:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([CH3:25])([CH3:24])[C:26]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:27])[CH:17]=1)[C:10]([CH3:29])([CH3:30])[CH2:9]2)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)O)c1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)N3CCOCC3)c1)N2
Yield: 90.7 %

Procedure:
2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (820 mg, 2 mmol), morpholine (0.53 mL, 6 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1140 mg, 3 mmol) in dichloromethane (10 mL) and triethyl-amine (1.7 mL, 12 mmol) was stirred at 25° C. for 36 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[3-(1,1-dimethyl-2-morpholin-4-yl-2-oxo-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.87 g, 91%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C, 28; H, 37; N, 3; O, 4; (M+H)+: 480.62, observed: 480.1.
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]=[C:19]([F:21])[CH:20]=[C:8]2[C:7]=1[OH:22])=O)C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=1[S:31]([NH2:34])(=[O:33])=[O:32].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[F:21][C:19]1[CH:20]=[C:8]2[C:7]([OH:22])=[C:6]([C:4]3[NH:23][C:24]4[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=4[S:31](=[O:33])(=[O:32])[N:34]=3)[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[N:9]2[CH:18]=1
Reactant: Nc1ccc(I)cc1S(N)(=O)=O
Reactant: CCOC(=O)c1c(O)c2cc(F)cn2n(CCC(C)C)c1=O
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cc(F)cn21
Temperature: 120 °C
Yield: 19.5 %

Procedure:
6-Fluoro-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 141, 136.7 mg, 0.441 mmol) and 2-amino-5-iodo-benzenesulfonamide (Example 4a, 131.3 mg, 0.441 mmol) were mixed in anhydrous pyridine (2 mL) and heated at 120° C. for 3 h. 1,8-Diazabicyclo[5.4.0]undec-7-ene (200 μL) was added and the mixture was heated at 120° C. for 16 h. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm, 20% ethyl acetate in hexanes) afforded the desired product, 6-fluoro-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 (0.047 g, 0.086 mmol, 19.5% yield) as a dark purple solid. LC-MS (ESI) calcd for C19H18FIN4O4S 544.01. found 544.97 [M+H+].
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[N:10]=[N:11][C:12]([O:15][CH2:16][C:17]2[N:18]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:19]=[N:20][C:21]=2[CH3:22])=[CH:13][CH:14]=1)=[O:8])C>O.C1COCC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([N:18]2[C:17]([CH2:16][O:15][C:12]3[N:11]=[N:10][C:9]([C:7]([OH:8])=[O:6])=[CH:14][CH:13]=3)=[C:21]([CH3:22])[N:20]=[N:19]2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1ccc(OCc2c(C)nnn2-c2ccc(F)cc2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A solution of lithium hydroxide monohydrate (163 mg, 3.88 mmol) in water (7 mL) was added dropwise to a suspension of 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (694 mg, 1.94 mmol) in THF (7 mL). The reaction mixture was then stirred at room temperature for 30 min and was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (635 mg, 99%) as a white solid. MS: m/e=328.3 [M−H]−.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:9][C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[C:12]([Cl:19])[C:11]=1[Cl:20])[CH2:5][C:6]([OH:8])=[O:7])[CH3:3]>O.C(O)C.[Pt]>[CH2:2]([N:4]([CH2:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([Cl:19])[C:11]=1[Cl:20])[CH2:5][C:6]([OH:8])=[O:7])[CH3:3]
Reactant: CCN(CC(=O)O)Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [Pt]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCN(CC(=O)O)Cc1c(N)ccc(Cl)c1Cl
Yield: 72 %

Procedure:
A solution of 0.344 g of ethyl N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride (compound VI) in 1.5 mL of water and 1.5 mL ethanol (with 5% isopropanol) was stirred and 5% sulfided platinum on carbon under hydrogen (50 to 100 psi) for 16 hours. The catalyst was removed by filtration. The filtrate concentrated, diluted with water and toluene, and basified (aqueous sodium hydroxide or potassium carbonate) to pH 9-10. The organic phase was separated, concentrated, and the crude material purified by low-temperature recrystallization from toluene in hexane to give compound I in 72% yield.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH:4]=[CH:5][C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7])[CH3:2].N1CCCC[CH2:24]1.C(OC1C=CC(C2C=CC=CC=2)=CC=1)(=O)C#C>>[N:3]1([CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[O:7])[CH2:1][CH2:2][CH2:24][CH2:22][CH2:21]1
Reactant: CCN(C=CC(=O)Oc1ccc(-c2ccccc2)cc1)CC
Reactant: C1CCNCC1
Agent: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Product: O=C(C=CN1CCCCC1)Oc1ccc(-c2ccccc2)cc1
Yield: 80 %

Procedure:
The compound 3 was prepared according to the method described for compound 2 employing piperidine (77 mg, 0.89 mmol) and compound 1 (200 mg, 0.89 mmol) to give white solid compound 3 (221 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 1.67 (br s, 6H), 3.30 (s (b), 4H), 4.83 (d, J=13.1 Hz, 1H), 7.19 (d, J=8.6 Hz, 2H), 7.34 (t, J=7.2 Hz, 1H), 7.44 (t, J=7.8 Hz, 2H), 7.59 (m, 5H). HRMS ESI (m/z): Calculated for C20H21NO2 ([M+H]+): 308.1572. found: 308.1646.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N+:11]([O-:15])=[CH:10][C:9]=1[Cl:16])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:38][C:39]1([CH3:50])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[S:41](=[O:49])(=[O:48])[NH:40]1>CN(C=O)C>[Cl:16][C:9]1[CH:10]=[N+:11]([O-:15])[CH:12]=[C:13]([Cl:14])[C:8]=1[CH2:7][C@@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[O:5][C:3](=[O:4])[CH2:2][N:40]1[C:39]([CH3:50])([CH3:38])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[S:41]1(=[O:48])=[O:49]
Reactant: O=C(CBr)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CC1(C)NS(=O)(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2S(=O)(=O)N1CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
(S)-4-(2-(2-bromoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)ethyl)-3,5-dichloropyridine (mixture obtained as described in Example 5, Step 1, 100 mg, 0.18 mmol) is dissolved in DMF (2 ml), then K2CO3 (30 mg, 0.22 mmol) and 2,3-dihydro-3,3-dimethyl-1,2-benzisothiazole 1,1-dioxide (71 mg, 0.36 mmol) are added. The mixture is stirred at RT for 5 hours. The reaction is quenched with water (10 ml), and the product extracted with Ethyl Acetate. The organic layer is washed with H2O (3×15 ml), dried over Na2SO4 and evaporated under vacuum. The crude is purified by preparative HPLC (Method 2), to yield 100 mg of the title compound (85% yield). MS/ESI+ 657.51 [MH]+; 1H NMR (400 MHz, acetone) ppm 8.40 (s, 2H), 7.38 (m, 2H), 7.36 (m, 3H), 7.03 (m, 1H), 6.81 (m, 2H), 5.63 (m, 1H), 4.14 (s, 2H), 3.90 (d, 2H), 3.54-3.29 (2H), 3.25-3.00 (2m, 2H), 1.27 (s, 6H), 0.72 (m, 1H), 0.30-0.05 (2 m, 4H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[NH2:13].[CH:14]1([NH:19][C:20]2[C:25]([CH:26]=O)=[CH:24][N:23]=[C:22]([S:28][CH3:29])[N:21]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[CH:14]1([NH:19][C:20]2[C:25]([CH:26]=[N:13][C:3]3[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[F:12])=[CH:24][N:23]=[C:22]([S:28][CH3:29])[N:21]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Reactant: COc1cc(OC)c(F)c(N)c1F
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(F)c(N=Cc2cnc(SC)nc2NC2CCCC2)c1F

Procedure:
In a 1-L round bottom flask, 10.00 g (0.0528 mol) of 2,6-difluoro-3,5-dimethoxy-phenylamine and 12.42 g (0.0523 mol) of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 500 mL of toluene with 3.65 g (0.0157 mol) of camphorsulfonic acid was fitted with a Dean Stark trap and heated at reflux. During the day, the toluene was drained three times from the finger and continued heating at reflux under nitrogen atmosphere overnight. The toluene was concentrated in vacuo and dried to give 25.30 g (quantitative) of the title compound. No further purification was necessary. MS (APCI) (m+1)/z 409.2.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])=[N:27][CH:28]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN
Reactant: Clc1ccc(Br)nc1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 440 [M+1]+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][O:31][CH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][CH2:37][C@@H:33]4[CH2:32][O:31][CH3:30])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: COC[C@H]1CCCN1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Product: COC[C@H]1CCCN1CCOc1n[nH]c2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(Cl)c3)c12
Yield: 58 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and (2R)-2-(methoxymethyl)pyrrolidine to give the title compound in 58% yield; NMR Spectrum: 1.43-1.49 (m, 1H), 1.61-1.70 (m, 2H), 1.81-1.87 (m, 1H), 2.32 (dd, 1H), 2.45 (s, 3H), 2.68 (m, 1H), 2.74-2.80 (m, 1H), 3.13-3.16 (m, 2H), 3.17 (s, 3H), 3.28-3.31 (m, 2H), 4.44 (t, 2H), 7.20 (d, 1H), 7.27 (br s, 2H), 7.73 (d, 1H), 8.14 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 510 (MH+).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(O[CH:15]=[CH:16][C:17](=O)[C:18](F)([F:20])[F:19])C.C(N(CC)CC)C>C(#N)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:17]([CH:18]([F:20])[F:19])=[C:3]([S:2][CH3:1])[C:4]=1[OH:11])[CH3:10]
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: CCOC(=O)CC(=O)CSC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc(C(F)F)c(SC)c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
60 g of ethyl 4-(methylsulphanyl)-3-oxobutanoate and 61.3 g of 4-ethoxy-1,1,1-trifluorobut-3-en-2-one were initially charged in 312 g of acetonitrile and cooled to 0° C. under nitrogen. Within 30 minutes, 17.2 g of triethylamine were added dropwise at 0° C. and then stirring of the mixture at 0° C. continued for 2 hours. The reaction was stirred at 20° C. overnight, concentrated and admixed with 265 g of 10% sodium hydroxide solution, the mixture was stirred for 1 h, and the solids were filtered off with suction, washed 3 times with 50 ml of 3.5% NaOH and dried by suction. The solids were then admixed with 250 ml of water and 250 ml of toluene, and adjusted to pH 1 with 10% HCl, and further HCl was metered in with continued stirring until the pH remains below 3. Finally, the filtered phases were separated and the water phase was extracted once more with toluene. The combined toluene phases were dried and concentrated: Yield 53.7 g (60.1% of theory). 1H NMR (CDCl3, 400 MHz): δ=11.73 ppm (1H, s), 7.95 ppm (1H, d), 7.22 ppm (1H, d), 7.11-7.25-7.39 ppm (1H, t, CHF2), 4.46 ppm (2H, q), 2.41 ppm (3H, s), 1.44 ppm (3H, t).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH:18]=[C:17]([CH2:19][NH2:20])[N:16]=[CH:15]1.[Cl-].[Cl-].[Ca+2]>C1COCC1>[NH:14]1[CH:18]=[C:17]([CH2:19][NH:20][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:16]=[CH:15]1
Reactant: NCc1c[nH]cn1
Reactant: O=C(O)CCCCc1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(CCCCc1ccccc1)NCc1c[nH]cn1
Reaction time: 0.5 h

Procedure:
8 mmol of N,N′-carbonyldiimidazole and 8 mmol of 5-phenylpentanoic acid are introduced successively into 10 ml of absolute THF and, after having stirred for 30 min, 8 mmol of (1H-imidazol-4-yl)methanamine are added to the mixture, moisture being excluded using CaCl2. At the end of 14 h, the solvent is removed by distilling under vacuum. The remaining oil is mixed with a small amount of water. The title compound is filtered under vacuum, dried and crystallized from ethanol/diethyl ether.